September 2014 by San Francisco Marin Medical Society

SAN FRANCISCO MEDICINE J O U R NA L O F T H E S A N F R A N C I S C O M E D I CA L S O C I E T Y

OUR BUGS, OUR SELVES The Microbiome and Health

VOL.87 NO.7 September 2014

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IN THIS ISSUE

SAN FRANCISCO MEDICINE

September 2014 Volume 87, Number 7

Microbiome and Health FEATURE ARTICLES

MONTHLY COLUMNS

14 Our Bodies’ Best Buddies: The Importance of Your Microbes Elisabeth M. Bik, PhD

Membership Matters

Ask the SFMS

16 Submicroscopic Microbiome: A Universe of Discovery Erica Goode, MD 18 Antibiotics: Effects on the Human Microbiome Stephen Follansbee, MD

20 The “Second Genome”: The Role of Microbes in Women’s Health and Disease Linda C. Giudice, MD, PhD

23 Genesis, Influence, and Effect: The Human Microbiome’s Many Facets Susan V. Lynch, PhD, and Ariane R. Panzer 26 NIH Human Microbiome Project: Endless Implications for Human Health and Disease Erica Goode, MD 28 Pre- and Probiotic Foods: Eating for a Healthy Gut Jo Ann T. Hattner, MPH, RDN, and Susan Anderes, MLIS 30 Why the Microbiome Matters: One Primary Care Physician’s Journey toward Understanding Payal Bhandari, MD

32 Infant Gut Microbiome: Factors That Affect Development Potential and Long-Term Health Yana Emmy Hoy-Schulz, PhD, MS

11 President’s Message Lawrence Cheung, MD, FAAD, FASDS

13 Editorial Gordon Fung, MD, PhD, and Steve Heilig, MPH 38 Medical Community News

40 Ten Questions: Member Profile of Maria Ansari, MD 42 Classified Ads 42 Upcoming Events

OF INTEREST 7 MICRA Update: Oppose Prop 46 39 New Clinic Dedicated to Rolland Lowe, MD 39 Update: SF Soda Tax 41 In Memoriam

34 Microbes of the Skin: The Barrier That Can Promote Immunity or Fight Invaders Jef Akst 35 Breathing Life into Lung Microbiome Research Rina Shaikh-Lesko 36 Rethinking Sterile: The Hospital Microbiome Carrie Arnold

37 Fecal Transplants and C. diff Karen Blum

Editorial and Advertising Offices: 1003 A O’Reilly Ave. San Francisco, CA 94129 Phone: (415) 561-0850 e-mail: adenz@sfms.org Web: www.sfms.org Advertising information is available by request.

MEMBERSHIP MATTERS Activities and Actions of Interest to SFMS Members

Both initiatives were supported by the SFMS. For more information about the Soda Tax, please visit http://www.sfms. org/ForPatients/SFSodaTax.aspx.

Change in Mailing Address for Medi-Cal TAR Submissions

Effective for dates of service on or after July 1, 2014, all paper treatment authorization requests (TAR) currently being mailed to the Los Angeles Field Office and the Northern and Southern Pharmacy Sections should be mailed to: West Sacramento TAR Processing Center, 820 Stillwater Road, West Sacramento, CA 95605-1630.

Save the Date: SFMS Career Fair on November 5

SFMS Physician Networking Mixer a Success More than forty residents, fellows, and physicians participated in SFMS’ Summer Networking Mixer at Ironside on July 17. Attendees took advantage of the opportunity to meet SFMS leaders and connect with colleagues from various specialties and practice settings. SFMS President-Elect Roger Eng, MD, welcomed member physicians and provided a brief update on the issues SFMS is championing on behalf of our members, including the No on Prop. 46/MICRA campaign and endorsement of the San Francisco Soda Tax Initiative. SFMS would like to thank the Cooperative of American Physicians (CAP) for its support of this event and the medical society. With great attendance and positive feedback from all, SFMS plans to organize similar social networking events in the coming months. Please check the SFMS blog or follow SFMS on Twitter (@SFMedSociety) for event details.

Two Health-Related Legislation Items Passed by the SF Board of Supervisors

The San Francisco Board of Supervisors passed the following health-related legislation in July 2014: Assisted Outpatient Treatment (“Laura’s Law”)—Requires SFDPH to implement a court-ordered Assisted Outpatient Treatment program for individuals with severe mental illness who meet strict eligibility criteria. Tax on Sugar-Sweetened Beverages to Fund Food and Health Programs (Measure E)—Places on the November 4, 2014, ballot an ordinance imposing a tax of two cents per ounce on the distribution of sugar-sweetened beverages, to fund Cityoperated programs and City grants for active recreation and improving food access, health, and nutrition; and to fund San Francisco Unified School District physical education, after-school physical activity, health, or nutrition programs plus school lunch and other school nutrition programs. 4

Calling all residents, fellows, and employers! SFMS will be hosting our fourth annual Career Fair on November 5 at the Enright Room at CPMC Pacific Campus. The event runs from 5:00 p.m. until 8:00 p.m. and is complimentary to all SFMS members. This is an excellent opportunity for physicians looking to practice in the Bay Area to network with representatives from a variety of practice types and settings, and for employers to connect with physician job seekers. As part of an effort to make participation accessible to all, we are offering a tiered pricing structure for employers; solo/ small group physician member practices can exhibit free of charge. For event details or to inquire about exhibiting, contact the Membership Department at (415) 561-0850 extension 200 or membership@sfms.org.

CME Certification Now Available Online

SFMS members can now take advantage of the CME certification service offered by the Institute for Medical Quality (IMQ). The Medical Board of California requires physicians to complete fifty AMA PRA Category 1 Credits™ during every two-year period, with reporting deadlines based on the physician’s personal license renewal date. IMQ’s CME Certification Program documents and verifies physicians’ CME activities. When certified by IMQ, physicians’ CME credits will automatically be accepted by the California Medical Board. Additionally, IMQ provides documentation of physicians’ CME in the event of a medical board audit. Users are able to check the status of CME credits, keep track of their progress, and print their transcripts at their convenience from IMQ’s online CME certification user portal. IMQ’s CME certification is $30 for CMA members, $55 for nonmembers. Physicians also can request that their CME certification information be sent to hospitals, health plans, specialty societies, and others for credentialing or membership renewal purposes at no additional charge.

SAN FRANCISCO MEDICINE SEPTEMBER 2014 WWW.SFMS.ORG

Membership Desktop Reference

SAN FRANCISCO MEDICAL SOCIETY

2014-2015

MEMBERSHIP DESKTOP REFERENCE

SAN FRANCISCO MEDICAL SOCIETY, 1868 – 2014

The 2014–2015 SFMS Membership Directory and Physician Desk Reference has been mailed out to all active physician members. The annual Directory is one of the most valued benefits of membership and is the only pictorial directory of physicians in San Francisco. This resource is complimentary to all SFMS physician members currently practicing medicine and is used throughout the year by physicians and their staff. For questions or information about the Directory, please contact Ariel Young at (415) 561-0850 extension 200 or ayoung@sfms.org.

SB 492 (Optometrist Scope Bill) Eliminated from Legislative Session

SFMS/CMA has successfully quashed a scope-of-practice bill (SB 492) that originally would have allowed optometrists to perform scalpel and laser surgical eye procedures and medication injections. This dangerous bill originally proposed such a broad expansion in the scope of services that could be provided by an optometrist that it would have placed patients at risk of significant harm from having medical conditions diagnosed and treated by practitioners who lack the education, training, and experience to safely provide primary medical care. SFMS/CMA was able to get most of the egregious language in the bill stripped leaving only provisions that would have allowed optometrists to administer flu and shingles vaccines. Sen. Ed Hernandez, author of the bill, has signaled that he would not push the bill forward for a vote on the Assembly floor. SB 492 is now in the Assembly inactive file. SFMS/CMA would like to thank all the physicians who took time to call, write and fax their legislators to oppose the bill.

Noridian Denials of E&M Services

The Centers for Medicare and Medicaid Services (CMS) experienced some editing issues with new patient E&M codes that resulted in incorrect denials by Medicare contractors. Noridian inadvertently subjected established patient E&M codes to incorrect editing, resulting in incorrect denial of codes 9921199215. Noridian has corrected the editing for both the new patient codes and the established patient codes, and claims received by Noridian on and after July 16, 2014, should be processing correctly. Noridian is beginning the process of mass adjustments. Due to the number of claims involved (300,000 claims going back to October of 2013), this process could take a month or so to complete. They are asking that physicians not resubmit the claims.

Physician Payments Sunshine Act: Key Steps Physicians Need to Take

The Physician Payments Sunshine Act (Sunshine Act) requires certain manufacturers (of drugs, medical devices, and biological) that participate in U.S. federal health care programs to report certain payments and items of value given to physicians and teaching hospitals. As part of this program, manufacturers are now required to submit reports on payment, transfer, and ownership information. Physicians have the right to review their reports and challenge reports that are false, inaccurate, or misleading. CMS plans to release the data on September 30, and physicians have until December 31 to file disputes regarding 2013 report data. Physicians are advised to register with CMS’ Open Payments to review all reported data prior to the initial data release. Visit http://bit.ly/1rZDDsG for detailed information and links to the registration portal. WWW.SFMS.ORG

September 2014 Volume 87, Number 7 Editor Gordon Fung, MD, PhD Managing Editor Amanda Denz, MA Copy Editor Mary VanClay

EDITORIAL BOARD Editor Gordon Fung, MD, PhD Obituarist Erica Goode, MD, MPH Stephen Askin, MD Erica Goode, MD, MPH Toni Brayer, MD Shieva Khayam-Bashi, MD Linda Hawes Clever, MD Arthur Lyons, MD John Maa, MD Chunbo Cai, MD Payal Bhandari, MD David Pating, MD SFMS OFFICERS President Lawrence Cheung, MD President-Elect Roger S. Eng, MD Secretary Richard A. Podolin, MD Treasurer Man-Kit Leung, MD Immediate Past President Shannon UdovicConstant, MD SFMS STAFF Executive Director and CEO Mary Lou Licwinko, JD, MHSA Associate Executive Director, Public Health and Education Steve Heilig, MPH Associate Executive Director, Membership and Marketing Jessica Kuo, MBA Director of Administration Posi Lyon Membership Assistant Ariel Young BOARD OF DIRECTORS Term: Jan 2014-Dec 2016 Benjamin C.K. Lau, MD Ingrid T. Lim, MD Keith E. Loring, MD Ryan Padrez, MD Adam Schickedanz, MD Rachel H.C. Shu, MD Paul J. Turek, MD

Term: Jan 2012-Dec 2014 William J. Black, MD Andrew F. Calman, MD John Maa, MD Todd A. May, MD Kimberly L. Newell, MD William T. Prey, MD Steven H. Fugaro, MD

Term: Jan 2013-Dec 2015 Charles E. Binkley, MD Gary L. Chan, MD Katherine E. Herz, MD David R. Pating, MD Cynthia A. Point, MD Lisa W. Tang, MD Joseph Woo, MD CMA Trustee Shannon Udovic-Constant, MD AMA Delegate Robert J. Margolin, MD AMA Alternate Gordon L. Fung, MD

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

oppose prop . 46 a costly threat to your personal privacy californians can't afford .

Prop. 46 is Costly for Consumers • Trial lawyers out to profit from medical lawsuits carelessly threw Prop. 46 together without any concern for your pocketbook or your privacy, your health or your health care. • If they get their way, medical lawsuits and jury awards will skyrocket. Someone will have to pay those costs. And that someone…is you.

Prop. 46 Jeopardizes People’s Access to their Trusted Doctors • If Prop. 46 passes and California’s medical liability cap goes up, you could also lose your trusted doctor. It’s true. Many doctors will be forced to leave California to practice in states where medical liability insurance is more affordable. • Even respected community clinics, including Planned Parenthood, warn that specialists like OB-GYNs will have no choice but to reduce or eliminate vital services, especially for women and families in underserved areas.

Prop. 46 Threatens People’s Personal Privacy • Money isn’t the only thing Prop. 46 will cost you. It could cost you your personal privacy, and the doctors you trust and depend on. • Prop. 46 forces doctors and pharmacists to use a massive statewide database filled with Californians’ personal medical prescription information. A mandate government will find impossible to implement, and a database with no increased security standards to protect your personal prescription information from hacking and theft – none. • And who controls the database? The government – in an age when government already has too many tools for violating your privacy. That’s why a diverse and growing coalition of trusted doctors, community health clinics, hospitals, family-planning organizations, educators, local leaders, public safety officials, businesses and working men and women urge Californians to oppose Prop. 46.

Increased costs. Losing your doctor. Threatening your privacy. Exactly what happens when trial lawyers play doctor.

No on Prop. 46 Paid for by NO on 46 − Patients, Providers and Healthcare Insurers to Protect Access and Contain Health Costs, with major funding from the Cooperative of American Physicians Independent Expenditure Committee and the California Medical Association Physicians’ Issues Committee.

Oppose Proposition 46 Prevent Increase Health Care Costs and Protect Access to Care – Vote No on 46 On November 4, 2014, voters will be asked to weigh in on Proposition 46, a costly ballot measure that will make it easier and more profitable for lawyers to sue physicians, community health clinics, and hospitals, resulting in billions in increased health care costs annually. If the trial lawyers get their way, medical lawsuits and payouts will skyrocket, and someone will have to pay the price. California’s nonpartisan Legislative Analyst has taken a close look at Prop. 46 and concluded that it could increase state and local government health care costs by “hundreds of millions of dollars annually.” We know that these increased costs would reduce funding available for vital state and local government services such as police, fire, social services, parks, libraries . . . and the list goes on. This is just another example of trial attorneys pulling money directly out of the health care delivery system and our communities to line their own pockets. As physicians, it is our job to provide, care for, and protect our patients—but Prop. 46 does just the opposite. Taxpayers up and down the state will be on the hook for hundreds of millions of dollars in increased state and local government costs each year and could lose critical state and locally provided services that so many count on. That’s just how Prop. 46 will impact state and local government costs. An independent study estimates that this proposition will increase health care costs across all sectors by almost $10 billion annually. How does that affect patients throughout California? It translates to about $1,000 per year in higher health care costs for a family of four. For many families, that’s the difference between being able to afford groceries or health care each month.

As we forge ahead to Election Day, please consider getting involved in the No on Prop. 46 campaign. • Sign up at www.NoOn46.com to add your name to the growing list of individuals and groups opposed to Prop. 46. • Get important facts and information that will help you spread the word about this costly measure at http://www.cmanet.org/micra-resources. Please note that you will need to log into the CMA website to access the information. • Be part of our outreach team. If you have direct patient contact, become part of our outreach team by contacting info@ sfms.org or (415) 561-0850. • Volunteer to be a hospital coordinator in your area. We’re always looking for informed and engaged physicians to help educate about the dangers of this initiative. Visit http:// www.cmanet.org/issues-and-advocacy/cmas-top-issues/ micra/join-the-fight/. Need more information? Check out the campaign website www.NoOn46.com to learn more about the impacts this ballot measure would have on health care and your patients. Together we can defeat the costly MICRA measure - Vote No on Prop. 46.

If Passed, Prop. 46 Will: • Quadruple the limit on medical malpractice awards, which will significantly increase your annual medical malpractice insurance premium and reduce access to quality health care for Californians. • Threaten personal privacy by requiring use of the defective CURES prescription drug program database. • Require random alcohol and drug testing of physicians. Prop. 46 imposes a “presumption of negligence” if a physician is unable to take the test within the mandated twelve-hour time frame.

Prop. 46 was written by trial attorneys for trial attorneys—not for the patients of California, who will be forced to pay, plain and simple.

WWW.SFMS.ORG

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

Order Form increased costs. losing your doctor. threatening your privacy.

VOTE NO ON PROP. 46 • JOiN TOdAy! The California Medical Association (CMA), along with a broad coalition of doctors, community health clinics, hospitals, local governments, public safety, business and labor opposes Proposition 46, because it would make it easier and more profitable for lawyers to sue doctors and hospitals.

The Medical Injury Compensation Reform Act (MICRA) has helped contain health costs and reduce frivolous lawsuits — but trial attorneys want to change the law. We need your help — join today to get involved in the campaign to oppose their deceitful measure. •

It jeopardizes patient access to quality health care.

•

The measure would be costly for consumers and taxpayers.

•

Proponents have drafted a misleading measure intended to fool voters.

Vote no

Join the campaign to defend MICRA Today. Here’s how: - I’d like to participate in Speaker’s Bureau training.

www. N O

- Sign me up for CMA’s Legislative Key Contact list. - I will serve as hospital coordinator at my local hospital. - Please send me commitment cards to distribute to my colleagues.

MICRA_Poster_16x14_2014.indd 1

- Please send me ________ number of lab coat cards (available in batches of 100). - Please send me ________ number of English language patient brochures for my office. - Please send me ________ number of Spanish language patient brochures for my office. - Please send me ________ number of campaign buttons.

costs Increased r u r d octo Los ing yo pr ivacy r u yo g Threaten in

O n 4 6 .c o

Vote no ASK ME 7/2/14 1:54 PM

- Please send me ________ number of office posters. - Please send me ________ number of bumper stickers. Name: Address: Phone number: Occupation:

To order: online at NoOn46.com, email grassroots@cmanet.org, fax (916) 444-5689 or mail to CMA Grassroots at 1201 J Street, Suite 200, Sacramento, CA 95814. Questions? Please Contact Yna Shimabukuro at (916) 551-2567.

PAYOR REIMBURSEMENTS HEALTH CARE

PROFESSIONAL DEVELOPMENT

KEEPING

SFMS

DISPUTES

PHYSICIAN

MEDICAL RECORDS

CME

REFORM

CODING

FINANCIAL MANAGEMENT

BILLING

& IMPLEMENTATION

ASK THE

CONTRACT NEGOTIATIONS

EHR SELECTION

PRACTICE MANAGEMENT

Covered California More than 289,000 Bay Area individuals have enrolled in Covered California plans, which significantly surpasses original targets. However, with expanded patient base and limited plan networks, many physicians are faced with confusion about participation in various Covered California plans and mirror products. To help SFMS members and their staff determine their practice’s participation status, SFMS has put together this FAQ.

Verify Your Participation Status

Physicians are encouraged to verify their participation status on the individual exchange plans’ online provider directories. When searching, it’s important to select the correct exchange product type, as Anthem Blue Cross and Blue Shield of California are using significantly narrowed networks for their exchange products.

What if I Have Questions about My Participation Status?

If you show as participating and aren’t sure how/why, contact the plan directly and ask that it provide a copy of the notice sent to you, including the terms (e.g., reimbursement rates, termination/ opt-out provision, etc.). If you are not listed as participating and are interested in joining the network, inquire with the plan about how to join its exchange networks. PLAN NAME AND WEBSITE

When Scheduling Appointments It is important that front office staff have a clear understanding of their physicians’ participation status. With all of the new exchange plans added, it is no longer satisfactory to simply accept “I have Blue Shield” as an indication of whether the patient can be seen in-network. When scheduling, it is important to determine in advance whether the physician is indeed in the patient’s network. When scheduling an appointment, practices should request that the patient provide the office with a copy of the front and back of their insurance ID card. Having a copy of the ID card in advance will allow the practice to clearly identify whether they are in the patient’s network and also to verify patient eligibility before the visit. Taking these steps can help patients avoid out-of-network costs and frustration when they are faced with larger-than-expected bills.

Having Trouble Finding an In-Network Provider or Facility?

Patients who are having trouble finding an in-network physician or facility are encouraged to contact the Department of Managed Health Care’s Help Center at (888) 466-2219 for assistance. We also ask that physicians notify CMA if they are experiencing difficulties finding in-network providers to whom they can refer patients, so that we can raise the issue with the plan, Covered California, and the appropriate regulator. Contact CMA’s physician helpline at (888) 401-5911 or economicservices@cmanet.org.

Still Have Questions?

Visit SFMS’ Covered California Resource Center at www.sfms. org/ForPhysicians/CoveredCalifornia.aspx. At the resource center, you can download physician and patient FAQs, view information and updates on payor contracts, and access on-demand webinars about the exchange’s impact on physicians and their practices. Additionally, SFMS/CMA members and their staff can access free one-on-one assistance through our reimbursement helpline at (888) 401-5911 or economicservices@cmanet.org.

EXCHANGE PRODUCT NAME

Under “Plan Type/Network,” select one of the following: • Pathway X - HMO/Individual via Exchange • Pathway X - PPO/Individual via Exchange • Pathway X Tiered (EPO)/Individual via Exchange Under “Select a Plan,” select one of the following: Blue Shield of California* • 2014 Individual and Family EPO Plans (including Covered California) www.blueshieldca.com (click “Find a Provid• 2014 Individual and Family PPO Plans (including Covered California) er”)

Anthem Blue Cross* www.anthem.com/ca (click “Find a Doctor”)

Health Net www.healthnet.com/portal/home (click “Provider Search”)

Under “Plan,” scroll down and under “Covered California,” select one of the following: • HMO - CommunityCare Network • PPO - Individual & Family • PPO - Small Business (this is the SHOP)

Note: The Anthem Blue Cross and the Blue Shield websites will require you to also select a specific plan tier (e.g., gold, silver, etc.) to complete the provider search function. Select any tier except the HSA tier.

PLAN

CONTACT INFORMATION

Anthem Blue Cross

Network Relations: (855) 238-0095 or networkrelations@wellpoint.com

Blue Shield of California Health Net of California Chinese Community Health Plan WWW.SFMS.ORG

Provider Services: (800) 258-3091

Provider Services: (800) 641-7761 or provider_services@healthnet.com

Delegating to Chinese Community Healthcare Association (IPA): (415) 216-0088 ext 2806

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

NORCAL Mutual is owned and directed by its physician-policyholders, therefore we promise to treat your individual needs as our own. You can expect caring and personal service, as you are our first priority. Visit norcalmutual.com, call 877-453-4486, or contact your broker.

A N o r c A l G r o u p c o m pA N y

PRESIDENT’S MESSAGE Lawrence Cheung, MD, FAAD, FASDS

No on Proposition 46 In this November election, California voters will decide the fate of Proposition 46, which reads, “Drug and Alcohol Testing of Doctors. Medical Negligence Lawsuits. Initiative Statute.” Supporters of this proposition refer to it as the Troy and Alana Pack Patient Safety Act of 2014. On the surface, this proposition aims to “improve patient safety,” but in reality it is composed of three separate and distinct measures that will threaten the delivery of quality health care in California. You will read and see a good deal of material throughout the pages of this month’s magazine relating to Proposition 46—it’s purposeful, as we enter the final weeks leading up to Election Day. Now more than ever, we must rally together and inform our colleagues, friends, and families of the dangers this measure holds. Although buried at the end of the initiative text, the third and final part of the measure holds the key to what Prop. 46 is really all about: A measure to change California’s successful MICRA law to quadruple the cap on non-economic damages in medical lawsuits to $1.1 million, with annual increases going forward. If lawyers get their way, medical lawsuits and jury awards will skyrocket—leading to a big increase in health care costs. In fact, California’s former Legislative Analyst found Prop. 46 would increase health costs for consumers and the state by about $9.9 billion annually; that translates to more than $1,000/year in higher health care costs for a family of four. In the communities that I serve, that cost increase will often mean a tough choice for families—health care, or groceries? California’s current independent, non-partisan Legislative Analyst’s Office (LAO) said impacts to state and local governments (i.e., taxpayers) would be “several hundred million dollars annually.” In its evaluation, the LAO warned “even a small percentage change in health care costs could have a significant effect on government health care spending.” The Medical Injury Compensation Reform Act (MICRA) has been hugely successful in ensuring patients have access to affordable, quality medical care. Before MICRA, physicians were faced with rising medical malpractice insurance rates that were forcing many to reduce vital services and, in some cases, close their doors altogether. With millions of new patients entering the health care delivery system today, I cannot think of a worse possible time to reduce access and increase health care costs, which is exactly what would happen if Prop. 46 were to pass. To hide the self-serving nature of Prop. 46 (trial lawyers not only wrote the measure but have funded more than 90 percent of the campaign), the measure includes two unrelated provisions to draw voter attention away from the lawsuit provisions. Drug testing of physicians was added for this very purpose. If Prop 46 were to pass, hospitals would be required to randomly drug test physicians, and drug testing would be performed on any physician involved in a hospital case in which an adverse event occurs or is discovered to have occurred. Failure of a physician to submit to a drug test within twelve hours of discovery of the adWWW.SFMS.ORG

verse event shall be a cause for the suspension of the physician’s license. The American Civil Liberties Union of California and its various local chapters are opposed to this measure for this reason, among others. Why is this piece even in the ballot initiative? One of the proponents for Prop 46, Jamie Court, cynically told the LA Times on December 10, 2013, that drug testing of doctors was “the ultimate sweetener,” designed to deceive voters from the real reason behind the initiative, to make lawsuits easier and more lucrative for the lawyers who wrote and funded Prop 46. The final piece of Proposition 46 requires a physician, pharmacist, or veterinarian to check with the Controlled Substance Utilization Review and Evaluation System (CURES) database whenever a schedule II or III drug is prescribed. Unfortunately, the CURES database is woefully underfunded and physicians are often met with error messages and outdated information if they are able to log in. In fact, a recent report shows that in its current capacity, CURES will not be able to handle the number of queries that are anticipated to be generated by this measure. Practically speaking, it will lead to serious delays for patients to access their medications, and physicians will be put in the untenable position of having to decide whether or not to check the database or provide the care their patients need. What is more, Prop. 46 does not contain any provisions to fund an expansion of the CURES database or pay for increased security measures to ensure that our patients’ personal prescription drug history is kept safe. While proponents may claim mandatory use of the CURES database will increase patient safety, we already know that the drug provisions were included as political maneuvering to sweeten the initiative for voters. There is no question that more lawsuits against health care providers will increase costs, and our patients—along with all consumers and taxpayers in the state—will have to burden those increased costs.

If you have not signed up to oppose Prop. 46 as an individual or as a practice, please visit the website (www.NoOn46.com) and do so today.

In order to win in November, everyone must take action. If you have not donated to the No on Prop 46 campaign, you can easily do so by visiting the NoOn46. com website and clicking on “contribute.” You can also order buttons, lab coat cards, bumper stickers, posters, and patient brochures to display in your office.

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

s L S ice t c A ER isco Pra C l LO LOYn FraMnecdica Sa nd P g a n EMFeatusripitals a re

The Enright Room at CPMC Pacific Campus 2333 Buchanan St, San Francisco Refreshments and hors d’oeuvres provided by the SFMS

For detailed event information, including a list of confirmed exhibitors, please visit http://www.sfms.org/Membership/StudentResidents.aspx

EVENT OPEN TO ALL UCSF, CPMC, ST. MARY’S, AND KAISER PERMANENTE SF RESIDENTS AND FELLOWS

EDITORIAL Gordon Fung, MD, PhD, and Steve Heilig, MPH

Our Bugs, Our Selves? One way to tell that any health issue has “arrived” in the public’s eye is when there is a diet book named for it, and thus we grinned when a review copy of The Microbiome Diet arrived while we were preparing this issue of San Francisco Medicine. Authored by a physician, the book offers a “scientifically proven way to restore your gut health and achieve permanent weight loss.” The book is packed with recipes featuring “superfoods” and advises “stress-free eating”—which sounds like good enough advice. Not to add to any stress here, but about three pounds of each of us is bacteria and other microbial species. That’s a lot of bugs—100 trillion or so, although that just has to be a rough estimate, as nobody has really counted. Of course, the vast majority are our friends, or at least benign hitchhikers, or we wouldn’t survive a day. A Darwinian perspective holds that we are in constant struggle for dominance, or at least cooperative homeostasis, with microbes in, on, and around us. In the process, our bugs help us digest, fight off other less friendly pathogens, and much more. But remember The Selfish Gene—the book and concept that made biologist Richard Dawkins famous in the 1970s? In it, he posited that each human is in fact simply a way our genes seek to keep themselves in existence. This hyper-Darwinian perspective has been debated and refined ever since, but now an even “creepier possibility” has just been reported in a medical journal and in the New York Times—that, as with genes, a human body is just a way microbes ensure there will be a host for more microbes. UCSF evolutionary biologist Carlo Maley (who usually specializes in evolutionary analysis of neoplasms, especially Barrett’s esophagus and acute myeloid leukemia) and colleagues hold that “bacteria within the gut are manipulative” and release “signaling molecules” into our gut, which influence not only our physiology—our immune, nervous, and endocrine systems, for starters—but even our behavior. Mainly, they try to tell us what to eat, so that they get what they need to thrive, be that fat, sugar, micronutrients, you name it. And maybe you thought you’d developed a finely tuned palate and preferences here in San Francisco? It’s just your bugs. But researchers are also finding more and more ways our microbiome can influence our health—even our moods. Of course, we can influence the bugs as well, both for taste and for health. Maley and colleagues note that “because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.” These “interventions” can alter our internal microbiome quickly and notably, for better or worse. We’re just learning how that occurs and how we might use it to our benefit, with fecal transplants being the most striking recent example. WWW.SFMS.ORG

San Francisco Medicine editorial board member Erica Goode, MD, would seem to agree; she was especially helpful in putting this theme issue together and we offer our sincere thanks. In her own articles herein, Erica provides background on the discovery and evolving concept of our microbiome and warns that, despite how important it appears to be, continued research on the microbiome is imperiled by lack of funding. Other authors offer more perspectives, and some prescriptions as well. Infectious diseases specialist and former SFMS President Stephen Follansbee, MD, explores the antibiotics angle, with the now-familiar imperatives for better and reduced use of antibiotics among his recommendations arising from microbiomial awareness. Linda Giudice, MD, illustrates the many implications of the microbiome for women’s health, including some of the most common diagnoses. Jo Anne Huttner and Susan Anderes summarize dietary guidance in this realm—much more concisely than in a book. Editorial board member Payal Bhandari, MD, details her own developing awareness of the medical importance of the microbiome and how she advises patients in this regard. Other pieces explore developmental, dermatalogical, lung health, and other issues, and an important piece on “the hospital microbiome” warrants all our attention, given the never-ending struggle to minimize hospital-acquired infections. So, maybe it’s our own microflora urging us to say this, but after being professionally indoctrinated to fear and fight bacterial contamination, it’s nice to have some confirmation that at least some of them are our friends. We’ll see how all this microbiome knowledge plays out in terms of useful clinical information in the long run. In the meantime, please pass the yogurt.

Welcome New Members The SFMS welcomes the following members:

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

OUR BODIES’ BEST BUDDIES The Importance of Your Microbes Elisabeth M. Bik, PhD Antony van Leeuwenhoek probably could not believe his eyes. It was 1683, and the Dutch scientist had put some tooth

scrapings from his own mouth under the primitive microscope that he had built himself. He had used similar microscopes to look at algae and ciliates in lake water, but now he wanted to study a different type of sample. He decided to not clean his mouth for a couple of days, and to use the material growing between his teeth for a new experiment. He must have been very excited when he looked through the lens and saw hundreds of tiny creatures wiggling and moving. “I then most always saw, with great wonder, that in the said matter there were many very little living animalcules, very prettily a-moving,” he wrote to the Royal Society of London.1 That observation made van Leeuwenhoek the first human to study and describe bacteria—the beginning of microbiology. Most of the famous pioneers in that field focused on the causative agents of infectious diseases, such as Robert Koch’s research on anthrax, cholera, and tuberculosis, and Louis Pasteur’s work on developing vaccines for anthrax and rabies. The devastating effects of bacterial and viral diseases on humans throughout history led to the belief that most microorganisms are detrimental to our health. Even nowadays, disturbing headlines about flesh-eating bacteria or deadly microbes present on dollar bills or lurking in your kitchen sink make some people think that the only good germ is a dead germ. Fortunately, most bacteria are not harmful, and many of them are our closest friends. As van Leeuwenhoek discovered, human bodies are home to trillions of microbes. An often-used but not very wellfounded quote states that our bodies have ten times more microbial cells than human cells, or, in other words, that we are only ten percent human. Luckily, the microbes are much smaller than human cells, and there is plenty of room for them. Most of these microbes are bacteria, with Archaea and yeasts present in lower numbers. Humans are not the only hosts of large microbial communities. Nearly all living organisms, both animals and plants, from microscopically small nematodes to elephants, from microalgae to sequoia trees, are associated with microbes that play important roles in their physiology.

Who They Are: Composition of the Human Microbiome

The microbes associated with our bodies are pretty much everywhere: on our skin, between our teeth, in our saliva and stomachs, but the largest group of them is housed inside our large intestine. There are hundreds to thousands of different bacterial species within a single person. Together, we call these conglomerates of microbes the human microbiome, or microbiota. New molecular techniques have allowed scientists to look at millions of microbial DNA molecules from a single sample, such as stool or an oral swab. Because many bacterial species are hard to grow in the lab, these DNA-based methods have provided a more 14

Antony van Leeuwenhoek’s figures of bacteria from the human mouth. Letter 39, 17 September 1683. unbiased view of the human microbiome composition than culturing. Surprisingly, Escherichia coli, previously thought to be the most abundant inhabitant of our intestinal tract because it grows easily on culture plates, was found to constitute only 0.1% of the distal gut flora. Instead, molecular studies showed that the majority of bacteria in the human gut belongs to the Firmicutes and Bacteroidetes groups, which are much harder to recover by culture.1 Every body site harbors a distinct microbial community.2 Characterized by different physiological properties, each body habitat will appeal to a different set of bacterial species, similar to the ways plant communities vary between different climate zones, altitude, or soil types. Not only do the human-associated microbial conglomerates differ between anatomical sites, they also differ between individuals. That makes us unique from the inside as we are from the outside!

How They Got There: It All Starts at Birth

The assembly of a newborn’s individual microbiome takes place mostly in the first three years of life, starting with the simple communities obtained in the delivery room and gradually increasing in complexity until the conglomerates resemble an adult-like microbiome. Although low amounts of bacteria have been found in placentas, the main colonization of an infant’s body starts during birth, and delivery mode plays a pivotal role in this process. Minutes after birth, vaginally born infants’ skin contains Lactobacillus and Prevotella species very similar to the species found in their moth-

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er’s vagina. Infants born via Cesarean section carry a more skin-like flora that does not match the skin microbiomes of their mothers but might have derived from other people present in the delivery room. The microbiome differences between these infant groups last for many months, and C-section-delivered children appear to have a higher risk for asthma, atopic diseases, and obesity later in life.3

What They Do: Functions of the Human Microbiome

Not only have scientists investigated who our bacterial inhabitants are but we have also learned about what they can do. Together, the human gut microbiome contains 150 times more genes than our own genome, therefore supplementing our own functional capacity with an enormous additional potential.4 An important function of the gut microbiome is the digestion of complex carbohydrates in our food for which we lack the enzymes. The presence of a gut microbiome allows a mammalian host to break down these starches and fibers and to extract more energy out of the diet. Germ-free mice, born and raised in sterile incubators, need to eat 30 percent more food to remain at the same body weight as mice with a conventional microbiome. In addition, the gut microbiome is involved in an ever-increasing list of other functions, such as lipid metabolism, blood glucose levels, release and response to hormones, vitamin synthesis, and the correct development of anatomical structures and the immune system.1

Microbiome and Obesity

About 35 percent of American adults are obese, and sedentary lifestyle and poor food choices are obvious causes. But, given the important roles that our gut microbes play in food digestion and fat metabolism, could they be involved in obesity as well? Studies from the laboratory of Jeffrey Gordon have shown that obesity is indeed partly determined by the composition of our microbiome. Although the precise role of the microbiome in obesity is as yet unclear, obese humans have less bacterial species in their stool than lean people. Working with human pairs of twins discordant for obesity, Gordon’s group showed that stool from an obese human twin could transfer obesity to mice, while mice that received stool from the lean human twin stayed thin.5

Collateral Damage of Antibiotics

The human-associated microbiome is relatively stable over time in the absence of travel, diet changes, or diseases.6 However, a single course of antibiotics can have a dramatic impact on its composition. Most antibiotics are designed to kill broad groups of bacteria and cannot distinguish between the pathogenic bacteria causing a sore throat or skin infection and the beneficial microbes in our guts. Each time we take a course of antibiotics to treat an infection, we are also killing parts of our microbiome. The gut communities usually bounce back, but it can take weeks or even months to reach their starting point. In some cases, the intestinal microbiota never completely recovers from this perturbation, and particular groups might be permanently lost.7 Antibiotic use can also lead to antibiotic-associated diarrhea. This is often caused by a toxin-producing bacterium called Clostridium difficile, which is normally present at very low abundance in the human gut, where it’s competing with many other bacteria for space and food. It is less sensitive to antibiotics than most beneficial gut microbes and can take advantage of the open space left by antibiotics. The overgrowth of C. difficile can lead to persistent and WWW.SFMS.ORG

hard-to-treat diarrhea, and C. difficile infection is now the leading cause of hospital-acquired infections.8

Low Exposure to Germs

Despite an increasing awareness that some microbes might be good for us, many people try to avoid contact with germs. We eat nearly sterile food, put paper on the toilet seat, disinfect toothbrushes with UV light, and clean grocery carts and exercise equipment with germ-killing wipes. In addition, we wash our skin with antibacterial soaps and decimate our gut bacteria when we take antibiotics for a suspected infection. While many infectious diseases have rapidly declined in the past decades, many other diseases such as allergies, inflammatory bowel diseases, asthma, celiac disease, diabetes, and obesity are on the rise. In his recent book Missing Microbes, Martin Blaser links their increase to the overuse of antibiotics, which has not only contributed to an increasing number of antibiotic-resistant strains but is also detrimental to our microbiome.9 At the age of three years, the average U.S. child has already received three to six doses of antibiotics, exactly during the time that their microbiome is developing.10 Since our microbiome is involved in many processes in our bodies, including educating and balancing our immune system, the increased use of antibiotics and reduced exposure to bacteria early in life might be related to the increase in diseases of the immune system and obesity.

A Healthier View of Microbes

Obviously, we do not want to return to the Dark Ages, when infectious diseases could kill half of a continent’s population. We should support vaccination, treat life-threatening infections with antibiotics, and wash our hands with regular soap. But knowing how important a healthy and diverse microbiome is for our health, we should embrace the thought that low amounts of bacterial exposure might be good. Maybe we should not disinfect children’s school desks or buy antibacterial soap, and take antibiotics only when it’s absolutely necessary. Maybe we should be eating more live bacteria by consuming fermented food and yogurts with probiotics, and let the kids play in that dirty sandbox. Even grosser treatment options are emerging. Stool transplants, in which a patient’s own microbiota is killed and replaced with the gut microbes of a healthy donor, have been successfully used to treat patients with recurrent C. difficile diarrhea.8 People have even suggested that we should smear babies born via C-section with rectal and vaginal samples from their moms, immediately after birth. But realizing that we have to take care of our internal microbes is already a start. Microbiome research is a very hot topic and an exciting field to work in, and scientists expect to find many more roles that these little buddies play in our health.

Elisabeth Bik, PhD, is a research associate at the Department of Microbiology and Immunology at Stanford University School of Medicine. For the past twelve years she has worked in the laboratory of David Relman, MD, on the characterization of the human microbiome in hundreds of oral, gastric, and intestinal samples. She currently works on the microbiota analysis of marine mammals and children with inflammatory bowel diseases. Her blog, www.microbiomedigest.com, is an almost daily compilation of scientific papers in the rapidly growing microbiome field. Find her on Twitter at @MicrobiomDigest. A full list of references is available online at www.sfms.org. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

SUBMICROSCOPIC MICROBIOME A Universe of Discovery Erica Goode, MD At the dawn of rational pharmacologic and multifactorial treatment of disease, going back to Hippocrates, most worldwide cultures proffered mechanical, physical, herbal, and spiritual treatments to patients. These

often seemed to work, usually with no understanding of mechanisms of action. Many were helpful (Florence Nightingale’s use of open windows and clean, laundered bedding for Crimean evacuees), some were harmful (bloodletting and various surgical procedures). Epidemiology was the first logical method for understanding disease transmission and prevention. Dr. Ignaz Semmelweis (1818–1865), the Hungarian obstetrician who linked the ungloved hands of physicians who came straight from autopsies to birthing beds to the deaths of hundreds of women of puerperal fever, made this connection. Working tirelessly to convince his dismissive colleagues of this gruesome issue, pinpointing cause and effect, he nevertheless died heartbroken, with very little recognition of the value of his work until decades later.1 Dr. John Snow, a young English physician, painstakingly linked the fecal-laden water of the Broad Street Pump in London to deaths from cholera. The outbreak began in 1848 when the first devastating cases of cholera began rapidly killing people, eventually leading to 50,000 deaths. However, even his mounting evidence that those drinking from that pump were afflicted was dismissed for several years. Gradually, his methods gained traction against the skeptics who believed in spontaneous generation and miasma and their supposed effects.2 Microscopy had been in use for other purposes since the seventeenth century, but the knowledge of its benefits in identifying microbial agents of disease, with confirmation using Koch’s postulates, occurred centuries later. Robert Koch, a German physician and bacteriologist (1843–1910), won the Nobel prize for this work in 1905. The discoveries by these thoughtful men required determination, patience, commitment to detail, and courage—but with the current era of genetic sequencing technology and its improvements since the late 1990s, an even more daunting task is underway. While our newer sequencing techniques are faster than cultures in identifying microbes, this brings us smack against legions of newly characterized submicroscopic entities, which doubtless have commensal, symbiotic, functional properties relating to our immune systems and our unique genetic, metabolic, hormonal, and cellular selves. Currently, the microbes selected for probiotic mixtures and sold commercially—whether Lactobacillus, Bifidophilus, or others; whether alone or in kefir, yogurt, or GoodBelly juice—are those characterized by culture and microscopy. These may or may not make a significant difference in our individual microbiota if we are healthy. They can lead to noted improvements, however; 16

several of my patients have experienced a resolution of off-putting methane-laden flatus when using kefir regularly. Lactobacilli are known to inhabit the healthy vagina, but this is the proverbial tip of the iceberg. Thus Lactobacilli, in a vaginal insertion packet, may resolve a yeast infection arising in a diabetic or otherwise disrupted microbiome . . . or not. (A medical student friend joked in the 1970s that perhaps “strawberry yogurt would work better than plain”). We know from the NIH Human Microbiome Project Common Fund that 70 percent of the three-pound adult human microbiome resides in the gut, with its football field-sized mucosal surface lining the “small” intestine while the remainder cohabits the nasopharynx, mouth, vagina, urogenital tracts, and skin and its niches, more or less in that order. Moisture invites biofilm and colonization. This potpourri of bacteria, fungi, parasites, yeasts, and viruses dwells in our interstices and gut crypts, influencing our well-being in one way or another. Our microbiome not only has unique metabolic pathways, which influence our health and provide ongoing nutrition for the microbiome itself, but it also make vast numbers of (usually) helpful and complex chemicals. Michael Fischbach, PhD, a microbiologist at UCSF, has stated that fully one-third of developed antibiotics have derived from the work of microbes.3 The trick is to narrow the spectrum of newer antibiotics to avoid destruction of the complex connectedness of the healthy human microbiota. We know almost nothing about the potential for microbe-derived endogenous production of protective substances. Our microbiome coat, as it were, is unique to each of us. Its relative stability is established early in life, but it is not fully resistant to potentially harmful change, especially following broadspectrum antibiotics, bouts of diarrhea, wounds, and other serious illnesses. And then there’s the environment. As an example, in a newly cleaned, empty hospital room, a swab of a patient bedside table will contain myriad species identified by their various 16S rRNA genetic sequences. Indeed, the Hospital Microbiome Project has identified, whether in the ventilation systems, light switches, cafeterias, computer keys, or the NICU or other “sterile” areas, legions of uncultivable but potentially critical microbes.4,5,6 These same techniques of genetic sequencing and computational techniques have found an array of microbes, albeit in lower concentrations, in anatomic sites previously thought to be sterile: lachrymal glands, lungs, placenta, mother’s milk. Disruptions can control—or at least annoy—us from cradle to grave. And then there is the biofilm (think dental plaque, see sidebar on opposite page) lining our moist surfaces and influencing the “talk,” usually a healthy detente, between our immune globulins in the subsurface of gut crypts and the mucosal microbiota. A disrupted biofilm leads to loss of the matrix supporting the microbiota, and thus to

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disease. It is composed of an aggregate of sessile microbes encased in a self-generated, hydrated exopolysaccharide matrix, strongly attached to a surface.7 In contrast to the seemingly quaint nineteenth- and twentieth-century preamble outlined earlier, the burgeoning task before us, of myriad worldwide researchers working to identify and characterize the human microbiome, appears Sisyphean. The collation of reports by thousands of collaborators, with a data bank being assembled via the NIH Human Microbiome Project (HMP), resembles the work of astronomers as they sort through the universe, noting movements of black holes, moons, and comets in relation to galaxies and one another. A concern for the HMP, built upon data acquired during the Human Genome Project and funded from 2007 to 2015, is that politically there may be little will for the current Congress to adequately fund the project beyond next year, unless physicians, researchers, and citizens declare the necessity for doing so. In some ways, this gets us back to epidemiology. What common factors in our environment, whether dietary; petrochemical; BPA-related from plastics; antibiotics, zealous use of “cleansers;” or overprotection of our children from pets, sand-boxes, or dirt, leads to the rise in inflammatory bowel problems, autoimmunity, asthma, obesity, and other twenty-first-century ills? It is imperative, as I see it, that we further characterize the role of our current world, and its relationship to the vast, seething, undisclosed coat of submicroscopic entities that we hold near and dear. Meanwhile, ever-increasing articles and reports of data arising from the HMP continue to inform professionals and the public. Lively discussions of our microbiome and its pilot-fish control over our lives is reported in journals (JAMA, The Lancet, Scientist, Nutrition Reviews, Environmental Health Perspectives, and scores of others) and in the popular press (the New York Times, San Francisco Chronicle, and the occasional magazine).8

A few definitions may be in order:

Metagenomics: Community gene content Metaproteomics: Community protein content Computational technology and statistical clustering: Classification used to correlate and associate microbial composition, gene, and protein content

References

1. Semmelweis Museum, Budapest, Hungary. 2. Johnson S. The Ghost Map. Riverhead Books, NY. 2006. 3. Conway C. Mining our microbiome: Culturing for cures. UCSF Magazine. Spring, 2014:13. 4. Arnold C. Rethinking sterile: The hospital microbiome. Environmental Health Perspectives. DOI, 10:1289; 122-9182. hep.niehs.NIH.gov. 5. Feazel LM. Opportunistic pathogens enriched in shower head biofilm, Proc. Nat. Acad. Sci., 2009; 106:(38):16393-16399. 6. Zhang L et al. Microbiological pattern of arterial catheters in the ICU. BMC Microbiology. 10:266-2010. 7. Jain A et al. Biofilms: A microbiological life perspective: A critical review. Crit. Rev. Ther. Drug Carrier Systems. 2007; 24:393-443. 8. Brody J. A probiotics boom, if not a boon. New York Times. 7/22/14, D5. See full author bio on page 27. WWW.SFMS.ORG

Biofilm: The Development and Maintenance of This Essential Gut Microbiota Platform In the living healthy human, biofilm (found in the mouth, skin, gut, and genitalia) anchors the microbiome of organisms that serve us. Bacteria do not float about in random Brownian motion but are swept along beyond stomach chyme, where most should be killed or reduced in numbers due to stomach acidity and enzymes, unless excessive use of PPIs blunts this optimal first bactericidal management. Biofilm can be either helpful or harmful if imbalance occurs.1 Despite the gastric barrier to swallowed bacteria, the distal ileum develops a healthy, functioning microbiota under normal circumstances. The tethering medium is biofilm. Microbiota can communicate, specialize metabolically, and in some ways facilitate communication with the host immune system. This gathering of sessile microbes is encased in a hydrated exopolysaccharide matrix, firmly affixed to a surface.2 Biofilm forms by initially adhering to a cliff or edge. A planktonic bacterium such as E. coli becomes entrapped, communicates with its associated bacteria, and over time changes gene expression by as much as 38 percent, while transforming into a sessile form that is stable within the biofilm.3 The normal conglomerate of gut microbes and biofilm function as a unit, via their resistant barrier and ability to sequester at least a portion of the microbiome mass even when a broad-spectrum, long course of antibiotics is taken. Microbes harbored by biofilm are generally protected from predation by amoebas, bacteriophages, and other pathogens.4 Biofilm also shields microbes from the host’s cell-mediated and humoral immune responses.5 However, at times this system fails, especially in an already depleted individual. The biofilm itself is likely to be malfunctioning if the individual has an illness such as inflammatory bowel disease, Crohn’s or celiac disease, Barrett’s esophagus, or H. pylori. In these illnesses, the biofilm malfunctions, inflamed mucosa is exposed, normal gut flora is poorly tolerated, and damaged tissues are further inflamed. On a practical level for physicians prescribing antibiotics, broad-spectrum agents in particular not only reduce populations of usual microbiota but their effect upon biofilm sessiles is more ominous. These are the bacteria that can evolve into more destructive, persistent phenotypes, giving rise to such issues as toxigenic E. coli and C. difficile. A final dilemma for practitioners is that of biofilms that invariably coat nonbiological materials, such as shunts, catheters, arterial and venous IUDs, orthopedic prostheses, heart valves, biliary stents, and even contact lenses. Each of these has been shown to be associated with infectious processes; endocarditis from endovascular catheters being one example.6 While this summary is a simplistic view of what is already known about the structure, microbial qualities, and multiple functions of biofilm, the Human Microbiome Project (HMP) is exploring this enormous realm. Firm information will continue to evolve only as the HMP provides guidance on practices for maintaining and/or rebalancing a healthy human biofilm and planktonic microbial ecology. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

ANTIBIOTICS Effects on the Human Microbiome Stephen Follansbee, MD We live in relationship, in health and in disease, to our microbiome, unique to each of us. The study of the ways in which the commercial availability of antibiotics has affected this relationship has become a rapidly growing field.

“Facts” and “Definitions”

Microbiome: The ecological community of commensal, symbiotic, and pathogenic microorganisms that share our body spaces. The microbiota includes bacteria, archaea, viruses, and eukaryotes. They outnumber human cells by 2.5–10:1 and weigh up to three pounds. The bacterial component is the largest. Bacterial 16S rRNA gene sequencing: This laboratory technique has markedly expanded the field, because 60–80 percent of microbiota cannot be cultured using available technology. It allows for more accurate documentation of the spectrum of organisms as well as their relative proportions. The Human Microbiome Project (HMP) (see page 26): Funded by NIH since 2007, its first phase (2007–2012) funded three initiatives, including multi-omic analysis of the vaginal microbiome during pregnancy, longitudinal multi-omics microbial profiling in healthy and disease-state individuals, and characterization of the gut microbial ecosystem for diagnosis and therapy of inflammatory bowel disease (IBD.) The second phase, 2013–2015, is an initiative to create integrated datasets of biological properties from both the microbiome and the host using multi-omics technologies. The European equivalent of this project is the MetaHIT consortium. Multi-omics data analysis: High-throughput analysis of various data sets, looking at measurements of various systems to establish more relevant relationships and causality beyond simple genetic analyses. These datasets include metaproteomics, metagenomics, transcriptomics, metabolomics, nutrigenomics, and pharmacoproteomics. Human antibiotic prescribing in the USA: Between 1945 and 2010, there have been 258 million courses of antibiotics prescribed, about 833 prescriptions for every 1,000 people. By age, this includes 1,365 courses per 1,000 babies (ages zero to two years) and about eight courses from three to ten years. CDC suggests that there is an average of seventeen courses of antibiotics prescribed to each young person before the age of twenty years. Antibiotic use in animal husbandry: Since 1946, antibiotics have been used to increase animal weight, now accounting for 80 percent of all antibiotic use in the USA. Amphibiosis: A concept in microbial ecology that an organism may have one of two relationships to the human host, either symbiotic or parasitic. It is easy to see why there should be concern over the impact of antibiotics on the human microbiome. In fact, this interaction antedates the availability of pharmaceutical antibiotics. Bacteria 18

are the source of “natural” antibiotics. It is postulated that Archaea, which are highly resistant to known antibiotics, evolved from grampositive bacteria to resist the “natural” production of antibiotics. If these changes occur naturally and affect evolution over millions of years, it is not difficult to acknowledge the potential effect widespread use of pharmaceutical antibiotics would exert.

Antibiotic Resistance

The most obvious issue is emergence of antibiotic resistance. Examples include methicillin-resistant Staphylococcus aureus (MRSA), extremely drug-resistant Mycobacterium tuberculosis hominis, acyclovir-resistant herpes simplex hominis, and vancomycin-resistant enterococcus. One interesting study (Jakobsson et al, PLOS ONE 2010) looked at throat and stool samples in three individuals at baseline and at up to four years after a single treatment course with clarithromycin and metronidazole for H. pylori. After four years, the diversity of the microbiota seemed to have mostly recovered and resembled pretreatment states, but some individual exceptions remained. In addition, after four years some high levels of the macrolide resistance gene erm(B) were still found. Several studies, both in animal husbandry and in humans, have shown that antibiotic resistance in the intestinal tract may not be confined to the administered antibiotic. Cross-resistance can develop to other antibiotics in the same class or to antibiotics in other classes. An example is the appearance of bacterial aminoglycoside Ophosphotransferases in a swine study, where litter mates were randomized to receive a diet with or without a performance-enhancing antibiotic mixture (ASP250) containing chlortetracycline, sulfamethazine, and penicillin (Looft et al, PNAS 2012). After fourteen days of antibiotics, the expected increase in resistance to beta-lactamase drugs (penicillin), tetracyclines, and sulfamethazine was seen. However, a similar increase was seen in the emergence of the aminoglycoside O-phosphotransferases, conferring resistance to the class of medications called aminoglycosides, not found in ASP250.

Metabolism and Efficacy

Another area that is familiar to us is the indirect influence of antibiotics on drug metabolism and efficacy. The influence of antibiotics on the efficacy of warfarin is well recognized. This may be an example where the perturbation and resilience of the pharmacometabiome seems to be of shorter duration than other effects of the same antibiotic course on the diversity and resistance of the microbiota. In other words, the dosing of warfarin can return to baseline more rapidly than predicted simply by examining the microbiota. Another example is Eggertella lenta, which carries a cytochrome operon that causes inactivation of digoxin. It is an anaerobic, nonmotile, non-sporulating gram-positive rod and a normal inhabitant of the colon. It is rarely described as a human pathogen. However, its ability to inactivate di-

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goxin has recently been described. The influence of a short or more prolonged course of antibiotics that might indirectly “treat” this normally commensal organism is not understood.

Obesity

The microbiome is thought to contribute to human metabolism. The most discussed is probably the relationship of the microbiome to risk for obesity. There has been a lot of research looking at the effect of low-dose continuous antibiotic administration (STAT or subtherapeutic antibiotic treatment) and pulse administration (PAT or pulsed antibiotic treatment.) Some of the PAT studies are the most interesting. One study involved PAT (amoxicillin with or without tylosin versus no antibiotic) to female infant mice for three days at ten to fourteen days, at twenty-eight days, and at thirty-seven days of age. Following out to 150 days of life, PAT mice showed more muscle mass than control and increased bone area and mineral content. Interestingly, the microbiota diversity in fecal pellets was permanently decreased out to 150 days, more than 100 days after the last course of antibiotic (800 species in mothers and controls, reduced to 700 after one course of antibiotic, and even further reduced to 200 species if the mice were given tylosin). Not only were there significantly fewer species but the spectrum of species was not as evenly distributed as seen in control mice not given the antibiotic. Epidemiologic studies of children demonstrate that receiving antibiotics within the first six months of life is associated with higher risk of obesity (Avon Longitudinal Study of Parents and Children—ALSPAC—in Britain). Much more work needs to be done to understand and expand this experimental and epidemiologic data. These issues are somewhat illustrated by Dr. Martin J. Blaser’s own professional and personal journey with Helicobacter pylori. The journey is outlined in his book Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues. He is one of the world’s experts on H. pylori as a result of his laboratory and epidemiologic research. H. pylori resides only in the stomach lining and is known to be associated with higher risk for gastric ulcer and gastric cancer. In the absence of any symptoms, he discovered he was H. pylori antibody positive, and positive for the virulence factor CagA protein. In the absence of symptoms, he was treated, under the now mistaken thought that “the only good H. pylori is a dead H. pylori.” Six months after antibiotic treatment, with falling antibody titers and clearing of the organism on repeat gastroscopy, he developed symptoms of gastrointestinal reflux disease (GERD). It is now know that H. pylori may help protect against symptoms of GERD. It is also thought that early colonization in children (but not adults) may help lower the risk of subsequent asthma. Thus H. pylori provides an example of amphibiosis.

Alterations in Fecal Microbiota

Treatment for various conditions associated with alterations in the fecal microbiota is still in its infancy. The most established is fecal microbiota transplantation (FMT) for relapsing Clostridium difficile colitis. This diagnosis has become much more common, related to more widespread use of broad-spectrum antibiotics as well as increased virulence of C. difficile. Although C. difficile is part of the normal flora of the human colon, the production of toxin can lead to severe and life-threatening disease. All treating clinicians are aware of the high risk for disease relapse after an apparently successful initial course of antibiotics for this diagnosis. Fecal transplantation has WWW.SFMS.ORG

been used for more than 100 years in animal husbandry. The benefit of this treatment for recurrent disease in humans has been increasingly recognized over the last five years. However, the mechanism of action is not well understood. Is it related to the microbiota themselves, such as the Firmicutes and Bacteroidetes phyla, or some other aspect such as bile acids or other immunologic or metabolic factors? Development of equally effective commercial (not human-derived) preparations depends on better information. There are examples where apparently successful approaches to disease treatment using immunologic methodology have not be successful. Bovine colostrum was tried for recalcitrant cryptosporidium enteritis in the setting of advanced HIV infection. Despite reports of efficacy in cows, it does not work in humans.

Next Steps in Microbiome Research

The discussion has attempted to suggest some of the problems with and gaps in the current knowledge. These are outlined in the proceedings of the first NIH-sponsored workshop entitled Human Microbiome Science: Vision for the Future, conducted July 23-25, 2013 (http://www.genome.gov/27554404). Despite the immense expansion of knowledge about the microbiota in stool and vaginal flora, there is much more to be developed for a fuller understanding of the impact of and solution to antibiotic-associated changes in the microbiome. Given the rather primitive knowledge at present, are there recommendations that can be made now? I believe the answer is yes. My suggestions include: (1) The development of better diagnostic tools to establish the diagnosis of infection rather than simple colonization; (2) fewer antibiotic courses, eliminating use in clinical situations where antibiotics have shown little impact; (3) shortening the duration of treatment to a course shown to be efficacious (e.g., prolonged course of macrolides has no impact on the chronic cough associated with pertussis); (4) use of an antibiotic with narrowest spectrum of activity (corollary: development of newer antibiotics with more restricted spectra of activity); (5) development of new approaches to treatment that do not involve direct-acting antibiotics (e.g., FMT or more focused immunologic or anti-inflammatory interventions); (6) development and use of better vaccines (e.g., the diphtheria toxin-conjugated pneumococcal vaccine, which appears to decrease spread of pneumococcus); (7) continued promotion of reduction of antibiotic use in animal and poultry husbandry, which the SFMS and CMA have been advocating for more than a decade; and (8) possibly promoting the concept of developing a more robust microbiome early in each infant’s life. Stephen Follansbee, MD, is a retired HIV and infectious diseases specialist in San Francisco. Since completing his postgraduate training at UCSF, he practiced for sixteen years with the Infectious Diseases Associates Medical Group and then another sixteen years with Kaiser Permanente in San Francisco. He is a clinical professor of medicine at UCSF and longtime member and past-president of the SFMS. Since retirement his main activities have been to say “no” to most requests for new responsibilities and to say “yes” to becoming certified in scuba diving. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

THE “SECOND GENOME” The Role of Microbes in Women’s Health and Disease Linda C. Giudice, MD, PhD Due to major advances in sequencing and bioinformatics approaches, the past decade has witnessed an explosion in defining microbial communities and identifying new microbes and their gene expression in various body organs. Since fewer than 1 percent of microbes can

grow and form colonies on agar plates, metagenomics (gene-based and/or 16S ribosomal DNA-sequence-based technologies) has been pursued to detect microbes regardless of their culturability. This approach seeks to understand biology at an aggregate level, is high throughput, and overcomes two limitations of microbe characteristics: unculturability and genomic diversity. This has given us insight into how diet, mode of delivery, and where one lives affect microbial habitats and communities, the diversity of these communities, and how microbes have an ongoing conversation with the host’s metabolic and immune systems that affects health and disease.1-3 Women’s health is affected by microbes in the vagina, placenta, bladder, gut, and other habitats. Indeed, some data suggest sex differences in autoimmune disorders may be related to the gut microbiome.4 This new branch of science, our “second genome,” i.e., our microbiome, offers great promise regarding insights into normal physiology, the dynamics between host homeostasis and pathogenesis of diseases that are unique to or more prevalent in women, and the promise of novel diagnostic and therapeutic approaches.

The Vaginal Microbiome

The microbiome of the human vagina is a collection of resident bacteria that play a key role in preventing colonization and infection by undesirable organisms. The vagina and its unique microflora comprise a finely balanced and dynamic ecosystem that can be affected by multiple factors, including infection, menstrual cycle stage, contraceptive agents, personal habits, and pregnancy.5 Early metagenomic studies of the vaginal microbiome in nonpregnant “healthy” women6-8 revealed that vaginal bacterial communities placed into groups dominated by Lactobacillus species—L. crispatus, L. gasseri, L. iners, L. jensenii—and a fifth group characterized by a much-reduced Lactobacillus content. The Human Microbiome Project (HMP, see page 26) reported the structure, function, and diversity of the healthy human microbiome (microbes and their genes), sampling eighteen body habitats in 113 women, including three in the vagina, and fifteen samples in 129 men.9 Diversity of microbes (i.e., the number and abundance distribution of distinct types of organisms) within a given body habitat revealed that each habitat was characterized by a small number of highly abundant “signature taxa,” although with much interindividual variability. In most samples, high-abundance taxa were accompanied by low-abundance taxa from the same species, and taxonomic and genetic diversity were lowest in vaginal samples and highest in oral (supragingival plaque) samples, and intermedi20

Figure 1: Vaginal Bacterial Community Groups Differ in Women of Different Race/Ethnicities

Source: Revel www.pnas.org/cgi/doi/10.1073/pnas.1002611107

ate in skin and buccal mucosa. While low diversity is normal, high diversity in the vagina is linked to bacterial vaginosis (BV), with diversity reverting to non-BV levels after treatment.10 Additionally, the bacterial community composition of the posterior fornix, dominated by Lactobacillus, changes with vaginal pH.11 Also, the vaginal microbiome in nonpregnant women correlates with race/ethnicity (Figure 1 above), and microbiota in various habitats depend heavily on age and country of origin.12 The temporal dynamics of vaginal bacterial community composition confirmed changes in five major classes of bacterial communities, with one being Lactobacillus poor.13 Some communities changed markedly over short time intervals and others were relatively stable, although community function, measured by the vaginal metabolome, was maintained despite changes in bacterial composition. Lowest community constancy coincided with menses, and highest with preovulatory peak estradiol and also with mid-luteal peak progesterone. Of all metadata evaluated, including hormonal contraception, community type, sexual activity, lubricant use, and douching, only sexual activity had a significant (negative) effect on constancy, independent of time in the menstrual cycle. As women in this study were healthy and asymptomatic, the role of diversity and constancy of the vaginal microbiome in reproductive health has yet to be fully appreciated.

The Microbiome in Pregnancy

Vaginal microbiome: Across gestation, the stability of the vaginal microflora as a function of vaginal Lactobacillus species present suggests that L. crispatus promotes normal flora and that L. gasseri and/or L. iners are conducive to abnormal flora.14 Metagenomic analysis of the microbiome at three sites in the vaginas of twenty-four pregnant women across gestation revealed that microbial diversity and richness were less in pregnancy than in nonpregnancy, and diversity increased from fornix to introitus and changed with gestational age.15 In a pilot study, our team16 confirmed reduced vaginal microbiome diversity during human pregnancy versus nonpregnancy and also demonstrated that race/ethnicity is an important variable. Furthermore, variability in study outcomes globally differ with

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ism but of a shift in the vaginal bacterial ecosystem.19 Our team found that diversity of the vaginal microbiome during human pregnancy inversely correlates with PTB.16 However, the recent findings about the placental microbiome18 raises questions about the role of the microbiome in other body habitats that may influence the maternal immune response and susceptibility to preterm labor and PTB. Neonatal and infant microbiome: Bacterial communities from mothers and their newborns sampled from maternal skin, oral mucosa, and vagina (one hour before delivery); neonatal skin, oral mucosa, and nasopharyngeal aspirates (less than five minutes after delivery); and meconium (less than twenty-four hours after delivery) revealed that neonates initially harbor undifferentiated communities across multiple body habitats, regardless of delivery mode and in contrast to highly differentiated maternal communities. Vaginally delivered infants acquire bacterial communities resembling their own mother’s vaginal microbiota (mainly Lactobacillus, Prevotella, or Sneathia), and C-section infants harbor bacterial communities similar to maternal skin (mainly Staphylococcus, Corynebacterium, and Propionibacterium).20 Longitudinal study of intestinal microbiota revealed significant changes occurring between nine and eighteen months of age, during the transition from breastfeeding to solid foods, and by thirty-six months the establishment of an “enterotype” microbiome.21 In another study, similarities between infant-mother microbiotas also increased with children’s age, and the infant microbiota was unaffected by mother’s health status.17 Transitions of gut and other body-habitat microbiota in the neonatal period and childhood are important to determine potential contributions to health and disease in subsequent years.

Figure 2: The Placental Microbiome Most Resembles the Non-pregnant Human Oral Microbiome

Source: Aagaard et al Sci Transl Med 2014

sampling sites and types of samples (vaginal mucosa, cervico-vaginal fluid, posterior fornix, mid-vagina, introitus).16 Gut microbiome: There is a dramatic global shift in gut microbiota from the first (T1) to third (T3) trimesters, with great expansion of diversity among women.17 The gut microbiota of the T1 and nonpregnant fecal samples were similar, as were T3 and one-month post-partum specimens. Change in diversity from T1 to T3 was unrelated to pre-pregnancy BMI, gestational diabetes, or parity. T3 stool showed strongest signs of inflammation and energy loss and, when transferred to germ-free mice, induced greater adiposity and insulin insensitivity compared to T1.17. The T1 to T3 increased adiposity; higher-circulating HbA1c, leptin, insulin, and cholesterol levels; and increased insulin resistance observed were proposed due to maternal gut microbiome shifts and associated inflammation—an interesting hypothesis needing further evaluation, especially with the known role of human placental lactogen in these processes in T3. Placental microbiome: The paradigm of the placenta as a sterile organ has recently been challenged by findings that it harbors a unique microbiome that is most similar to the nonpregnant human oral microbiome.18 The placental microbiome correlates with a remote history of antenatal infection, such as urinary tract infection (UTI) in the first trimester, and preterm birth (PTB).18 While antibiotics used to treat these infections may affect the placental microbiome, how the placental microbiome is established and altered is of great debate. Given the placental microbiome is not similar to the vaginal or stool microbiomes, regardless of delivery mode, and is not structured by Group B Streptococcus colonization or affected by maternal diabetes or BMI, a provocative hypothesis has been posed that it is established by hematogenous spread of oral microbiota during early placentation and vascularization.18 These data, yet to be replicated, bring new light to the role of oral health and pregnancy outcome and warrant further investigation. Preterm birth: A prevailing hypothesis is that PTB results from ascending infection from the vagina—not of a specific microorganWWW.SFMS.ORG

The Urinary Microbiome: Another Paradigm Shift

Asymptomatic women: Contrary to common belief, the lower urinary tract is not sterile. Several studies have determined the urinary microbiome of asymptomatic, culture-negative (<100,000 CFU/ml) healthy women, with specimens collected by voiding, transurethral catheterization (TUC), or suprapubic aspiration (SPA).22-24 In normal women, Siddiqui et al found variable bacterial 16S rDNA sequence richness, including fastidious and anaerobic bacteria previously associated with female urogenital pathology.22 Brubaker and colleagues found that voided urine samples contained mixtures of urinary and genital tract bacteria, whereas communities identified in parallel urine samples collected by TUC and SPA contained 395 genera from twenty-two phyla and were similar to each other.23 Another study demonstrated that midstream urinary collection had a similar microbiome compared with TUC24 suggesting a noninvasive approach to sample urine for microbiome analyses in a variety of conditions. Pelvic organ prolapse and urinary incontinence: Interestingly, urine samples from asymptomatic controls versus pelvic or-

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The “Second Genome” Continued from the previous page . . . gan prolapse/urinary incontinence (POP/UI) cohorts have similar microbiomes.25 However, a recent study suggests a bacterial link to incontinence.26 Bacterial communities isolated from urine of women with urinary incontinence differ depending on the type of incontinence, and the microbiota of patients with urge incontinence are readily distinguished from those with stress incontinence, with the latter having markedly reduced bacterial diversity.26 While this is the first study to provide evidence supportive of an infectious association with a subtype of urge urinary incontinence, if confirmed, it offers the promise of therapies directed at bacteria or their antigens identified in the urinary bladder of affected women, reducing symptoms and the impact on daily activities attributable to urge incontinence. Interstitial cystitis: Interstitial cystitis (IC), more common in women, is a chronic inflammatory condition of the bladder of unknown etiology. High-throughput sequencing of the 16S variable regions V1, V2, and V6 revealed reduced bacterial-sequence richness and diversity and a significant difference in the community structure of IC urine versus normal controls.27 More than 90 percent of the IC sequence reads were identified as bacterial genus Lactobacillus, compared with 60 percent in control urine. The shift in bacterial community composition and reduced microbial diversity and richness accompanied by a higher abundance of Lactobacillus in IC urine has been proposed to contribute to the symptoms experienced in patients with IC.27 This supports other independent observations correlating symptoms abating concomitantly with diminished colonization and exacerbation with accumulation of Lactobacillus.27 This approach offers an exciting area of research to understand the biological basis and potential personalized therapies of this enigmatic disorder. Asceptic bacteriuria (ABU) and urinary tract infections (UTI): In ABU, bacteria are present in the urine, but the inflammatory response and symptoms are minimal. Differentiating ABU from UTI is important because ABU overtreatment can result in antimicrobial resistance, whereas UTI undertreatment can result in increased morbidity and mortality. In a study of twenty-six healthy controls and twenty-seven healthy subjects at risk of ABU (due to spinal cord injury and neuropathic bladder), Venter and colleagues28 reported that urine microbiomes differ by normal bladder function, gender, and type of bladder catheter used (intermittent transurethral catheterization, indwelling Foley catheter, normal voiding). Ten bacterial taxa (Lactobacillales, Enterobacteriales, Actinomycetales, Bacillales, Clostridiales, Bacteroidales, Burkholderiales, Pseudomonadales, Bifidobacteriales, and Coriobacteriales) showed the most relative abundance, and metaproteomics confirmed the 16S data. Functional human protein-pathogen interactions were noted in subjects where host defenses were initiated and, interestingly, different taxa were differentially predominant in urine from men versus women. These studies form the basis of a novel approach to determine candidate communities for targeted therapies, if needed. Metagenomics has been used to assess possible bacterial communities in leukocyte esterase-positive/culture-negative urine from symptomatic patients. Using culture and targeted PCR, the majority of UTIs were found to be caused by Escherichia coli (35.15 percent), followed by miscellaneous bacteria (23.03 percent), and 22

by Enterococcus faecalis (19.39 percent).29 However, a large fraction of fastidious and anaerobic bacteria (22.43 percent) was only detected using PCR and is commonly undetected in routine diagnostic laboratories examining urine specimens with culture only. The molecular approach using broad-range 16S rDNA PCR, sequencing, and bioinformatic analysis to uncover these “hidden” pathogens offers an opportunity to get a more complete assessment of urinary pathogens, especially in leukocyte esterase-positive and culturenegative urine specimens. Sex and age differences: Comparing urinary microbiomes from asymptomatic adult women and men reveals that women have a more heterogenous mix of bacterial genera and representative members of Actinobacteria and Bacteroides phyla, and that conventional microbiological methods were inadequate to identify about two-thirds of bacteria found in these specimens.24 Fouts et al found a preponderance of Lactobacillales in women and Corynebacterium in men.28 Also, preliminary data suggest age-related differences in the urinary microbiome, with fluctuation in abundance among age groups (twenty-six to ninety years old) and age-specific genera Jonquetella, Parvimonas, Proteiniphilum, and Saccharofermentans, although the clinical significance of this remains unclear.24

Future Directions

The microbiome is a new frontier in women’s health. While there are abundant data on the role of the gut microbiome in influencing host metabolism and immune homeostasis,1-3 data on hormonal effects on these processes and sex-specific differences are wanting. Many questions arise. Is there a hormonal effect on microbiomes in various habitats throughout the body or in various hormonal states through which women transition? What are the effects of antenatal steroids, prenatal vitamins, 17-hydroxyprogesterone, or tocolytics on the gut, vaginal, oral, and placental microbiomes? What is the host immune/epithelial response to communities and novel microbes? Will we be changing the way we diagnose and treat UTIs, PTB, and gastrointestinal and other disorders with enigmatic etiologies? What is the reproductive tract microbiome in endometriosis, with abnormal uterine bleeding, with uterine fibroids, or in the presence of HPV, HIV, and other viral, fungal, and bacterial infections? What are effects of race, ethnicity, SES, intercourse, numbers of sexual partners, family history, personal habits (douching, environmental exposures) on microbiomes of various habitats? Perhaps some microbiomes are protective and treatment may cause more harm than good. What an opportunity for development of novel diagnostic and therapeutic approaches to a variety of disorders more common to or specific to women, and what an exciting time to be a physician who cares for women and a researcher and teacher focusing on women’s health and the female microbiome! Linda C. Giudice, MD, PhD, is a distinguished professor and chair of the Department of Obstetrics, Gynecology & Reproductive Sciences at UCSF. Review of this article by Dr. Michael Fischbach of UCSF is gratefully acknowledged. A full list of references is available online at www.sfms.org.

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The Microbiome and Health

GENESIS, INFLUENCE, AND EFFECTS The Human Microbiomeâ&#x20AC;&#x2122;s Many Facets Susan V. Lynch, PhD, and Ariane R. Panzer Traditionally, the medical community has viewed microbes as the cause of illness and sought to eliminate them. This notion, however, is shifting as current re-

search has illustrated that microorganisms living on and within the human body can not only live in harmony with their hosts but are actually necessary for maintenance of human health. The human body is made up of trillions of cells, but for every one of these human cells there are ten times more microbial cells. These microbes exist as part of complex communities composed of bacteria, fungi, and Archaea as well as eukaryotes. The composition of the microbiome varies from site to site across a single human body (for example, the composition of the oral microbiome is distinct from that of the gut); however, at least in healthy subjects, the microbial composition at or in a specific anatomical site is relatively similar from person to person. This entire collection of microbial communities on and within the human body is referred to as the human microbiome. In healthy humans, the relationship that exists between the host and its microbiome is beneficial for both organisms. Humans offer a protected, nutrient-rich environment in which microbes readily colonize and proliferate, while the host is the beneficiary of a wealth of microbial functions that it does not have the capacity to perform by itself. These microbial communities, particularly those resident in the gastrointestinal tract, perform critical functions, such as metabolism of indigestible dietary fibers to produce small-chain fatty acids, an essential energy form for the human cells that lines the gastrointestinal tract. Additionally, they participate in immune development during the critical neonatal stage of development, have been shown to afford protection against infectious microbes, and are associated with maintenance of the immune system in a state of homeostasis.

Variation Across Age and Geography

The composition of microbial communities on and within the human body is influenced by a range of common but variable exposures including diet, local environment, and host genetics, among others. Evidence for this comes from a large study published in 2012 by a group of scientists led by Dr. Jeffrey Gordon of Washington University, St. Louis. The study compared the gut microbiome of Malawian, Amerindian, and U.S. residents aged zero to seventy years and found that the composition differed considerably with age. According to their observations, the gut microbial community undergoes a period of rapid diversification and assembly over the first three years of life, a consistent feature across all three populations. While this had been observed in previous studies with smaller numbers of American children, the multinational study also discovered that U.S. and non-U.S. individuals had distinctive gut bacterial communities WWW.SFMS.ORG

with different functional capacities, which were highly reflective of the distinct diet and geographical residence of these groups.

Antibiotics and Species Loss

Antibiotics also significantly influence the human microbiome. Les Dethlefsen and David Relman from Stanford University found in 2010 that antibiotic administration rapidly decreases gut microbial diversity, and while these bacterial communities are able to rebuild themselves within a relatively short period of time (one to four weeks) following antibiotic exposure, the reassembled communities lacked certain species and did not completely recover to the pretreatment composition. Instead, these communities existed in an alternate yet stable compositional state. While the impact of species loss and the effect of this alternative stable state on long-term health outcomes is currently unknown, significant reductions in community diversity are emerging as a universal characteristic of a range of chronic inflammatory diseases of humans. These observations have led to growing concern that overuse of antibiotics in Western nations may represent a contributory factor to the growing prevalence of chronic inflammatory diseases associated with perturbed gut microbiota.

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Genesis, Influence, and Effects Continued from the previous page . . .

Early-life Microbial Development Early-life exposures appear to be especially influential on the developing gut microbiome during infancy. Current studies suggest that humans are initially exposed to microbial species during the birthing process and that difference in birth method greatly impacts which organisms form the initial microbial “seed” or inoculum of the neonatal system. Vaginally born infants are colonized at various sites across the body by microbes present in high numbers in the maternal vaginal tract during the birthing process, while children born via cesarean section are typically colonized by distinct microbes that strongly resemble those found on their mother’s skin. Recent studies have indicated that other early-life exposures, such as mode of nutrition (e.g., breast- versus formula-feeding) or environmental microbial exposures (e.g., microbial content of household dust), also have the potential to influence gut microbiome composition. It is thus the culmination of a variety of environmental exposures that influence both early-life microbiome development and—as is well established in epidemiological circles—the propensity to develop childhood disease. Hence an emerging consideration for microbiome studies, particularly those interested in dissecting the causal pathway to disease development, is the impact one’s local environment can have on the human microbial ecosystem and disease development.

Man’s Best Friend?

In 2013, a group of researchers led by Dr. Rob Knight of the University of Colorado showed that an individual’s microbiome is influenced by those individuals with whom they share an environment.

Researchers in this group found that even more so than humans, the dogs we cohabit with largely influence the composition of skin microbial communities.

Cohabitating adults who own a dog exhibit a greater proportion of shared microorganisms in their skin microbial communities and greater diversity within their bacterial communities. Interestingly, exposure to dogs during infancy has been associated with protection against allergic disease development in childhood, an observation made by Christine Johnson and Dennis Ownby of Henry Ford Hospital and Georgia Regents University respectively. Studies in Dr. Susan Lynch’s lab at the University of California, San Francisco, in collaboration with Drs. Johnson and Ownby, have shown that homes with dogs possess distinct house dust microbial communities compared to those with no pets. More specifically, homes with furred pets that spend time both indoors and outdoors were associated with house dust that had increased bacterial diversity as compared to homes in which there were either no pets or pets that remained exclusively indoors or were kept strictly outdoors. Other recent studies from this group have demonstrated that in the inner city, infants exposed in the first year of life to house dust containing high 24

levels of mouse, cockroach, or cat allergen in combination with approximately eighty distinct types of bacteria have significantly lower rates of allergy and recurrent wheeze at age three. Together these studies suggest that animals, insects, and even rodents impact microbial communities in the living environment, and that the microorganisms in our immediate environment have the propensity to influence disease development. Based on this research, Dr. Kei Fujimura, a researcher in the Lynch lab at UCSF, together with a team at the University of Michigan led by Dr. Nick Lukacs, posed the question, “Can exposure to distinct house dusts influence the way the airways respond to allergens, and, if so, is this response governed by changes in the gut microbiome?” To tackle this question, their experiment involved collecting dust from households with an indoor/outdoor dog or no pet present in the household and a mouse model of airway allergen exposure. Mice were gavaged daily with dust from the different households to recreate exposures associated with living in these distinct households. Following this, their airways were exposed to either cockroach allergen (CRA) or ovalbumin antigen (OVA) to induce an allergic airway response. Mice who received the dog-associated dust had significantly reduced allergic responses in their airways. Moreover, they also exhibited significantly different bacterial communities in their gut. Dr. Fujimura and colleagues next examined which specific organisms were enriched in the gut of protected animals and found that one of the most highly enriched species was Lactobacillus johnsonii. This led the team to consider whether the observed airway protection could be conferred by this single species. Thus the investigators isolated L. johnsonii from the gut of mice fed dog-associated house dust and used it to supplement a new set of mice prior to challenging their airways with CRA. The results demonstrated that L. johnsonii-supplemented mice were protected from airway allergen challenge. Even more exciting was that this protective effect extended beyond allergens; animals fed L. johnsonii and subsequently exposed to respiratory syncytial virus (RSV) were also protected against infection by this species. Protection was associated with an intact ability to clear the virus via IFN-gamma expression, coupled with significantly reduced airway Th2 cytokine expression, the expression of which is known to contribute to RSV pathology. Hence these more recent studies demonstrate that exposure to dog-associated household dust protects against airway allergen challenge, and that protection is associated with enrichment of a specific Lactobacillus species that, when fed to mice, can elicit much of this protective effect. Incidentally, studies of the vaginal microbiome of pregnant mothers have catalogued changes in microbiome composition as the mother nears her delivery date. Paramount to these changes is a significant enrichment of L. johnsonii, raising speculation that this species represents a key human-associated organism that influences gut microbiome composition in early infancy in a manner that may protect against childhood allergic disease development.

Microbiome Manipulation and Disease Treatment

Gut microbiome manipulation has become a hot topic, particularly following the success of fecal microbiota transplant (FMT) to treat persistent Clostridium difficile infection. C. difficile infection can lead to severe diarrhea and pseudomembranous

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colitis; infection and morbidity rates are on the rise and are associated with antibiotic exposure. This is particularly pertinent given the emerging data on gut microbiome decimation following antimicrobial administration, a scenario in which opportunistic pathogens like C. difficile can rapidly increase in number. While conventional antibiotic treatments for C. difficile are frequently initially efficacious, reoccurring infection rates are high and typically resistant to conventional antibiotics, thus necessitating alternative treatments. FMT involves introducing a fecal slurry from a healthy individual into the GI tract of a patient via colonoscope, enema, or nasogastric tube/gastroscope. The donor is often someone the individual with the infection cohabitates with and the hypothesis is that introducing a diversity of microorganisms from this healthy donor leads to restoration of the patient’s microbiome, which results in outcompetition of the pathogenic Clostridium species. Studies have shown that FMT for C. difficile is highly effective, with cure rates greater than 90 percent, indicating that gut microbiome manipulation is a feasible therapeutic approach for this indication. However, FMT treatment of other chronic inflammatory diseases that are also characterized by a loss of gut microbial diversity, such as ulcerative colitis and Crohn’s disease, has been less successful. This indicates that a more precise understanding of microbial community-derived pathogenesis and host immune response is necessary before gut microbiome manipulation becomes a mainstream therapeutic for other chronic inflammatory and autoimmune diseases.

Beneficial Microbiome Function

Human microbiome research has, until recently, focused predominantly on describing differences in community composition in states of health and disease.

The next step is to characterize exactly how these changes in community composition impact interactions between microbes and how the resulting altered microbial community functions impact the host.

A recent study that nicely demonstrates this comes from work by Dr. Trompette and colleagues, of the University of Lausanne, who observed that mice fed a high- versus low-fiber diet possess distinct airway and gut microbiomes. When the airways of these animals were challenged with house-dust mite extract, those on the high-fiber diet were less susceptible to developing allergic airway inflammation. The gut microbiome of mice fed a high-fiber diet were enriched for two bacterial families, the Bacteroidaceae and Bifidobacteriaceae, both of which are capable of metabolizing insoluble fiber into short-chain fatty acids (SCFA). Indeed, these animals exhibited an increase in both the production and circulating concentrations of SCFAs. Based on these findings, the researchers hypothesized that an increase in dietary fiber was protective against allergic airway inflammation due to the increase in circulating SCFA and so treated mice with the SCFA propionate. Treatment with propionate led again to a decreased susceptibility to allergic airway inflammation and led the authors to consider how propionate treatment affects immune cells and immune responses. They focused on WWW.SFMS.ORG

dendritic cells due to the important role these cells play in allergic airway inflammation, and they found that SCFA treatment increased production of dendritic cell precursors, which resulted in lung dendritic cells that were less effective at reactivating allergic (Th2) responses.

Understanding Microbial Ecology

Given the emerging data in the rapidly evolving field of human microbiome research, the importance of considering the microbial community in addition to human cells when treating disease is becoming abundantly clear. As has been observed for centuries in macro-ecological systems such as grasslands or forests, the human microbial ecosystem conforms to the established rules of ecology, with evidence for succession (changes in the microbial community structure over time), disturbance (e.g., exposure to antibiotics or dietary components that strongly select for the growth of specific species), and dispersal emerging from a variety of studies of various human populations across the globe. Fortunately, environmental (microbial) ecologists have developed a framework for the appropriate study of ecosystems and well-supported theories on how these bionetworks function, which are fully applicable to study of the human biome. Continued research within this established framework may lead to transformative insights into how the human superorganism functions and more effective ways of treating diseases, particularly those that have already been characterized by perturbation of our communities of microbial inhabitants. Susan Lynch, PhD, received her undergraduate and graduate degrees in microbiology from University College Dublin, Ireland, before performing her postdoctoral research as a dean’s fellow at the Department of Microbiology and Immunology at Stanford University in the laboratory of Dr. A.C. Matin. She is currently an associate professor of medicine in the Division of Gastroenterology at UCSF, where she also directs the Colitis and Crohn’s Disease Microbiome Research Core. Dr. Lynch’s research program focuses primarily on human microbial ecology and how the composition and function of both respiratory and gastrointestinal microbiomes contribute to a range of chronic inflammatory diseases and disorders. Ariane Panzer joined Dr. Lynch’s research group at UCSF in 2013. She is currently leading the animal component of a larger translational study examining how bacterial supplementation during a critical period of microbiome assembly impacts the composition and function of developing gut microbial communities in an infant population at high risk for asthma. She is also investigating the capacity of the human microbiome to serve as a prognostic tool for critically ill patients. She plans to attend graduate school and work toward a PhD in the biomedical sciences.

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The Microbiome and Health

NIH HUMAN MICROBIOME PROJECT Endless Implications for Human Health and Disease Erica Goode, MD The Human Genome Project (HGP) was the massive, ten-year precursor to the Human Microbiome Project (HMP). Developed and coordinated by the National

Human Genome Research Institute (NHGRI) and completed in 2003, it sequenced and mapped the genome of Homo sapiens. The next step was clear: We needed to know much more about our microbiota, since the Genome Project demonstrated that our personal genome encodes only an insultingly low 20,000 proteins, on the order of the fruit fly genome. However, humans provide a scaffold upon which our microbes build complex ecosystems; by adulthood, each of us carries about three pounds of microbes, hence many more microbial genes than our own. Bacterial proliferation grows to about 100 trillion in the distal ileum and colon alone. Researchers worldwide were already studying the intricate, metabolic processes of identifiable, beneficial gut microbes, an example being gut bacterial production of significant vitamin K2, which, when absorbed, assists in circulating osteocalcin in bone uptake of calcium and possibly also deterring calcium deposits in arterial plaque. This immediately leads to a question: When we prescribe a broad-spectrum antibiotic, are we destroying the equivalent of Ukraine, known as the breadbasket of Europe? The hope is that, once we know more, we’ll be able to tailor treatments more precisely. Then there are myriad environmental forces; unfamiliar dietary substances (trans fats, manufactured colors, flavorings); plus toxins, inert materials (propylene glycol), personal behaviors. . . . What do all these do to alter our friendly bacterial coat? The NIH HMP, and thousands of research projects being channeled to its database, will catalogue and begin to answer many such questions critical to human health and disease.

Phase I: Analytic Development, Data Analysis, Access

The preliminary plans and early goals for the Human Microbiome Project (HMP) began in 2007 as a five-year project. Phase I charged five academic centers with developing a reference catalogue of human microbial DNA, beginning with a large cross-section of healthy adult human subjects volunteering for sequencing studies and clarification of their own genome patterns and those of their microbiota. Initial data was to include 600, and eventually 1,000, bacterial genomes. Since only a fraction of these were previously cultured and identified, most of the genomes were those only identifiable by 16S rRNA gene sequences, including several nonbacterial microbes.1 The next goal was to characterize the complexity of microbial communities at individual bodily sites, to see if a “usual core” microbial array existed specific to site. These included the 26

gut, female tracts (vaginal and urogenital), mouth, nasopharynx, and skin (http://www.hmpdacc.org). In this initial phase, the NIH NHGRI project team, with an advisory group from twenty-two NIH Institutes and Centers, provided $8.2 million to four DNA sequencing centers: Baylor College of Medicine, Houston; Broad Institute of MIT and Harvard University; Craig Venter Institute, Rockville, Maryland; and the University of Washington, St. Louis. These centers were charged with characterizing core human niche microbiomes, discovering how they were acquired and preserved, and what disruptors could alter this balance. They were also asked to determine persistence of these colonies over time. Are constellations from postauricular skin similar to those on the abdomen? Are the gut microbes of mothers and their children similar? What might be comparable between mouth and gut microbes? How does the microbiome function in those areas, and why? What new techniques are needed to refine microbe genomic data beyond that of known, cultured microbes? What was the relative concentration of specific species of bacteria, viruses, fungi, parasites? How does this seething, metabolically active mass contribute to or detract from our host energy supply and health? What evolutionary means have provided this homeostatic control by our relatively benign microbiota, with commensals and symbiotics coexisting in a stable pattern? The HMP program’s Working Group has developed a common set of sampling and sequencing protocols, rigorous standards, and quality-control guidelines to ensure that data from the various centers and sequencing platforms are reliable and comparable. This is then provided to the Institute for Genome Sciences (IGS) at the University of Maryland School of Medicine, Baltimore, to establish and maintain a Data Analysis and Coordination Center (DACC) to track, gather, store, and distribute data (hmp.dacc.org). Various legal, ethical and social safeguards have been embedded into the Project’s methods, to insure safeguards for human subjects.1

Phase II: Assessing the Microbiota’s Functions and Impacts on Health

Phase II, funded through 2015, includes hundreds of demonstration projects conducted by researchers in the U.S., Canada, Europe, and Asia, designed to clarify the patterns of microbiota seen in various disease states, as well as how they differ in prominence and function from what is shown to be a “normal” complement of bacterial, viral, and fungal microbes. Research centers worldwide are working on specific projects, many relating to the gastrointestinal tract. Remarkable changes in our thinking are the result, one example being work done at Caltech by June

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Round and Sarkis Mazmanian, relating to the abundant immune system operating at brush border, in the appendix, and in Peyer’s patches in the gut.2 Prior to their work, it seemed logical that immune globulin surveillance would vanquish any bacteria capable of disrupting or “messaging” the host immune system, in view of lumen integrity. However, knowing that host and gut microbes usually coexist, despite information being provided to the gut immune system, their work demonstrates that benevolent, symbiotic, and commensal bacteria have evolved, along with our immune surveillance system, to coexist. Especially in early childhood, gut bacteria are influencing the development of an adaptive immunity, while the immune system feedback is altering GI microbiota. As with host cell function, gut microbes create both pro- and anti-inflammatory activity in the course of their normal metabolism, which in turn helps regulate the immune system. Since gut microbes are by far the predominant group among one’s total microbiota, and especially with the active conjoint alteration of host immunity and intestinal microbe community composition, many studies focus on that organ.

Early Microbiome Studies with Health Implications

An example of work with the youngest of subjects: About 10 percent of premature infants in NICU settings are prime candidates for developing necrotizing enterocolitis, which kills up to 30 percent of this group if not addressed early. What, if anything, can we do to alter an infant’s biofilm acquisition and microbiome to provide better defense against this deadly process? One study is currently determining whether alleles in the infant lend susceptibility, whether age at delivery worsens mortality rate, whether composition of microbe biomass is different among babies who succumb versus survivors. Probiotic mixtures have been provided in prior studies, but composition has varied and optimal mixtures have yet to be determined.5 It is unknown what harm befalls us with vast changes in gut microbiota, through diarrhea from infection or through use of antibiotics or chemotherapy. We don’t know whether a healthy, intact appendix provides added protection, since its contents are largely unavailable to the normal gut but may well repopulate a gut presented with a devastating infectious diarrhea, for example. Obesity, and the many approaches being made by “experts” to assail this health issue, is critical. Studies being funded by the HMP are yielding a number of intriguing possibilities. One such study, using adolescent and adult monozygotic and dizygotic twin subjects and a highly amplified means of determining microbe gene sequences, demonstrates a very different gut microbe pattern in the obese twins, whether mono- or dizygotic.6 Analysis of 16S rRNA datasets from three PCR-based methods, plus shotgun sequencing of community DNA, showed obese subjects to have a lower ratio of Bacteroidetes relative to Actinobacteria, with Firmicutes remaining similar to normal ratios seen in lean subjects. The microbiome in the obese subject is also less diverse than in lean individuals. Research into the effects of infant feeding on the microbiome could potentially also provide critical breakthroughs in the study of obesity. This requires focused studies of the microbiome in developing infants receiving bottle versus breast milk. Without the oligosaccharides and small numbers of normal bacteria in the mother’s milk, and the change in her milk composition as WWW.SFMS.ORG

the nursing infant grows, development of a healthy gut biofilm and microbiome will be different in the formula-fed infant. This may well relate to a known tendency toward overweight among adults who were bottle fed as infants.7 More work needs to be done regarding human genetic alleles associated with familial obesity versus tempering contributions via the microbiota in that individual. We know that gut microbe profiles normalize toward a lean individual’s pattern, with significant weight loss toward the norm, whether in response to a regular program of diet and exercise or bariatric surgery.8 An example of this change was shown in a study of gut microbiota following Roux-en-Y gastric bypass surgery. The research examined changes in gut flora and associated changes in gene expression in white adipose tissue, and it showed that the predicted weight loss was associated with both the richness of gut microbiota (including a rise in Proteobacteria) and with altered WAT gene expression.9 However, the ratios of Bacteriodetes and Firmicutes (specifically Bacteroides thetaiotaomicron and Eubacterium rectale), and possibly Actinobacteria, that colonize the gut are relatively equal, with an abundance of dietary carbohydrate as substrate. However, with a shift to less dietary carbohydrate, changes in luminal metabolism occurs, leading to more selected amino acids and sugar transport enzymes, and possibly shifting toward less nutrient being delivered to the host.10 In contrast, the altered Bacteriodetes and Firmicute ratio in obesity leads to changes in microbe fermentation patterns that can explain weight gain. Metagenomic studies are showing that the human gut microbiome can indeed ferment indigestible carbohydrates to short-chain fatty acids, thus producing excess caloric energy that contributes to the obese phenotype.11 Overall, the current conception of the relative influence of any array of microbes, set against multiple shifting conditions in the gut, is staggeringly complicated. To summarize for now, as Peter Turnbaugh (of Washington University, St. Louis, Center for Genome Sciences) states, “Perhaps the genes supplied by our microbes are part of what make us human.” Clearly, the genomes of our resident microbiome provide traits never found in human genomes. We have begun to meet our microbiota, and it is us. We are on the threshold of vast new knowledge, hidden until we had the tools to find it. Erica Goode, MD, MPH, is board-certified in internal medicine. She practices general medicine with an emphasis on nutrition and is deeply interested in the potential for enhancing health through rediscovery of simple complementary principles. Dr. Goode holds a medical degree from the UCSF, where she currently maintains an Associate Clinical Professorship and her Masters in Public Health Nutrition from UC Berkeley. Before getting her medical degree, she worked as a public-health nutritionist for years and wrote a weekly nutrition column for the Washington Post. Among other professional activities, she is a member of the Ethics Committee at CPMC and frequently lectures on eating disorders, cancer and nutrition, health care reform, and other topics. Dr. Goode is a longtime member of the SFMS and of the San Francisco Medicine editorial board. A full list of references is available online at www.sfms.org. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

PRE- AND PROBIOTIC FOODS Eating for a Healthy Gut Jo Ann T. Hattner, MPH, RDN, and Susan Anderes, MLIS We now know that humans are primarily made up of microbial cells, predominantly bacteria, with the most abundant population residing in our gut. Through multifaceted mechanisms, these bacteria protect us by preventing infection and enhancing immunity. That makes gut health very relevant to overall health. Justin Sonnenberg, a microbiologist at Stanford University, suggests that we look at the human body as “an elaborate vessel optimized for the growth and spread of our microbial inhabitants.”1 These microbial inhabitants in the human gut need attention and care.

Physicians have the opportunity to encourage patients to nurture their gut microbiota by eating a diet rich in probiotics and prebiotics. The probiotics add live, active, healthful bacteria, while prebiotic fermentable fibers feed beneficial gut bacteria, providing fuel and nutrients.

Probiotics

In 2002 the World Health Organization defined probiotics as “Live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host.”2 We know that microorganisms meet probiotic criteria when they are not harmful (pathogenic), remain viable during processing and shelf life, survive digestion, are able to bring about a response in the gut, and are associated with health benefits.3 Humans have the opportunity to support a large, diverse gut ecosystem, for their better health, with what they eat.

Food Sources of probiotics

The best sources of probiotics are yogurt and kefir. There are alternative food sources for patients who cannot tolerate milk products. Yogurt is made by fermenting dairy milk with live active cultures of Lactobacillus bulgaricus (Lb) and Streptococcus thermophilus (St). According to Bruce German of U.C. Davis, “Yogurt is perhaps the most complex and biologically active of all foods in the market-

place.. . . . In traditional yogurt, the mixed culture system of Lactobacillus and Streptococcus delivers a remarkable combination of enzymes and metabolites that enhance safety, nourishment, taste, and flavor.”4 Yogurt improves gut health by providing a safe food with proteins and lipids in an absorbable form with a reduced amount of lactose. The active bacteria Lb and St provide lactase enzyme for lactose digestion, so lactose-intolerant people can usually tolerate yogurt. Greek yogurt is traditionally made with goats’ milk and is filtered, producing yogurt with a thicker consistency and with higher solids. In the U.S., it is made primarily from cows’ milk and with a variety of processes including the traditional method. When milk protein solids are added, it is a “Greek-style” yogurt. Consumers have readily switched from traditional yogurt to Greek, likely because of the higher protein content claims and for the creamy consistency. Kefir is a fermented milk drink made with traditional cultures. Commercial kefir has been studied for its positive effects on gut health, including improved lactose digestion.5 Kefir’s use for centuries in Europe adds to its credibility, and many people prefer it over yogurt. Physicians can recommend that patients try various yogurts and kefirs, beginning with the plain and adding their own moderate amounts of juice, fruit, or honey. Another dairy food is the non-yogurt probiotic drink Yakult, which contains L. casei Shirota, which has been extensively studied with demonstrated benefits. Patients who relate they do not eat dairy due to “lactose intolerance” may well be able to eat small amounts of yogurt or kefir without symptoms. Physicians can advise small tastes with advancement as tolerated. For true cows’ milk allergy and for a vegetarian alternative, soybased yogurts are a good choice. Studies have demonstrated that soy in yogurt is a good substrate for probiotic bacteria.6 An example of another nondairy food is GoodBelly™, a fruit juice drink that contains probiotic bacteria, and is soy free. Almond, coconut, and ricebased “yogurts” may also be found in the refrigerator case at some grocery stores; however, these are far removed from the traditional mammalian yogurts. They do, however, contain the starter cultures Lb and St and are enhanced with other probiotic cultures.

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Health Benefits of Probiotics The health benefits of probiotics include maintenance and restoration of the GI barrier function, support of the immune system, reduction of constipation and diarrhea, improvement of digestion and availability of nutrients, and reduction of microbial pathogens and toxic substances.3

Prebiotics

Prebiotics are nondigestible, fermentable carbohydrates that stimulate and promote activity of beneficial gut bacteria. Prebiotics are the booster substance for probiotics. A natural example of this is found in human milk. Human milk contains small oligosaccharides that are undigestible by newborns. The role of these oligosaccharides in human milk was not at first understood and, in fact, researchers questioned why human milk would contain components unusable by the newborn infant. Researchers provided the explanation when they found that these small oligosaccharides were fueling beneficial bifidobacteria found in the newborn’s gut. The prebiotic oligosaccharides in human milk are specific to human milk. However, this model has provided interest among food scientists in adding oligosaccharides to foods and beverages—one example is infant formula—to enhance the growth of beneficial bifidobacteria.

Prebiotic Approach

The prebiotic approach uses whole foods with these nondigestible carbohydrates to stimulate growth and promote activity in beneficial bacteria, especially bifidobacteria. As the beneficial gut microbes increase in number, pathogenic bacteria such as Salmonella, Campylobacter, and E. coli decrease. Ingesting prebiotics is a practical way of manipulating the microbiota, since they support and increase the beneficial bacteria population in the gut. Together, probiotics and prebiotics are an important duo. In addition, prebiotic fibers are components of the healthiest foods on the planet—natural plant foods.

Food Sources

Food analysis research continues to appear in the literature, focusing on food composition, especially on fermentable fibers. However, many scientists consider the true test for a prebiotic food or ingredient to be, “Does it have a prebiotic effect when fed to humans?” Studies in rats precede human studies, and there have been a few human trials. Trials continue to emerge, often funded by food commodity groups. Recent human studies of individual foods include wild blueberries, kiwifruit, almonds, and green tea, all of which exhibited prebiotic activity. Analyses of foods continue; for example, the California Raisin Marketing Board analyzed raisins. On the horizon are analyses of oat, corn, and other grains. This listing of whole-plant food sources that contain prebiotic fiber is a valuable resource.

Benefits of Fermentation

When the nondigestible carbohydrates in the prebiotic plant foods reach the lower bowel, the gut microbes go into action. This process, which results in the production of acids and gases, is fermentation. The benefits of fermentation include acids decreasing the pH level of the colon, which is detrimental to the survival of pathogenic bacteria; short-chain fatty acid production, which proWWW.SFMS.ORG

vides fuel for the beneficial bacteria; enhanced mineral absorption, especially calcium and magnesium; and enhanced immunity.3

Eating for Gut Health

How should physicians advise their patients on how often to eat probiotic and prebiotic foods? Patients can be directed to eat probiotic foods every few days to replenish the gut microbiota. Presently it is thought that probiotics do not take up permanent residence; rather, they do their job while in the gut and then pass out in the stool. Physicians may counsel patients to eat prebiotic foods every day to feed and support healthy gut microbes. When introducing new whole plant foods to their diet, patients should eat them in small servings and increase as tolerated. Two diets that emphasize prebiotic foods, which physicians can recommend to patients, are the DASH diet and the Mediterranean diet, as both encourage numerous servings of vegetables and fruits. Physicians might suggest to patients that they use yogurt or kefir as the dairy choices in these diets to provide probiotic foods.

Key Message

“The health of the gut is enhanced with a diet rich in pre- and probiotics.” Physicians can use this message with patients and follow up by asking, “What new pre- and probiotic foods are you eating?” Over time, patients will exhibit changes in their eating patterns, accompanied by improved gut health. Jo Ann Hattner and Susan Anderes have been working together since 1999 on Stanford Medical School’s online nutrition courses— Jo Ann as a content writer and Susan as the webmaster and medical librarian. They collaborated on writing Gut Insight (published in 2009) and updating Help! My Underwear Is Shrinking (second edition released in 2013), and they continue to work together on numerous professional presentations and papers. A full list of references is available online at www.sfms.org.

Prebiotic Foods Fruits

apple, banana,* berries, raisins, wild blueberries, kiwifruit, agave

Vegetables

Onion,* garlic,* leeks,* shallot,* Jerusalem artichoke,* globe artichoke,* asparagus,* chicory root,* burdock,* yacon,* jicama, tomato, mushrooms, greens: dandelion,* salsify,* spinach, collard, chard, kale, mustard

Legumes or pulses lentils, dry beans, chickpeas, peas Whole grains

Seeds and nuts Other foods

whole wheat,* barley,* rye,* oats, brown rice, corn, buckwheat flaxseed, almonds honey, green tea

*Foods documented in the scientific literature as containing nondigestible, fermentable carbohydrates. The other foods listed have been analyzed for content or studied in vitro or in vivo in humans or animals.7-9 Prebiotic food references can be found at www.gutinsight.com.

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The Microbiome and Health

WHY THE MICROBIOME MATTERS One Primary Care Physician’s Journey toward Understanding Payal Bhandari, MD When I first began practicing family medicine, I was surprised by allopathic medicine’s implied belief that most ailments may simply represent isolated random occurrences. With experience, I have learned that in many cas-

es illness develops as the consequence of collective factors over a period of time. The good news is that many of these factors can be influenced such that a disease may be prevented or treated by simple measures. In my quest to discover the underlying causes of patients’ conditions, I have realized that the answer is often not initially obvious . . . that is, until I dig deeper.

How to Identify and Treat the Root Cause of Illnesses

The root cause can be identified by addressing the following factors: Take time to attentively listen to patients. Try to understand their physical complaints, medical history, medications taken, and stressors. Review the patient’s previous labs. Rule out the obvious, such as medications, which can lead to poor gut digestion. Ask about the patient’s daily schedule, including their sleep, work/school, exercise, and eating schedule; what they eat, and how rushed they feel when eating. By trying to characterize the whole person, I realized a large percentage of patients’ aliments stem from either inflammation and/or nutrient deficiencies. For example, asthma and allergies are directly triggered by an immune response to allergens in the environment. Heart disease is now understood to be caused by systemic inflammation. I followed my “gut” instincts to find the link between the immune system creating excess inflammation and the digestive tract causing nutrient deficiencies.

What We Understand about the Gut

The gut houses more than 70 percent of the body’s healthpromoting bacteria, called the microflora. The microflora drives our immune system by regulating its response—particularly inflammation. Inflammation serves a protective role in responding to tissue injury or infection.1 Digestion begins from the moment food touches the mouth. Thirty percent of protein is digested in the mouth, where key enzymes are released from the salivary glands. The digestive tract’s motility and blood supply directly impact the production of gut enzymes. These enzymes help break down food and assimilate essential nutrients. For example, the enzyme gastrin produces acid in the stomach. A sufficient amount of stomach acid is essential for the microflora to absorb essential nutrients such as vitamin B12, iron, folic acid, calcium, magnesium, zinc, and copper. These nutrients nourish all of the body’s cells, including the cells lining the gut wall, the microflora, muscles, bones, and reproductive tissue. The gut is the body’s first line of defense against most pathogens and toxins. Powerful stomach acid destroys most disease-causing microorganisms. Healthy microflora prevent the overgrowth of bacteria, which produce toxic substances in the large bowel.2 30

What Alters the Gut The digestive process is altered by factors such as stress, illness, medications, diet, birth by C-section, and not being breastfed.2 Chronic stress has the most impact, since stress slows down gut motility and its blood supply. Medications such as NSAIDs and steroids decrease the blood flow to the gut and subsequently decrease gastrin production. Antacids and PPIs shut off stomach acid production. Vaginal deliveries and breastfeeding expose babies to healthy flora that boosts their immune system. When stomach pH increases, the gut’s microflora cannot effectively absorb many essential nutrients nor provide sufficient nourishment for enterocytes, the microbiome, and the body’s other cells to effectively regenerate. With enterocytes no longer capable of maintaining an intact gut lining, and an imbalanced healthy gut flora, pathogens and toxins can easily translocate across the gut’s brush border. For example, proteolytic bacteria such as Clostridium difficile are a part of the normal gut flora. C. difficile’s overgrowth produces excess toxic substances such as phenols, indols, and ammonia from the digestion of proteins.4 Chronic overgrowth of proteolytic bacteria produces excess toxic compounds that injure the intestines and create long-term inflammatory changes associated with old age (i.e., heart disease, dementia). Antibiotics kill harmful pathogens and healthy microbes in the gut, causing symptoms such as dyspepsia, bloating, increased flatulence, constipation, and diarrhea. Research shows that it can take up to four years for the microbiome to fully recover after antibiotic treatment.2 Long-term changes to the microbiome can occur when antibiotics are given in utero, in early childhood, with long-term or recurrent use, and through the consumption of antibiotic-fed animal products. A classic example is when a young child is given antibiotics multiple times for recurrent otitis media. As a teen this patient receives long-term antibiotics for acne treatment. The impact of repetitive antibiotic use on the gut’s microflora can often trigger inflammatory bowel disease in this patient as a young adult. Being too clean is also hazardous. Antibacterial soaps contain chemicals such as triclosan, which damage the liver, thyroid gland, and muscles while increasing the risk of bacterial resistance.2 Excessive hand washing and bathing wash away natural oils, leading to dry skin, skin breakdown, and increased risk of developing skin infections. The typical American diet is rich in ready-made, processed foods stripped of nutritious value but full of sugar, salt, and other preservatives. These staples include refined grains, animal protein, soy, potatoes, corn, alcohol, and caffeine. They do not provide the necessary nutrients to drive optimal digestive function and reignite a healthy immune system. Another factor is food sources with suboptimal nutrient value. Fruits and vegetables are often sprayed with toxic pesticides, which hurt reproductive tissue, trigger cancer, and contaminate the envi-

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ronment.6 During the long journey from the field to consumption, produce loses a significant amount of its nutrients.3 Produce is often harvested weeks before it is naturally ripened. A number of studies have demonstrated fruits and vegetables have more concentrated array of vitamins, minerals, and antioxidants when they are allowed to grow to maturity under direct sunlight, without pesticides or manufactured fertilizer exposure. Making healthy dietary choices is not simply a matter of eating more produce. It pays to know more about each plant, from seedling to table, in order to appreciate its nutritional value. The body has the ability to self-heal if it is given the right tools to be nourished. Connecting a person to their body is initially done through food: How we eat is critical to achieving optimal digestive function; what we eat is critical to optimal digestive nourishment.

Be Nourished, Not Just Fed

The first step to increasing the nutritional value of a person’s diet is to consume primarily plant-based foods. Most essential nutrients and prebiotics (the microbiome’s “food”)1 are derived from the colorful array of fruits, dark green leafy vegetables, beets, garlic, scallions, chives, shallots, artichokes, mushrooms, whole grains (i.e., unrefined wheat, brown rice, barley, oats), legumes (i.e., lentils, black beans), plain nuts (i.e., almonds, walnuts), and seeds (i.e., flax, chia). When whole grains and legumes are eaten in the same meal, a complete protein is formed that has the same high-quality protein content as in meat, eggs, and dairy products, but with a significantly higher antioxidant level.7 Patients should decrease the consumption of processed foods, refined sugar and flour, red meat, caffeine, and alcohol. They provide limited nutrition, are empty fillers, and cause big sugar surges that disrupt the microbiome. Advocate for consuming fermented milk products, like active plain yogurt and kefir, which contain live lactic-acid bacteria that lower intestinal pH.1 Patients should consider taking a daily refrigerated probiotic supplement. Probiotics contain live microbiome-derived factors that stimulate the growth of healthy microorganisms.1 Refrigeration allows these factors to be alive when administered. Probiotics have to be supplied in adequate amounts in order to trigger the targeted effect on the host. I usually recommend any one of the following probiotics: Lactobacillus rhamnosus GG 10 billion organisms, Lactobacillus reuteri 100 million organisms, Saccharomyces boulardii 200-250 mg, and/or Bifidobacterium infantis 100 million organisms.2 Teaching patients how to prepare their food is also critical. To allow for the best bioavailability of nutrients, cook the food in a little bit of fat (i.e., olive oil) for a short time on the stove top, steam in the microwave, or slow cook in a crock pot.3 Boiling or deep frying are not recommended. Warm foods and beverages stimulate gut motility and the activation of digestive enzymes.8 On the flip side, cold foods and beverages slow down this digestive process, causing delayed recognition of satiation. This is the reason many restaurants set the thermostat low and provide ice-cold water. I have had great success in eliminating patient symptoms such as constipation, bloating, or poor morning appetite by slightly altering their diet. For example, one minor but effective change is limiting dry, raw, and cold foods, such as a large dinner salad, in the evening since these foods are slowly digested overnight. Instead, have warm, cooked meals such as vegetable stir-fry or lentil soup for dinner. Lightly cooked small evening meals will be more easily digested, allowing for better sleep WWW.SFMS.ORG

and enhanced energy the next morning. Last, teach patients how to consume the best-quality food. Shopping for organic produce is essential to limiting consumption of toxic pesticides. Produce sold at a farmer’s market has been harvested when it is ripe. Since this produce is exposed to the sun longer than produce sold at the grocery store, more nutrients will be available on and just under the skin.7 Understanding how to store and cook food is key to preserving the flavor and gaining the most nutritional value. For example, storing fresh tomatoes at room temperature preserves their flavor. Cooking tomatoes for 30 minutes allows for more bioavailability of vitamin C, glutamate, and lycopene.3

Decreasing Stressful Eating Habits

Identifying stressful eating patterns (i.e., irregular eating schedules, disproportionate meal sizes, chewing too fast, being stressed while eating) is the first critical step to ramping up digestion. The peak of digestion occurs between 10 a.m. to 2 p.m., and 10 p.m. to 2 a.m. I often recommend patients have a regular eating schedule with lunch being the largest meal of the day.8 Food will then be more effectively used for energy. When dinner is a light meal, optimal homeostasis of normal body functions can occur while sleeping. Planning what a person will eat and having healthy food readily available is also critical to decreasing stress. When a person waits to be hungry and then decides to search for food, a stress response is triggered that directly hinders optimal digestion. As gut motility and the activation of digestive enzymes slows down, the satiety signal is delayed. Overeating can often occur, along with decreased motivation to eat nutritiously. The enjoyment of eating without being distracted is critical to optimal digestion. If you chew your food too quickly, overeat, or are stressed, more than thirty percent of digestive enzymes will not be adequately activated. Patients can feel lighter and more energetic while lessening issues like heartburn and irritable bowel syndrome by having a regular eating schedule of smaller portions and mindfully consuming mostly nutritious, plant-based meals.

Key Message

By understanding the importance of digestive health, I am able to treat the patient as a whole person. Optimizing patients’ gut health can be done by embracing other key environmental factors (i.e., stress, sleep, eating habits, nutrition). When our diets consist primarily of wholesome, plant-based foods, our body will receive sufficient nourishment to jump-start and rebalance our internal regulatory systems. We may feel full longer, be more satisfied, and have more energy. As a person makes the connection between how their diet directly impacts their well-being, they become more empowered and motivated to address other stressors within their lives. Payal Bhandari, MD, is a solo family physician at Advanced Health and a member of the SFMS. A graduate of the University of Massachusetts Family Practice residency, Dr. Bhandari has been practicing in San Francisco since 2005. Her practice is focused on addressing the root cause of illnesses by mixing the latest research in evidence-based medicine with integrative holistic care. She cares for all ages, with a focus on the whole person, especially through nutrition, sleep, mental, and other lifestyle stressors, to help patients return back to wellness. A full list of references is available online at www.sfms.org. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

INFANT GUT MICROBIOME Factors That Affect Development Potential and Long-Term Health Yana Emmy Hoy-Schulz, PhD, MS Moms and dads try to make sure that infants have the healthiest possible start through prenatal care, proper vaccinations, and a nutritious diet. Experts recommend

the position an infant should sleep in, when to give solid food, and which foods to give. Health care providers measure and track infant growth, reflexes, sensory perception, movement, and development. But there is one factor critical for healthy growth and development that for many years has been overlooked: the microbiota. This consortium of bacteria that live on or in the human body has been called the “organ within an organ” because of the numerous functions it provides. Yet only recently have we begun to explore how the microbiota is acquired, how it develops over time, and the implications it may have on health. The gut microbiota is known to play a number of important roles, including aiding digestion and producing amino acids and vitamins, providing resistance to pathogens, and stimulating development of the gut and immune system. Studies using animals living in sterile environments that have no bacteria have shown that the presence of microbiota is essential for proper development of gut structure and function and development of gut-associated lymphoid tissues (GALT) formation. Dysbiosis of the microbiota has been associated with inflammatory bowel disease, antibiotic-associated diarrhea, Clostridium difficile infection, gallstones, liver disease, allergy, type I diabetes, autism, and cancer. However, little is known about how the composition of the microbiota affects infant growth and development.

Birth and Before

Dogma has long held that infants begin to acquire their microbiota at birth, based on the presupposition that the fetus is sterile in utero. However, recent studies have found bacteria in amniotic fluid, umbilical cord blood, and fetal tissues from full-term healthy pregnancies with no evidence of infection. In addition, the meconium is not sterile, supporting findings that there may be uterine microorganisms that contribute to the initial infant microbiota. One study using mice found that labeled bacteria could be detected from the meconium of pups whose mothers were fed the labeled bacteria, but not of control pups whose mothers were not fed the bacteria.1 While the mechanisms of this transmission have not yet been elucidated, other studies support the idea that maternal transmission of bacteria to the fetus can occur. 32

At the time of birth, the neonate is exposed to a multitude of bacteria that continue to colonize the infant. However, not all infants are exposed to and colonized by the same bacteria. Neonates who were born via vaginal delivery have gut microbiota that closely resembles that of their own mother’s vaginal microbial community, whereas those born by cesarean section have gut microbiota that resembles the microbiota of the skin. In addition, colonization by several prominent bacterial groups is delayed in cesarean section babies. The long-term consequences of the early composition of the microbiota are not clear. Epidemiological data has shown that children born via cesarean section are more likely to develop a number of immune-mediated or inflammatory diseases, such as asthma, type I diabetes, allergic rhinitis, and inflammatory bowel disease. Some investigators speculate that altered microbiota leads to suboptimal training and regulation of the developing immune system, which could in turn contribute to such conditions.

Factors in Infancy

Diet also influences the composition of the infant gut microbiota. Breast milk—which harbors bacteria—and the skin microbiota of the nipple and breast transfer organisms to the infant. The specific composition of breast milk has been suggested to promote the growth of vaginally acquired lactic-acid producing bacteria in the infant gut. Studies have found higher levels of “healthy” bacteria—Bifidobacteria and Lactobacillus—and fewer “unhealthy” bacteria—Enterobacteriaceae—in breast-fed infants compared to formula-fed infants. Some epidemiological studies have found that breast-feeding decreases the risk of obesity later in life, with longer duration of breast-feeding providing larger reduction of risk. Different microbial communities can have different energy harvest efficiencies and can modify metabolism, making it possible that microbial acquisition early in life contributes to future risk of obesity. Antibiotics are another factor that has a significant effect on the composition of the microbiota. In infants, antibiotics have been shown to reduce the numbers of Bifidobacteria and Lactobacillus for up to one month post-administration and to reduce the number of different species of these groups and the overall diversity for at least two months.2 These prolonged effects suggest that antibiotics disrupt the development of the microbiota. The impact of antibiotics during infancy on the composition of the adult microbiota has not yet been determined.

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As the diversity of our microbial communities has only recently been explored, the relationship between early microbial community composition and infant development is unknown. Factors early in life that affect the composition of the microbiota, such as delivery mode, feeding practices, and the use of antibiotics, may have long-term health effects. This begs the question of what impact the increasing rates of cesarean sections and antibiotic use in infants are having on our health as a society and what can be done about it. Nearly a third of all births in the United States are via cesarean section. Children have the highest rates of antibiotic use, and the use of broad-spectrum antibiotics, which can impact numerous commensal bacteria in addition to the intended target, is increasing. Between 2000 and 2010 the rate of broad-spectrum antibiotic prescriptions doubled. Reducing the rates of unnecessary cesarean sections and antibiotic administration and administering narrow-spectrum antibiotics rather than broad-spectrum antibiotics may help prevent disruptions to the developing microbiota. But what about situations where there is no alternative? Is there a way to redirect the microbiota?

Probiotics

Probiotics—defined by the WHO as “live microorganisms which, when administered in adequate amounts, confer a health benefit to the host”—are one option to alter the microbiota. Probiotics have become increasingly popular in recent years and are being studied for a number of indications. Through animal models, certain strains of probiotics have been shown to have antagonistic effects against pathogens and to have immunomodulatory effects. Clinical trials are studying the effects of probiotics on a diverse number of conditions, including gastrointestinal diseases such as diarrhea (acute, persistent, and antibiotic-associated), Crohn’s disease, inflammatory bowel syndrome, irritable bowel syndrome, lactose intolerance, Clostridium difficile infection, and colitis; allergies, ectopic dermatitis, and eczema; respiratory infections; weight gain; cholesterol levels; colon cancer; and dental caries. Research suggests that in healthy adults, probiotics do not achieve long-term colonization, potentially due to the presence of an intact and diverse microbial community occupying nutritional and geographic niches in the gastrointestinal tract. As a result, daily or alternate-daily dosing is required to achieve consistent levels of probiotics in the gut. However, in infants it has not yet been determined whether long-term colonization can be achieved in the absence of ongoing probiotic administration. Since the microbiota of infants is not yet fully established, it may be more amenable to colonization by administered probiotics. Infants who have missed opportunities for maternal transfer of the microbiota or have had disruptions in the development of the microbiota stand to benefit most from probiotics if this is in fact the case. One study that found that infants born by cesarean section were more likely to develop asthma or allergies than vaginally born infants also found that administration of probiotics reduced the incidence of allergy in caesarian but not vaginally delivered infants.3 This suggests that the use of targeted probiotic administration in infants may be able to modify disrupted microbial communities to more healthy states and improve long-term health. As we learn more about the microbiota and the myriad of WWW.SFMS.ORG

functions it provides and the factors that can alter it, the impact of interventions that affect it should be considered when determining treatment strategies. Only recently has in-depth study of the microbiota been possible, and the effect of the composition of the microbiota early in life on long-term health and development is not yet fully understood. We should value our genetically microbial organ and find ways to protect and promote the development of the microbiota as we do our genetically human organs. Yana Emmy Hoy-Schulz, PhD, MS, is a postdoctoral fellow in the lab of Dr. Julie Parsonnet in the Department of Medicine, Division of Infectious Diseases at Stanford University. Dr. Hoy-Schulz is a graduate of Yale College and Stanford University School of Medicine. She has studied the effects of infection on the microbiota and is currently collaborating with the International Center for Diarrheal Disease Research, Bangladesh, on a clinical trial of probiotics in infants.

References: 1. Jimenez E et al. Is meconium from healthy newborns actually sterile? Res Microbiol. 2008. 159:187–193. 2. Fouhy F et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Chemother. 2012. 56:5811-5820. 3. Kuitunen M et al. Probiotics prevent IgE-associated allergy until age 5 years in Cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol. 2009. 123:335–341.

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SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

MICROBES OF THE SKIN The Barrier that can Promote Immunity or Fight Invaders Jef Akst The microbial communities that inhabit the skin are perhaps the most diverse of the human body, and they are suspected to be key players in host defense. New

evidence suggests that commensal skin bacteria both directly protect humans from pathogenic invaders and help the immune system maintain that delicate balance between effective protection and damaging inflammation. While causal links between the skin’s commensal microbes and health or disease remain to be demonstrated, the clues that have accumulated in the last few years paint a suggestive picture. “None of us in the field—and this is true for the gut, this is true for the skin—none of us can actually tell how our experimental observations really relate to human disease, but we’re getting, all of us, closer to mechanistic insights,” said immunologist Yasmine Belkaid, chief of mucosal immunology at the National Institute of Allergy and Infectious Disease (NIAID). Recent research has begun to document how skin commensals interact with one another, with pathogenic microbes, and with human cells. Staphylococcus epidermidis secrete antimicrobial substances that help fight pathogenic invaders, and Propionibacteriumacnes use the skin’s lipids to generate short-chain fatty acids that can also ward off microbial threats. Meanwhile, these and other skin microbes may be able to alter the behavior human immune cells and impact the local molecular environment. “The field is exploding in terms of the types of observations that have been made,” said Richard Gallo, chief of dermatology at the University of California, San Diego, School of Medicine, “and they’re reaching into every aspect of immunology.”

Intimate Exposure

toes are frequented by Corynebacterium. And the dry sites of the body, the broad flat surfaces of skin like the forearm or leg, which are exposed to different environments, are home to Staphylococcus species, in particular S. epidermidis. These areas are also home to the skin’s most diverse microbial communities, likely due to their relatively high exposure to the environment. In addition to the diversity in the skin’s microbial composition across the body, different layers of skin appear to harbor distinct communities. In 2012, skin biologist Patrick Zeeuwen of Radboud University Medical Center in Nijmegen, the Netherlands, and his colleagues conducted a tape-stripping experiment in which volunteers used an adhesive to peel back layers of their stratum corneum—the outermost layer of epidermis. Sampling the microbiome at each level, the researchers found that bacteria are not uniformly distributed, and that even the deepest layers of dead tissue harbor a microbial community. Human skin is also home to a handful of fungal species, most notably of the genus Malassezia. In a 2013 Nature study, National Cancer Institute dermatologist Heidi Kong and her colleagues sequenced the fungal microbiomes of fourteen different sites on the skin of ten healthy adults, finding that all areas except for the foot were dominated by the Malassezia. For reasons that are still unclear, the heel, toenail, and toe web harbored much more fungal diversity. The question skin microbiome researchers are now trying to address is the function of these microscopic stowaways. “Particularly for skin, we are only just now understanding who is there,” said Kong. “The next, much more complex, part of this is what are they doing there and how are we responding to them.”

The skin is characterized by a multiplicity of habitats, including invaginations, appendages, and various glands and follicles. Such diversity in environment, not surprisingly, breeds diversity at the level of the microbiome. Moreover, the skin is in constant contact with the outside world. As a result, the bacterial communities that populate the skin are some of the most varied human microbiomes. “Between humidity and hygiene approaches and clothing and everything else, [the environment that skin microbes are exposed to] has infinitely more variation,” said Gallo. Nevertheless, the skin is not simply ridden with a random suite of bacterial species found in the environment. Surveys of the bacterial communities that live on the skin of healthy adults have revealed three distinct skin microbiomes, each with fairly strong patterns of microbial composition. The oily, or sebaceous, sites of the head, neck, and trunk—where exocrine glands secrete a mixture of lipids called sebum—are dominated by Propionibacterium, including P. acnes, which is associated with blemishes. Moist sites such as the crease of the elbow, below a woman’s breasts, or between the

The influence of the human microbiome on immunity has long been recognized. But how exactly skin commensals interact with invading pathogens and with our immune system is only just being revealed. Recently, molecular microbiologist Gitte Julie Christensen, of Aarhus Universitet in Denmark, and her colleagues found that the P. acnes strains associated with healthy skin carry genes for thiopeptides, antimicrobial compounds that inhibit the growth of gram-positive species. P. acnes associated with acne, on the other hand, don’t appear to produce such compounds. In culture, Christensen said, “We can see that these health-associated strains are much better at killing other bacteria than the other strains. They can kill off Staphylococcus epidermidis, the main competitor on skin.” S. epidermidis itself plays a notable role in host immunity. In 2009, Gallo and colleagues showed that the species secreted lipoteichoic acid (LTA), which prevents inflammatory cytokine release from keratinocytes of human skin. Other bacteria may “help educate the adaptive immune system,” said Gallo, and “in ways that are not

Immune Links

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completely understood, influence the development of T-cells and antigen-presenting cells.” To more fully understand how the skin’s microbial residents influence host immunity, NIAID’s Belkaid turned to germ-free mice. In the summer of 2012, she and colleagues published a Science study demonstrating that the addition of S. epidermidis to the skin of the sterile mice altered T-cell function to boost host immunity. “We were able to show that these microbes were sufficient to make the immune system of the skin capable to control infection,” said Belkaid. The researchers have since found that different microbes affect distinct parts of the immune system. “How the microbes communicate with the immune system is highly specific to each microbe,” said Belkaid. “There are some microbes able to control some aspects of immunity and, on the dark side of that, [there] are microbes that are able to promote inflammation and contribute to pathogenesis.” Indeed, while some microbes are secreting protective antimicrobials, others are inducing the release of cytokines that have been associated with disease. Another hint of the skin microbiome’s involvement in immunity came last October, when Kong and her colleagues found that immunodeficient patients tended to have more permissive skin. That is, people with primary immunodeficiencies harbored more diverse bacterial and fungal communities, including species not normally found on healthy adults. “It’s possible that the focal defects in the immune system allow or permit these otherwise uncommon bacteria and fungi to be present on these patients,” said Kong. As the importance of the skin microbiome in health and disease is further investigated, researchers are also looking into the possibility of manipulating it. Christensen, for example, is collaborating with a local Danish company to develop an ointment to provide the skin with “good” bacteria. “The idea is to put these bacteria in a cream or in a serum and then apply it to your face to reestablish a natural skin community,” she said. While there are now a handful of skin probiotics are on the market, none are regulated by the U.S. Food and Drug Administration as therapeutics and thus cannot make claims about treating or preventing disease. And most scientists will tell you there’s not enough evidence yet to know one way or the other whether such probiotic cosmetics work. But Belkaid and others do see microbiome manipulations as a way of the future. Between changes in lifestyle, diet, hygiene practices, and more, “We have dramatically altered our skin microbiota,” she said. “I think anything we can do to restore more balance or more appropriate microbe composition in the skin, as in all the different tissues, is extremely important.” Gallo agreed. “I think there’s a lot of validity to [the idea of skin probiotics]. Most of the work there just needs a little bit more rigorous proof.” It could be important, he added, given the diversity of the skin’s bacterial communities, for such probiotic approaches to be personalized. “Since we do know for sure that there’s a lot of difference between the microbiome on individual skin, it may not be so simple as bottling one type of microbe in a spray that’s going to help everyone.” The original article was posted on The Scientist website on June 13, 2014 and can be accessed at http://www.the-scientist. com//?articles.view/articleNo/40228/title/Microbes-of-the-Skin/. Reprinted with permission of The Scientist. WWW.SFMS.ORG

Breathing Life into Lung Microbiome Research Rina Shaikh-Lesko If the human digestive tract were a river from the mouth extending through the stomach and intestines, ending at the anus, the lungs would be pools alongside that river that are often swept by eddying currents, according to Gary Huffnagle from the University of Michigan, who began studying the bacterial communities that inhabit these pool-like organs nearly a decade ago. “There’s a constant flow into [the] lungs of aspirated bacteria from the mouth,” he said. But through the action of cilia and the cough reflex, among other things, there’s also an outward flow of microbes, making the lung microbiome a dynamic community. Like the placenta, urethra, and other sites of the body now known to harbor commensal bacteria, researchers and clinicians once considered the lung to be sterile in the absence of infection. Over the last 10 years, however, evidence has been building that, although it is far lesspopulated than the mouth or gut, the disease-free lung, too, is populated by a persistent community of bacteria. Shifts in the lung microbiome have been correlated with the development of chronic lung conditions like cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD), although the relationship between the lung microbiome and disease is complicated. The surface area of the healthy lung is a dynamic environment. The respiratory organ is constantly bombarded by debris and microbes that make their way from the mouth and nose through the trachea. Ciliated cells on branching bronchioles within the lungs beat rhythmically to move debris and invading microbes, while alveolar macrophages constantly patrol for and destroy unwelcome bugs. When researchers first began to study the possibility of a lung microbiome, skeptics abounded. As Leopoldo Segal of the New York University Langone Medical Center started presenting his research at conferences in 2009, “it was not uncommon to have someone stand up and say I was looking for life on the moon,” he recalled. The most common criticism of his and other early studies was that, because the microbes found in the lungs were a subset of those from the mouth, they could simply have been the result of contamination. In the time since, several groups have replicated Segal’s findings that a subset of oral bacteria live in healthy lungs and many researchers now accept the idea of a lungspecific microbiome. The lung microbiome is about 1,000 times less dense than the oral microbiome and about 1 million to 1 billion times sparser than the microbial community of the gut, said Huffnagle. That is in part because the lung lacks the microbe-friendly mucosal lining found in the mouth and gastrointestinal tract, instead harboring a thin layer of much-lessinviting surfactant to keep the respiratory organs from drying out. In a review article published in The Lancet Respiratory Medicine this March, Huffnagle and his colleagues argued that the lungs are like the South Pacific, with small islands of clustered bacteria and wide stretches of unpopulated regions between them. It appears that the lung microbiome is populated from the oral microbiome, and among this population exists a small subset of bacteria that can survive the unique environment of the lung. The most common bacteria found in healthy lungs are Streptococcus, Prevotella, and Veillonella species.

The original article was posted on The Scientist website on June 13, 2014, and can be accessed at http://www.the-scientist.com//?articles. view/articleNo/40162/title/Breathing-Life-into-Lung-MicrobiomeResearch/. Reprinted with permission of The Scientist. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

The Microbiome and Health

RETHINKING STERILE The Hospital Microbiome

When the University of Chicago’s new hospital pavilion opened in February 2013, it looked pristine. Floors shone, and stainless steel gurneys gleamed in the new Center for Care and Discovery. Even after the doors opened and the first patients were admitted, surfaces still looked largely sterile. It was exactly as it seemed a hospital should be—as devoid of microbial life as humans could possibly make it. Jack Gilbert’s data told a different story. Gilbert, an environmental microbiologist at Argonne National Laboratory, and his platoon of graduate students, postdocs, and research assistants descended on the hospital several times each day, even before it opened to the public. Armed with cotton swabs, they focused their efforts on the floors devoted to surgery and oncology. Each team member took samples from floors, beds, linens, sinks, computers, nurses’ stations, air vents, and more. If you could name it, Gilbert’s team rubbed it with a cotton swab to obtain a small sample of the microbes living there. They repeated this process several times a day for more than a year as part of the Hospital Microbiome Project, an $850,000 endeavor funded by the Alfred P. Sloan Foundation to learn more about the microbial community, or microbiome, in various hospital environments—how microorganisms transfer between humans and surfaces and how the microbiomes develop over time. These researchers believe they can potentially reduce hospital-acquired infections by understanding the array of microorganisms that live in hospital environments, identifying the operational characteristics of buildings that influence these microbiomes, and tweaking indoor ecosystems to help prevent the spread of pathogens. “When a pathogen invades, it doesn’t do this in isolation; it does this in the context of thousands of other species,” Gilbert says. “Very few studies have examined the rest of the communities that exist in hospitals.”

Hospital-Acquired Infections

In 2010, 35.1 million Americans spent at least one night in a hospital.1 The Centers for Disease Control and Prevention estimate that 5 percent of patients admitted to hospitals will acquire an infection during their stay, potentially leading to 99,000 deaths annually2 and costing $10 billion per year.3 As long as sick people have sought care in hospitals, there has been the potential for the spread of infectious disease. With the advent of penicillin and other antibiotics, concerns about disease transmission diminished, but the rise of antibiotic-resistant bacteria has changed that thinking. Historically, these infections have been blamed on the presence of harmful bacteria, and increasingly stringent infection-control procedures and standards for sterility have been seen as the solution.5 A new hypothesis says that hospital36

Carrie Arnold

acquired infections are being driven not by the existence of harmful microbes but by the absence of helpful species. Underneath the bright lights and on the stainless-steel gurneys lives a large community of microorganisms, most of which are harmless and some potentially beneficial.6 Hospital microbiomes, some researchers think, form a key part of a hospital’s “immune system” and in some cases may help protect patients against infectious diseases. “For the past 150 years, we’ve been literally trying to just kill bacteria. There is now a multitude of evidence to suggest that this kill-all approach isn’t working,” Gilbert says. “We’re now trying to understand that maybe, just maybe, if we could cultivate nonpathogenic bacteria on hospital surfaces, then we could see if that would lead to a healthier hospital environment.”

The Microbes in Our Midst

“It’s very hard to clear out all of the microbes from a particular ecosystem,” says Jonathan Eisen, a microbial ecologist at the University of California, Davis. In a review published in Genome Biology, Gilbert and coauthor Scott Kelley wrote that there “probably exists a microbe that will survive on almost any [built-environment] surface or condition.”16 Simply put, sterility doesn’t exist. Far from being a homogeneous layer of unicellular life, scientists have discovered that the microbes in buildings vary widely depending on environmental conditions and the people who inhabit the rooms. Some members of indoor microbiomes are precisely what scientists would have expected. Past studies have shown the bacteria colonizing hospital therapy pools17 and showerheads18 to be moisture-loving, soildwelling Mycobacteria and Proteobacteria. Showers aren’t the only hospital spaces that select for a unique array of microbes. When investigators at the University of Colorado Boulder surveyed the microbes present in Foley catheters—a common source of hospital-acquired infections20—they found that the bacteria present on the outside of the catheter were significantly different from those on the inside.21 Most of the microbes present in the hospital environment, however, arrive via humans, whether brought in on the soles of our shoes, on our cell phones, or our bodies themselves. Like Pigpen’s permanent aura of dirt in the Peanuts cartoon, humans are surrounded by a cloud of microbes.23 “Humans shed microbes wherever we go,” Gilbert says. Each time we touch an object, we can (and do) transfer millions of microbes from our body to the environment.24 Because the types of microbes available to be transferred vary from person to person25 and body part to body part,26 different surfaces are likely to host different species. Gilbert’s preliminary, unpublished results from the Hospi-

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tal Microbiome Project show that, within hours of a new patient’s arrival, the microbes in a room changed to reflect the composition of the latest inhabitant. “Within hours, the new person’s microbiome became the dominant force in that room,” he says. The reverse process has also been demonstrated, according to research analyzing the microbes found in the neonatal intensive care unit (NICU) at Magee-Womens Hospital of the University of Pittsburgh Medical Center.31 Just as many of the microbes found in the built environment are associated with humans, researchers now know that humans can acquire many of their microbes from their environment.

A Breath of Fresh Air?

Sorting out the factors that influence the makeup of indoor microbial communities could help scientists identify spaces and objects at high risk of carrying pathogens. These researchers also believe simple tweaks to building design, such as altering humidity and ventilation systems, could help reduce the number of pathogens in the indoor environment. Architects are looking at such tweaks in the context not just of hospitals but also other public areas. Some of the changes may be simple, like not placing restrooms next to areas where food is prepared, to prevent the bathroom microbiome from migrating into the kitchen. Microbial ecologist James Meadow, a postdoc at the Biology and the Built Environment Center at the University of Oregon, hypothesizes that installing windows that can open to the outside may also help seed the hospital with a different microbial community.39 Understanding how pathogens are transmitted from place to place and person to person might not sound like a huge shift, says Meadow, but it has revolutionized how scientists think about hospitals and the microbes that live there. “If we disturb one thing by moving or sterilizing it, we need to understand what else might change,” he says. Changing the hospital environment to prevent infections seems like a new idea, borne of high-throughput genetic sequencing and other advancements of modern biology. But Meadow notes that it might just be an old idea whose time has come.41 “Back in the 1800s, Florence Nightingale knew that patients did better with an open window,” he says.

Carrie Arnold is a freelance science writer living in Virginia. Her work has appeared in Scientific American, Discover, New Scientist, Smithsonian, and more. Reproduced with permission from Environmental Health Perspectives. This is a shortened version of a lengthy article rich with in-depth examples and references. Read the full version here: http://ehp.niehs.nih.gov/122-a182/. WWW.SFMS.ORG

Fecal Transplants and C.diff

Karen Blum

Fecal microbiota transplantation might seem off-putting to the average person, but the technique has been successful in helping many patients recover from dangerous Clostridium difficile infections (CDI), and a study published in mBio® suggests why. Fecal transplants work by restoring healthy bacteria and functioning to the gut, study authors found. The work provides insight into the structural and potential metabolic changes that occur following the transplants, which may aid in the development of new treatment methods for CDI. “The bottom line is fecal transplants work, and not by just supplying a missing bug but a missing function being carried out by multiple organisms in the transplanted feces,” says senior study author Vincent B. Young, MD, PhD, an associate professor in the Department of Internal Medicine/Infectious Diseases and the Department of Microbiology & Immunology at the University of Michigan in Ann Arbor. “By restoring this function, C. difficile isn’t allowed to grow unchecked, and the whole ecosystem is able to recover.” CDI has significantly increased during the past decade, Young says. Previous studies have estimated more than 500,000 cases in the United States annually, with health care costs ranging from $1.3 billion to $3.4 billion, he says, and up to 40 percent of patients suffer from recurrence of disease following standard antibiotic treatment. Fecal transplants, which have been successful at curing more than 90 percent of recipients, have been used successfully since the 1950s, says Young, though it hasn’t been clear how they worked. Historically, Young says, fecal transplants date back thousands of years. In fact, they were first documented in fourth century China, where physicians fed patients “yellow soup,” a mixture of fecal matter and water. The elder physicians may have become interested by observing sick animals try to self-medicate by eating healthy animals’ feces, says Young: “It’s an old idea. Even in ‘modern medicine’ it still dates back over fifty years.” With the recent reemergence of CDI associated with the appearance of a current epidemic strain known as B1/NAP1/027, interest in the technique has resurfaced. Young and colleagues used 16S rRNA-encoding gene sequencing to study the composition and structure of fecal microbiota in stool samples from fourteen patients before and two to four weeks after fecal transplant. In ten of the patients, researchers also compared stool samples before and after transplant to samples from their donors. All transplant patients, treated at the Essentia Health Duluth Clinic in Minnesota, had a history of at least two recurrent C. difficile infections following an initial infection and failed antibiotic therapy. Studying families of bacteria in the samples, investigators found marked differences among donor, pre-transplant, and post-transplant samples. However, those from the donors and post-transplant patients were most similar to each other, indicating that the transplants at least partially returned a diverse community of healthy gut bacteria to the recipients. While not as robust as their donors, the bacterial communities in patients after transplant showed a reduced amount of Proteobacteria, which include various infectious agents, and an increased amount of Firmicutes and Bacteroidetes typically found in healthy individuals, compared to their pre-transplant status. Then, using predictive software, researchers analyzed the relationship between the community structure of the micoorganisms and their function, presumably involved in maintaining resistance against CDI. They identified 75 metabolic/functional pathways prevalent in the samples. The samples taken from patients before transplant had decreased levels of several modules related to basic metabolism and production of chemicals like amino acids and carbohydrates, but were enriched in pathways associated with stress response, compared to donor samples or post-transplant samples. Further identification of the specific microorganisms and functions that promote resistance of bacterial colonization, or growth, may aid in the development of improved CDI treatments, Young says: “If we can understand the functions that are missing, we can identify supplemental bacteria or chemicals that could be given therapeutically to help restore proper gut function.” This article courtesy of the American Society for Microbiology, from mBiosphere, the blog of the open-access online journal mBio. The original post can be found at http:// mbioblog.asm.org/mbiosphere/2014/06/fecal-transplants-really-do-work.html.The original research article can be found at http://mbio.asm.org/content/5/3/e00893-14. full?sid=a4e555aa-680e-40e4-995c-c260d76ba524. SEPTEMBER 2014 SAN FRANCISCO MEDICINE

MEDICAL COMMUNITY NEWS CPMC

Edward Eisler, MD

After fourteen years at CPMC, Dr. David Goldberg, residency program director and chair of the Department of Psychiatry, has retired. Under Dr. Goldberg’s leadership, the Psychiatry Department has thrived and the residency training program has become one of the most sought-after programs on the West Coast. Dr. Alan Newman has been appointed as the new chair of the Department of Psychiatry. Dr. Newman comes to us from Medstar Georgetown University Hospital in Washington, D.C., where he was the associate professor of clinical psychiatry and center director for the psychiatry residency training program. Congratulations to Dr. Jeffrey Swisher, who has been appointed as chair of the Department of Anesthesiology for a five-year term. Dr. Swisher has been a member of the CPMC medical staff since 1999. At CPMC, he has served on a variety of committees, including the Credentials Committee and the Physicians’ Oversight Committee for the Electronic Health Record (EPAC), and he has been a member-at-large for the past three years on the Medical Executive Committee. Surgeons at CPMC are now implanting a device known as the NeuroPace in patients who suffer from seizures and who do not respond to medications or other treatments. The NeuroPace is an electronic simulator that can read the signals in the brain that precede an epileptic seizure. According to CPMC neurosurgeon Dr. Peter Weber, the device was effective in more than 60 percent of patients, with a significant number having their seizures cut by half. The results were so encouraging that, six months ago, the FDA approved NeuroPace for the treatment of epilepsy. Of the 440 acute care hospitals operating in California, CPMC is now ranked eighteenth by U.S. News & World Report, which released its national annual survey of hospitals this week. In 2013, we were thirty-seventh in California. Among the forty-seven Bay Area hospitals, CPMC ranked fourth—moving up a notch from fifth last year—and maintained its 2013 rank of second in San Francisco. 38

SFVAMC

Diana Nicoll, MD, PhD, MPA

Some news briefs from the San Francisco VA Medical Center (SFVAMC): Rebecca Shunk, MD, received the 2014 California Society of General Internal Medicine Leadership in General Internal Medicine Award. She is the director of the SFVAMC Center of Excellence in Primary Care Education, which focuses on teaching trainees to work in teams. Keith Armstrong, LCSW, director of Mental Health Social Work at SFVAMC, participated recently in a Congressional round table organized by the House Committee on Veterans’ Affairs, Subcommittee on Health. This round table discussed the transition of military service members into the community. Armstrong referenced his experiences in setting up the SFVAMC clinical services program at the City College of San Francisco, where there are more than 1,000 veterans on the GI Bill. Mike Steinman, MD, a staff physician in the SFVAMC Geriatrics, Palliative, and Extended Care Program, was the recipient of the 2014 UCSF Academic Senate Distinction in Mentoring award. He has a research program centered on improving the prescription of medications to clinically complex geriatric patients. Marianne Nihart, MA, APRN, chief nurse, Mental Health and Critical Care Services, was selected as president-elect of the American Psychiatric Nurses Association. John McQuaid, PhD, associate chief, Mental Health, is the president-elect of the Association of VA Psychologist Leaders. Megan McCarthy, PhD, received the Association of VA Psychologist Leaders 2014 James Besyner Early Career Award for Distinguished Contributions to VA Psychology. Jennifer E. Boyd, PhD, received an American Psychological Association Presidential Citation for her work in advocacy, research, and innovative program development in the field of serious mental illness. Barry McKeown, RN, an SFVAMC telephone advice nurse, was recently selected to compete at the International Canoe Federation Paracanoe Sprint World Championship in Moscow.

Sutter Pacific

Bill Black, MD, PhD

In the past few years we have become increasingly aware of the critical role that our body’s resident microflora, the human microbiome, play in our general health and disease processes, in much the same way that humans in turn impact our macroenvironment, the earth. For instance, the human gut microbiome influences diverse gastrointestinal processes, including abdominal pain and dysmotility syndromes. Dr. Bill Snape, who heads up SPMF’s Neurogastroenterology and Motility program, has pointed out that “altered microbiota causing a leaky epithelial lining allows lymphocytes and mast cells into the submucosa, releasing chemokines and cytokines that can affect submucosal sensory neurons, causing a hyperactive pain response.” Dr. Snape and colleagues Drs. Mimi Lin and Nikhil Agarwal bring world-class expertise to the care of these patients with conditions that many in general gastroenterology and primary care fields find challenging—gastroparesis, IBS, GERD, and fecal incontinence. To identify the pathophysiology underlying these conditions, diagnostic tools include highresolution esophageal manometry; barostat studies of tone, compliance, accommodation, and sensation in the esophagus and stomach; esophageal impedance; electrogastrogram of stomach nerve and muscle electrical activity; pyloric manometry of gastric emptying; antroduodenal manometry to measure coordination between the stomach and duodenum; colonic transit studies; colon motility manometry; colonic barostat testing; anal and rectal manometry; defecography; endoscopic ultrasound; and pudendal nerve latency testing. While research on treatments for gut dysmotility and pain syndromes targeting gut microbiome modification through probiotics is still embryonic, Dr. Snape and colleagues employ a host of proven therapies for these conditions, including pneumatic dilation, Botox injection, endoscopic gastroplication, gastric electric stimulator therapy, biofeedback, pharmacotherapeutics, and bowel training. They also offer clinical trial investigational protocols.

SAN FRANCISCO MEDICINE SEPTEMBER 2014 WWW.SFMS.ORG

Asian Health Services Dedicates New Clinic to Long-time SFMS Member Rolland Lowe, MD Asian Health Services received a $1 million donation from Dr. Rolland Lowe and Kathryn Lowe. “My wife, Kathy, and I are happy to make this gift to Asian Health Services,” Dr. Lowe said in a statement. “The gift goes toward the new clinic and will benefit many medically underserved patients in our community.” The Rolland & Kathryn Lowe Medical Center is a 15,000 square foot facility on three floors. It houses twenty exam rooms and serves 10,000 patients annually at full capacity. It features a Geriatric Center of Excellence and a Family Medicine Center. Dr. Rolland Lowe, a longtime member of the San Francisco Medical Society, has long been a leader not only in the community but in the medical profession as well. He was the first Asian-American president of not only the San Francisco Medical Society but of the California Medical Association. At CMA, he spearheaded the founding of the community foundation, which continues to conduct many health-related projects of note. While in medical practice, Dr. Lowe cared for some 20,000 patients in more than four decades of practicing medicine in San Francisco’s Chinatown. Even though some of his patients had no insurance coverage, no one was ever turned away. He helped form the Chinese Community Health Care Association, which grew to include more than 150 practicing physicians to provide culturally sensitive and affordable, even free, care in the San Francisco Chinatown community. He has also been a longtime key supporter of Chinese Hospital, a facility providing quality care for the Chinese and greater Asian communities in San Francisco. The San Francisco Medical Society was proud and honored to participate in the dedication of the Rolland & Kathryn Lowe Medical Center. It is a fitting tribute to visionary leaders who have dedicated their lives to the betterment of our community and medicine.

Update: SF Soda Tax

John Maa, MD

A decades-long strategy employed by the tobacco industry was to pay scientific “experts” to cast doubt on the accumulating scientific evidence about the harms of cigarette smoking. That strategy is being used once again by the American Beverage Association, which paid a U.C. Davis nutritionist to write a recent op-ed against soda warning labels. In a response in the Sacramento Bee titled, “Don’t believe industry-paid ‘experts’ on soda and diabetes,” pediatric endocrinologist Dr. Robert Lustig wrote, “It is time for California to tune out beverage industry propaganda and tune in to the hard science showing how sugary beverages contribute to California’s bad health and rising health care costs. It is time for the beverage industry to stop paying off scientists. And it is time that we all learn the truth about the harmful effects of sugary drinks.” The full Viewpoint is available here: http://www.sacbee. com/2014/07/23/6574928/viewpoints-dont-believe-industry. html#storylink=cpy. The California Medical Association and the SFMS have both endorsed Proposition E, the SF Soda Tax, which will be decided on the November 4, 2014, ballot. A parallel move to tax soda in Berkeley will also be voted upon in November, and the eyes of the nation are closely watching the outcome of the Bay Area efforts. For more information, please visit www.choosehealthsf.com or the dedicated SFMS website.

Breathe Again !! CALIFORNIA SINUS CENTERS & Institute We CARE for: Bacterial Infections / Sinusitis Culture directed treatment Functional Endoscopic Sinus Surgery Orbital Decompression / Graves’ Disease Image Guided Surgical Navigation Revision - complex cases Frontal Sinusitis Advanced Endoscopic Techniques Sinuplasty Sinus Surgery WITHOUT packing Nasal Obstruction / Septoplasty Allergic Fungal Sinusitis Sinonasal Tumors / Polyps Smell / Taste problems CSF leak repairs Mucoceles / Abscesses In-Office CT Scanner Urgent appointments Joint care: ENT - Allergy Pulmonary

Atherton (Stanford area) Walnut Creek (East Bay) San Francisco (Union Square) Winston Vaughan, MD Karen Fong, MD

Kathleen Low, NP

Sacramento / Sonoma / Fresno

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11/15/13 2:54 PM

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SEPTEMBER 2014 SAN FRANCISCO MEDICINE

TEN QUESTIONS SFMS Member Profile: Maria Ansari, MD Member Spotlight profiles leading stakeholders from the medical community to get their personal views on their chosen profession. We hope to showcase members from across the SFMS spectrum to reflect the rich tapestry of our membership and help highlight some of the great work from our membership. What’s the biggest barrier to practicing medicine today? The uncertainty about the future of health care, the rising costs of delivering care, increasing regulatory demands, and the growing expectations of patients can lead to physician burnout and reduced professional satisfaction, particularly for physicians early in their career who do not know what to expect and have little mentorship in these aspects of practicing medicine.

If you could change or eliminate something about the health care system, what would it be? In a perfect world, we would eliminate the concept of a “waiting room.” No one likes to sit around and wait—least of all the millennial generation—and I think we can get there one day. In my practice, I offer telephone visits and video visits for patients who want them so they can avoid the waiting room altogether when clinically appropriate. I also try to see my patients on time, but sometimes one person may take longer than expected. Our emergency room has developed such an efficient triage and treatment system that their waiting rooms are already mostly bare. If we rid the entire health care system of waiting rooms and offer care on the spot, that would be terrific service and care. We are not there yet, but we are working hard organizationally to provide care on the patient’s terms. Why are you a SFMS member? I am a SFMS member so I can network with colleagues in this wonderful city where I have chosen to raise my family and work. In addition, I would like to get more engaged locally to advocate for important legislation that promotes health in our community. What advice would you give to a medical student or resident just starting out today? I think the best doctors are not just the brightest but the ones who care the most. If you have a very difficult or anxious patient, they are the ones who may need you the most, so draw them in closer.

What’s the best piece of advice you’ve gotten in your career so far? The best piece of advice I received was about leadership 40

in medicine. “If you are getting motion sickness in the back of the bus, then get out and drive.” Although I love being a clinician very much, I realized I could have an important impact on my patients’ and colleagues’ lives more broadly if I also served as a physician leader. What is the most rewarding aspect of being a doctor? For me, the best part of medicine is enjoying a strong doctorpatient relationship. Patients may tell us things they may not tell their best friend or spouse, and it is that unique and trusting connection that allows us to contribute toward healing and caring.

What is the most memorable research published when you became a physician? I am a cardiologist and heart failure specialist, and the biggest study to impact the lives of my patients in my career has been the U.S. Carvedilol Study, which came out in 1996. What is truly remarkable is this study demonstrated that beta-blockers, which were previously contraindicated in heart failure, dramatically improved lives and revolutionized the way we managed this potentially fatal disease.

What is your advice to other physicians on how to avoid burnout? When we really focus on the meaning in medicine and why we went into this field, it reminds us of the humanity of medicine and what a privilege it is to be able to care for patients for a living. I also think that in order to promote health in others, you have to start with yourself. I meditate, play tennis, hike, and spend time with my family to stay well. This February I also ran my first half marathon and am planning another half this fall. Do you have a favorite hospital-based TV show? No, I cannot watch TV shows about medicine. I’m too critical of their unrealistic portrayals of hospital work. If you weren’t a physician, what profession would you try? I wrote for a magazine during college and thought for a short time I would go into journalism. I felt I was too dry of a writer to be successful as a journalist!

Maria Ansari, MD, was born and raised in Michigan and attended the University of Michigan as an undergraduate and then for medical school and internal medicine residency. She was in danger of becoming a “lifer” at the University of Michigan before she headed to California to start her cardiology fellowship at UCSF. She completed her cardiology fellowship with advanced fellowship training in echocardiography, heart failure, and clinical research. After spending her early research career at UCSF, she left to pursue a primary focus in clinical cardiology at Kaiser Permanente in 2004. Dr. Ansari became chief of cardiology at the San Francisco

SAN FRANCISCO MEDICINE SEPTEMBER 2014 WWW.SFMS.ORG

Medical Center at Kaiser Permanente in 2007. Her accomplishments as chief included starting the first Northern California Kaiser Permanente Cardiology Fellowship program, developing a regional Adult Congenital Heart Disease program, and overseeing the development of one of the largest commercial TAVR (transcatheter aortic valve replacement) programs in the country. In July 2014, Dr. Ansari was asked to take on the roles of chief of staff for the hospital and serve as physician in chief for the Kaiser Permanente San Francisco Medical Center. Her primary goal in these new positions is to highlight a patient-centered approach and to help design systems that will continue to deliver on excellent service, access, and quality. She will also oversee the expansion of Kaiser Permanente San Francisco into a second campus at Mission Bay by 2016. Dr. Ansari lives in San Francisco’s Cole Valley neighborhood with her husband and two kids. You might see her running in Golden Gate Park with her University of Michigan gear on.

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In Memoriam

Erica Goode, MD

Richard Dean Rider, MD | October 25, 1923–June 24, 2014 Dr. Rider, a San Francisco general surgeon who practiced at Franklin Hospital (Ralph K. Davies Hospital since 1955), died at age 90. He was one of three sons of physician parents; both he and his older brother, J. Alfred Rider, pursued careers as surgeons. Dr. Rider, as he was known, graduated from the University of Chicago in 1943. His medical training was at McGill University Medical School, where he met his future wife, Connie Beebe, a surgical nurse. Following his residency in surgery and a staff position in Wichita, he and Connie were lured to San Francisco by his brother Alfred. The Riders and their family moved to Mill Valley. His avocation was automobiles, which he fixed endlessly in his spare time; he died owning fifteen cars, including his favorite, a 1958 Chevy Impala. It was acquired from a patient in lieu of payment for surgery; Dr. Rider assumed the remaining car payments. In fact, Dr. Rider often wrote off bills, reduced fees, and visited patients at home free of charge. He was known for never turning away a patient, including neighborhood children with cuts and fractures and, occasionally, injured animals who received surgery in the family kitchen. Dr. Rider was a member of the AMA, CMA, and San Francisco Medical Society from 1955 onward. He became involved early in caring for HIV/AIDS patients during the 1980s. His concern for the elderly extended to his work as medical director of the Crossroads Home Care and Hospice Facility. He made many “excess” home visits, which were often denied payment from Medicare and insurance companies. He was on the medical staff at CPMC until almost the end of his life, and he continued to scrub in with younger surgeons until his ninetieth year. He was at home in Mill Valley during his last days, supported by family and caregivers. His beloved wife died four years ago; his brother J. Alfred also predeceased him. He is survived by his younger brother, Dale Rider of Chicago, and five children and ten grandchildren. His type of medical care has expired with the dawn of this century; now it is EMRs, insurance scrutiny, and mandated decision trees for care. Time and financial constraints, administrative burdens, and the cost of living in the Bay Area have all taken a toll, and Dr. Rider was fortunate to have been ahead of this crushing tidal wave.

SEPTEMBER 2014 SAN FRANCISCO MEDICINE

UPCOMING EVENTS

CLASSIFIED AD Discover Health Medical Partners, Inc., N1 Health

9/20: Zero Prostate Cancer Run/Walk

The physicians of Discover Health are pioneers in direct access medicine in the San Francisco Bay Area. We provide clinic and house call medical and naturopathic services to adults and children throughout the region. We seek an energetic, self-directed team player to join our group as a full- or part-time associate in clinical practice. The ideal candidate is a board-certified or eligible FP, IM, or Med/Peds physician. In addition, the candidate is able to share in call coverage and make house calls in the Bay Area. You will join a multidisciplinary and comprehensive care team that includes internal medicine, pediatrics, and naturopathy. In addition to a top-notch facility, experienced administrative and medical assistant staff will support your clinical practice. Our EHR is user friendly and enables office and mobile charting. We are a family-focused practice that takes pride in caring for entire families across generations. Discover Health is a membership-based private practice that limits provider panels to allow you to spend the time necessary to address the physical and emotional needs of your patients. Discover Health is an Equal Opportunity Employer medical, dental, vision, and paid time-off benefits to qualified associates and employees. If you are interested in joining our team, please send your cover letter and CV to: manager@discoverhealthmd.com.

9:30 a.m. | Crissy Field, San Francisco | Join SFMS physician members from Golden Gate Urology for the second annual Zero Prostate Cancer Run/Walk. This tight-knit community activity brings together athletes, doctors, cancer survivors, and those who care about them to help end prostate cancer. Visit http://bit.ly/1u0RQ9G for more information about how to get involved.

Tracy Zweig Associates INC.

REGISTRY

PLACEMENT

FIRM

~ Physicians ~ Nurse Practitioners Physician Assistants

9/27–28: Leader’s Toolkit–Physician Leadership Course

San Diego County Medical Society | CMA’s two-day leadership course, Leader’s Toolkit, is a free, member-only program for SFMS members who are seeking leadership roles in organized medicine. Participants will learn real-world skills and will leave with actionable behaviors, tools, and concepts to help them be effective leaders in organized medicine. Some of the issues covered include change management, leading a team, responsibilities of a leader, setting boundaries and priorities, time management, parliamentary procedure, and understanding and leveraging critical relationships. For more information or to register, please contact Jennifer Moller at (916) 551-2541 or jennifer@cmsservices.org.

10/22 Webinar: Analyzing and Negotiating PPO Contracts 12:30 p.m.–1:45 p.m. | SFMS has teamed up with ACCMA to offer a webinar on PPO contracts. Learn from a successful PPO contracting expert about analyzing present contract rates and strategies for successful renegotiation. The training is free for SFMS members and $199 for nonmembers. For more information on this seminar, please contact Dennis Scott at (510) 654-5383 or dscott@accma.org.

11/5: SFMS Career Fair for Residents/Fellows/Physician Members

4:00 p.m.–8:00 p.m. | The Enright Room at CPMC Pacific Campus | SFMS will be hosting our fourth annual Career Fair on November 5 at CPMC Pacific Campus. The event is complimentary to all SFMS members. This is an excellent opportunity for physicians looking to practice in the Bay Area to network with representatives from a variety of practice types and settings, and for employers to connect with physician job seekers. For event details or to inquire about exhibiting, contact the Ariel Young at (415) 561-0850 extension 200 or ayoung@sfms.org.

Complimentary Webinars for SFMS Members

Voice: 800-919-9141 or 805-641-9141 FAX: 805-641-9143 tzweig@tracyzweig.com www.tracyzweig.com 42

CMA offers a number of webinars that are free to SFMS members. Members can register at www.cmanet.org/events. • September 17: Managing Difficult Employees and Reducing Conflict in the Practice | 12:15 p.m. to 1:15 p.m. • October 1: Family Medicine, Frontline of Care | 12:15 p.m. to 1:15 p.m. • October 8: Protect and Preserve Your Patient Relationships | 12:15 p.m. to 1:15 p.m. • October 29: Managing Up! For Managers | 12:15 pm to 1:15 p.m.

SAN FRANCISCO MEDICINE SEPTEMBER 2014 WWW.SFMS.ORG

you work to protect your patients. We work to protect you. as a physician, you probably know better than anyone else how quickly a disability can strike and not only delay your dreams, but also leave you unable to provide for your family. whether it is a heart attack, stroke, car accident or fall off a ladder, any of these things can affect your ability to perform your medical specialty. that’s why the SFMS/CMA sponsors a Group Long-term disability program underwritten by new york Life Insurance Company: • benefits not tied to a practice, giving you more flexibility with potential career changes • benefit payments that are 100% tAX Free — when you pay premiums yourself • High monthly benefits up to $10,000

Learn more about this valuable plan today! ——————————————————

Call Mercer for free information, including features, costs, eligibility, renewability, limitations and exclusions at: 800.842.3761 ——————————————————

• protection in your medical specialty for the first 10 years of disability with this critical protection, you’ll have one less thing to worry about until your return. SponSored by:

UnderwrItten by:

New York Life Insurance Company New York, NY 10010 on Policy Form GMR

Mercer Health & benefits Insurance Services LLC • CA Ins. Lic. #0G39709 777 South Figueroa Street, Los Angeles, CA 90017 • 800-842-3761 CMACounty.Insurance.service@mercer.com • www.CountyCMAMemberInsurance.com

OR SCAN TO LEARN MORE!

Our cancer experts shed light. You’re never in the dark. CPMC brings nationally-recognized cancer experts to our community, including our programs for melanoma led by Dr. Mohammed Kashani-Sabet and gynecologic oncology by Dr. John Chan. We take pride in providing timely access to our expert physicians, and personal follow-up with a patient’s primary or referring physicians means you’re always informed. Comprehensive cancer care at Sutter Health’s CPMC. It’s another way we plus you.

cpmc.org/cancer