IMMpress Magazine: Metabolism and Microbiome - Tiny Universes by IMMpress Magazine

IMMpress Magazine Magazine of the Department of Immunology, University of Toronto 2022 | vol.10 no.2 9 772291 239001 ISSN 2291-2398

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DESIGN DIRECTOR Kitty Liu

SENIOR EDITORS

CONTENT CONTRIBUTORS

Salma Sheikh-Mohamed

Philip SalmaJamesMeghanBaweletaBarbulescuIshoKatesLouisNgaiPollockSheikh-MohamedSiuLingTaiKarenYeung

FOUNDING EDITORS

YuriyCharlesBaglaenkoTran

IMMpress Magazine is a student-run initiative. Any opinions expressed by the author(s) do not necessarily reflect the opinions, views or policies of the Department of Immunology or the University of Toronto.

PhilipLouisBarbulescuNgai

Philip Marie-ChristineAmmarahManjulaBaweletaBarbulescuIshoKamathMeghanKatesFaustinaLauNaseerLouisNgaiPerryJamesPollockSiuLingTaiDeevaUthayakumarMatthewWongStephanieWongKarenYeungTianningYiDanielZangrandoEveyZheng

SOCIAL MEDIA COORDINATOR

DESIGN ASSISTANTS

IMMpress

Philip Marie-ChristineMeggieBaweletaBarbulescuIshoKuypersLouisNgaiPerryKarenYeungTianningYiDanielZangrando

Design notes

About the Cover

“The cosmos is within us. We are made of star-stuff. We are a way for the universe to know itself.”

Though invisible to the naked eye, the microbiome makes up around 0.3% of our total body mass and is equivalent to the number of cells in our human body. The complex relationship between the human body and the microbiome can be observed in processes as drastic as the manifestation of diseases and as simple as the absorption of nutrients. These small but mighty microorganisms hold sizable power in influencing the way our body functions. With increasing knowledge of the field, we are starting to explore how to manipulate it to improve our health and the outcome of disease.

In this issue, our design team has creatively used a wide range of co lour to represent the richness of the microbiome and the broad scoping aspect of metabolism. From illustrations to photographs, our design ers have craftfully used these visuals to convey such complex topics. It is truly imm pressive the visual story-telling skills our designers have! With that, we would like to thank all of our talented designers for all of their incredible creations this issue. This beautiful issue you hold before you would not have been possible without all of their hard work and artistic vision.

- Kitty Liu-

P LEASERE-READ, RE-GIFTAND I F Y UO ELCYCER,TSUMYLLAER

EDITORS-IN-CHIEF

- Carl Sagan

Drawing parallels from the vast universe we reside in, the cover of this issue depicts the tiny universes that reside within us. Like the universe, the human body is complex and full of intricacies. While we marvel at the bountiful stars above us, unable to fathom the grandness of it all, inside us is a massive galaxy of bacteria. Though already expansive, there is still much to unearth.

The Gut-Brain Connection: Role of Microbial

Letter from the Chair

hear

Metabolic Disorders: Critical Missteps in Metabolism

Treat Inflammation the Natural Way: the Natural Alternatives to Ibuprofen

Impact of the Gut Microbiota on Immunotherapy

Pica Cravings to the Extreme Nutrient deficiency or “weird” tastes?

patientswithadvancedepithelialtuthenumberofbeneficialgutbacteria, resultinginreducedimmunotherapy treatmenteffectiveness.Cancerpatientswhohadantibioticsadministeredwithin60daysofimmunotherapyfaredworsethanthosethat weren’tgiventheantibacterialdrugs. Antibioticsareadouble-edgedsword andcliniciansneedtobecognizantof bothdosageanddurationtoproperly

CSIMessengers2022 5 30 34

From Plant to Poop: the Power of Dietary Fibre

“Fat to Fit” While You Sit? The Secrets of Resting

12 13 17 20 W

Gene-uine Disgust — Why Do We Dislike Certain Foods

OnesuggestionisthatcertaingutmicrobespromoteastrongCD8+Tcell responseduringICBtreatment.Infact, supplementationwithprobiotics,or “good”bacteria,inhibitstumorgrowth bystimulatingCD8+Tcells.It’sworth pointingoutthatotherresearchrecommendsthatprobioticsupplements shouldbeavoidedduringimmunotherapy.Thereasonprobioticsshouldnot betakenisbecausetheymayimpact thebalanceof“good”bacteriaandpreventaneffectiveimmuneresponse. Suchconflictingresultsdemonstratethe complexityofthegutmicrobiomeand itsimpactondifferentcancertypes, emphasizingtheneedtofurthercharacterizespecificinteractions.

Nutrition in a Growing World: Weighing in on Nutritional

Different strokes for different folks

A D-lightful Vitamin: the Importance of Vitamin D for a Healthy Individual

We would love to your thoughts! send

facebook.com/IMMpressMagazine@immpressmag immpressmagazine.com CONTENTS VOL 10. NO 2. [2022] › CONNECT WITH US! › SUBMIT FEEDBACK

The power of the unseen to elevate the gourmet

notjustappealingtotheirtaste buds,butmoreimportantly, thatarenotunappealingto them.Whetherit’sdisgustover thetasteofcilantroorintolerancetoafoodgroupaltogether, thesciencebehindfoodpreferencesiscomplex.Factorsincludingallergies,genetics,socioeconomicalinfluences,and eventhegutmicrobiomehave beenimplicatedindetermining whatweeat.Geneticsspecificallyremainsapoorlyunderstoodcontributortodiet,althoughrecentresearchhas shedlightontoseveralgenetic variationsinindividualsthat canplayaroleindetermining whichfoodsweprefertoconsume.

How are Diets Changing our Immune Systems?

Improving Food with Fermentation — SuperFood or Super-Fad?

FEATURE ON METABOLISM AND MICROBIOME: TINY UNIVERSES

hydoweeatwhat weeat?Peopleenjoy

Letters from the Editors

us an e-mail at editor@immpressmagazine.com

Restoring the Balance of the Gut Microbiota: How Our Feces Can Help Fight Inflammatory Bowel Disease

Sleep and Immunity

Comment on our articles online or

Manipulating Metabolism: an Interview with Dr. Michael

Microbiome Research is Blasting Off

Apopularexampleofa highlypolarizingfooditemaffectedbygeneticsiscilantro. Thosewhodetestthisinnocuousleafyherbdescribeits tasteassoapyorbitter–nota tasteyouwantinyournext bowlofnoodles.Thisunpalatableflavourcomesfrom thepresenceofaldehydesin cilantroleaves.Peoplethat putridstenchleftbehindby asparagus,possiblyinfluencbuildsupinthebody.Individualswith“fast”ADHvariants GENE-UINE DISGUSTWHYDO WE DISLIKE CERTAIN FOODS -AmmarahNaseer hottopicnowadaysis discussionssurrounding themicrobesinourgut andthenumeroushealth benefitstheyprovide. Whatisn’tasfrequentlydiscussed, however,ishowgutmicrobialcompositioncanimpactanindividual’sresponsetocancertreatments. Consideredanimportantscientific breakthrough,immunotherapyactsto stimulatethebody’simmunesystemto recognizeandkillcancercells.Several typesofimmunotherapiesexist,includingimmunecheckpointblockade (ICB),adoptiveTcelltransfers,and cancervaccines,tonameafew.Eachof thesetreatmentsworksdifferently. ICB,forexample,targetscheckpoint moleculesthatactas“brakes”ofthe immunesystem,resultinginimmune cellactivation.Unfortunately,lessthan 30%ofpatientsbenefitfromICB. Whyexactlythishappensiscomplex butsomeofthediverseclinicalresponsestoICBcanbeattributedtodifferencesinthegutmicrobiome. Thegutmicrobiomeiscomposed oftrillionsoftinyorganismssuchas bacteria,fungi,parasites,andviruses andtheirpresenceorabsencecanpredictapatient’sresponsetoICB.Researchersstudythefecalcomposition ofpatientsonICBtogainkeyinsights intotheirgut’sbacterialdiversity,or lackthereof.Forexample,theabundanceofthebacterialspecies Akkermansiamuciniphila infecalsamplesof

A Brief Introduction to Bacteria, Viruses, and Parasites

morswasattributedtobetterresponsestoatypeofICBtreatment.On theotherhand,thepresenceofcertain bacteriacanalsonegativelyinfluence immunotherapyresponses. Ruminococcusbromii isabacteriumthat breaksdowncomplexsugarsinthegut anditsabsenceisassociatedwithbetteroutcomesinlungcancerpatients. Patientsundergoingcancertreatmentsareoftenprescribedantibiotics astheyaremoresusceptibletoinfections.Whilehelpfulinpreventinginfections,antibioticscanalsoreduce

IMPACTOFTHEGUTMICROBIOTA ONIMMUNOTHERAPYRESPONSES

It’sapparentthatgutmicrobescan alterimmunotherapyresponsesbyinteractingwithdrugsdirectlyorbyaffectingthehost’simmuneresponse. Furtherresearchwilllikelyexplore howthegutmicrobiomecanbesafely alteredtoimprovetheefficacyofvariousimmunotherapies.Infact,some microbesarealreadybeingusedin clinicaltrialstoaddressimmunotherapynon-respondersorprovidelongtermtreatmentforulcerativecolitis patients,whohaveahigherchanceof developinggut-relatedcancers.

Indeed,microbes.primitive

Philip Barbulescu Louis Ngai

Many thanks to our team of writers, designers, and editors for taking their time to create another great issue of IMMpress Magazine, we appreciate you all. As we near the start of the next school year, welcome to all new incoming and transfer students! Finally, we would like to say goodbye and thank you to Louis Ngai (Co-Editor-inChief) and to the wonderful Sarah Colpitts (Multimedia Director) as they step down from their positions. At the same time, we are thrilled to welcome Karen Yeung as Louis’s replacement, as she has proven herself in her great talents as writer, editor, and designer. We hope our readership will enjoy this issue and we hope everybody stays safe and healthy!

IMMpress Vol. 10 No. 2 2022 5

LETTER FROM THE EDITORS

We start off with an infographic about the importance of diet, specifically fibre, and how it can shape our health and our gastrointestinal health (p8)! We follow this article with two that detail why essential nutrients like calcium, folic acid (p10), and vitamin D (p12) are essential for a healthy life. We investigate the notion of food, how some certain foods have anti-inflammatory properties similar to ibuprofen (p13), how the definition of food is stretched in individuals suffering from Pica eating disorder (p14), and how some foods like cilantro can vary in taste based on genetic differences (p16). As food is metabolized, it goes through many complex pathways, but what happens when it goes wrong (p17)? On the other hand, is there a way to harness metabolism to control our immune cells? Find out in our interview with alumnus Dr. Michael St Paul (p18). Intimately connected with metabolism are microbes and their by-products. We look into the power of microbes in regulating brain function (p30), their influence in weight management (p28), their ability to help fight cancer (p22), and fight against disease-causing microbes (p24). We end this issue by summarizing key findings from this year’s Canadian Society of Immunology 2022 meeting where the symposiums covered topics including tumour and layered immunity (p34).

The vastness of our universe was put into the spotlight with the first images of the James Webb Space Telescope. These beautiful images, showing only a small fraction of the sky—a grain of sand held at arm’s length—has allowed humanity to delve into the unknown, to better understand our creation, and to see that we are but one of many other galaxies in the cosmos. But unique to us, so far, is that we are teeming with life. As some investigate the macroscopic to better understand our world, others turn towards the microscopic, the very first life on earth,

as they are, microbes gave life to more complex organisms, whether that be through the endosymbiotic relationship of the mitochondrion, or through the digestion of complex molecules. Metabolism, defined as the life-sustaining chemical reactions in our body, is heavily influenced by the microbial environment that feeds it. In this issue of IMMpress we investigate the universe within our body and explore the relationship between metabolism and microbes.

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IMMpress Vol. 10 No. 2 2022 7

I hope you are hungry. I know I am.

I am delighted to see that, after my 6-month administrative leave, IMMpress continues to deliver outstanding and topical articles. I am also very thankful to Prof. Jennifer Gommerman for her steady and bold leadership, as Acting Chair, during this period.

Juan Carlos Zúñiga-Pflücker, PhD Professor and Chair Department of Immunology

FROM THE CHAIR LETTER

Wishing all a great start to the Fall term, I hope you enjoy this issue, and importantly whether you are an alumnus of the department, or a prospective student, I really look forward to hearing from you.

This issue of IMMpress Magazine provides a full serving of nutritional microbiome-rich information that should satisfy anyone seeking to learn about the interface of immunity and metabolism. The IMMpress team has set a de licious table of articles featuring key aspects of nutrition, diets and dietary supplements, microbiome and immune modulation. There is lots to dig into, plus a wonderful interview with a recent alum, Dr. St. Paul, and a terrific review of this year’s Canadian Society for Immunology conference.

Happy to be back as Chair for the next year and a bit, to lead the Department of Immunology on its next 5-year Self-Study and External Review process, which will not only inform us as to how we are doing as an academic unit, but also help in the recruitment of our next departmental leader.

Doesnotdissolveinwaterandpassesthroughthegut withoutmuchintermsofdigestion.Notasourceofenergy butcanhelpinclearanceandfirmsupthepoop.

Beans Oats

Foundmainlyin fruits, vegetables, wholegrains,and legumes,theWorldHealthOrganizationdefinesdietaryfibresasany carbohydratethatis neitherdigested or absorbed bythesmallintestineandhavea degreeofpolymerization oftenormore monomericunits,thoughthiscriteriaisflexible.Dietaryfibrescanbecategorizedbasedonsolubility,viscosity,andfermentation. Thesecriteriahelptorelatethetypesoffibrestoitsrelevanthealthoutcomes.

Peas Pumpkin Orange Onion

FROMPLANTTOPOOP: ThePowerofDietaryFibre

The average Canadianconsumes 1/2 therecommended doseoffibre Dailyrecommendeddoseoffibre Age50oryounger 38grams 25grams 30grams 21grams Men Women Age51orolder

Nuts Rice

Soluble

Producesshort-chainfattyacidsthathelpsto supportabalancedgutmicrobiotawhileinhibitingthegrowthofpathogenicbacteria.Increases thebio-availabilityofsomeminerals,promotingnutrition.

8 IMMpress Vol. 10 No. 2 2022

Whatisfibre?

Overlappingwithsolublefibres,formsagelwith watertoevenouttheconsistencyofchyme–acombinationofpartiallydigestedfoodandgastricjuices. Addedviscosityalsoslows,allowingforbetterabsorption.

Classificationsoffibre

Itisimportanttokeepinmindthattheseclassificationsoverlap,andinreality,wholefibrousfoodsareoftenacomplex mixturecomprisedofbothsolubleandinsolublefibres,andthereforeplaymultipleroles.Measuresofsolubilityalsodepend onanindividual’svaryingstomachpH,microbialcomposition,andthequalityofthedietaryfibres.Avarieddietisbestto makesureyougetalltypesofdietaryfibresandmoreimportantly,thatyouconsumethedailyrecommendedgramsoffibre.

Viscosity

Insoluble

Fermentable

Dissolvesinwatertoformagel-likesubstance,whichis furtherbrokendownbythebacteriainthelargeintestine, providessomeenergy(calories),andslowsdigestion.

Howfibreaffectsthegut

Theresearchsurroundingdietaryfibresusesa widerangeofdietaryfibres thathavedifferentphysiochemicalandfunctional characteristics.Thismakesitmuchmoredifficulttodrawmeaningfulconclusionsduetoa lackofconsistency,andcomplicates theirfunctionindiseaseslikeirritablebowelsyndromeandinflammatoryboweldisease.Fibresupplementsaddanotherdegree ofcomplicationasitis uncleariftheyworkaswellasfibernaturally containedinfoods.Nevertheless,high-fibrefoodsare usuallygoodforyoubecausetheycontain highlevelsofvitamins,minerals,andbeneficialplantcompounds.Theincorporation offibrealso affectstherateofdigestion,therateofnutritionabsorption,thedegreeoffullness,andmicrobialcommunities. Allthatistosay,trytoseewhatworksbestforyourbody.Newsarticlesmanyoverinflatedatabuttheconclusionsareclear: peoplewhoeathealthiertendtobehealthier.

Howgoodisyourpoop? Type1 Type2 Type3 Type4 Type5 Type6 Type7 Separate,hardlumps Constipation Normal LowFibre Diarrhea Lumpy,dry,sausage-shaped Solid,sausage-shaped,cracksonthesurface Smooth,likesausageorsnake Softblobswithdefinededges Mushy,withraggededges Liquidstool [ [ [ -

-LouisNgai Dietary fibres Smallintestine Epithelium Largeintestine x x ▲ Waterbinding Microbialgrowth Immunomodulation ▲ Viscosity- ▼ glucose andlipidabsorption AdaptedfromGilletal., Nat.Rev.Gastro.&Hep.,2020 ▼pH Blocksphytateandiron, whichreducescalcium andzincabsorption ▲Stoolbulk ▲ Solubility Ca2+ Shortchain fattyacids Prevents pathogens Tight junction integrity FiguresmadewithBiorender IMMpress Vol. 10 No. 2 2022 9

TheBristolStoolChartisusedtoevaluateandclassifystoolintosevengroupsandcanbeusedtomonitoryourpoop.

10 IMMpress Vol. 10 No. 2 2022

The popularity of such supplements stems from a large body of scientific research linking a healthy diet to proper growth and development, and reduction in the risk for de veloping diseases such as type 2 diabetes, cardiovascular dis

Weighing in on nutritional supplements

Neural tube defects (NTDs) are a group of congenital disorders caused by im paired neural tube development during early gestation, leading to severe defects in the brain and spinal cord. Research over the past few decades have demonstrated a strong link between maternal folic acid supplementation and decreased rates of NTD. Folic acid is metabolized into folate, which is required for many processes related to fetal growth and development, including DNA replication, amino acid synthesis, and vitamin metabolism. Folate cannot be synthesized by our bodies and must be derived from the diet or by supplementation.

ease, stroke, and cancer. Indeed, 85% of surveyed Canadians taking supplements indicated that they did so to improve and maintain their health.

Calcium is best known for its role in maintaining bone health, but this mineral is also important for muscle and nerve function. Low calcium levels can lead to weak ening of the bones, increasing the risk of developing osteoporosis later in life. Various factors can influence calcium levels, including low dietary intake, high calcium excre tion, long-term corticosteroid usage, or diseases of the small intestine that reduce the body’s ability to absorb calcium. For individuals meeting any of the above criteria, calcium supplements may be recommended to meet their calcium needs.

However, there is growing evidence that taking too many calcium supplements may be detrimental to cardiovascular health. A 2010 meta-analysis of 11 randomized clinical trials involving calcium supplements suggested that taking these supplements could increase the risk of heart attack by up to 30%. While the underlying reasons for these observations are unknown, it is possible that high calcium levels could lead to the buildup of calcium-based plaques in blood vessels, which is associated with coronary heart disease.

INnutritionCALCIUMAGROWINGWORLD

For many people, nutritional supplements are a regular part of their diet. In 2015, over 45% of Canadians reported taking at least one type of nutritional supplement, including but not limited to vitamins, minerals, fibres, and fish oils. In general, nutritional supplements are defined as any substance consumed in addition to normal food that is used to correct a nutritional deficit.

Experimental and observational studies since the 1980s have shown that folic acid supplementation during pregnancy can reduce the risk of NTD occurrence by over 70%. Based on these studies, Canada began fortifying various cereal food products with folic acid in 1998, leading to a 46% reduction in the rate of NTDs over the next 10 years. Currently, Health Canada recommends a daily dose of 0.4 mg of folic acid per day to women who are or are thinking of becoming pregnant.

FOLIC ACID

Various dietary nutrients have been identified that, when lacking, contribute to disease. For example, severe deficiency of ascorbic acid (vitamin C) causes scurvy, a disease common in the past when access to fresh fruits and vegetables was limited. By extracting these key nutrients from our food and distilling it into a single pill or dose, nutritional supplements promise to deliver the best advantages of a healthy diet in the most efficient package.

Nicknamed the “sunshine vitamin”, vitamin D is a unique nutrient in that we obtain most of what we need by synthesizing it ourselves in the skin following sun exposure. Vitamin D is required for optimal calcium and phosphate absorption, and parathyroid hormone regulation. It is often used in combination with calcium supplements to treat diseases related to bone deficiency, such as nutritional rickets and osteomalacia. Various observational studies have also suggested that low vita min D levels are associated with negative outcomes in cardiovascular, autoimmune, neurological, and infectious diseases, as well as cancer and total mortality.

supplements had an increased risk. Such observations may be due to synergistic effects of different nutrients acting upon one another, as is the case for vitamin D enhancing calcium uptake.Based

Although there is a perception of nutritional supplements as a benign health product as they are essentially a con centrated nutrient extract, the adage “too much of a good thing” is particularly relevant to their consumption. Like any drug, exceeding the recommended dosage of nutritional sup plements can lead to adverse effects. There is also evidence that our bodies handle these concentrated doses of micro nutrients differently compared to when they are gradually absorbed with other nutrients from our diet. For example, a 1997 study showed that high dietary and supplemental calcium levels were associated with opposing kidney stone outcomes – women with a high dietary calcium intake had a decreased risk for kidney stones, while those taking calcium

on what we’ve learned about nutrition over the past few decades, it seems clear that nutritional supplements provide limited benefits to generally healthy adults and can sometimes even lead to harm. However, there is still a role for nutritional supplements for individuals who are truly experi encing a nutritional deficit, whether due to a medical condi tion or malnutrition.

Vitamin D has been identified by Health Canada as a shortfall nutrient, in which a significant proportion of Canadians do not meet the average daily intake require ment. This has been attributed to lifestyle and environmental changes that have reduced our sun exposure, such as less time spent outdoors and increased air pol lution. Although vitamin D supplementation is recommended to maintain healthy vitamin D levels, it is important to emphasize that these supplements should be taken in moderation. High levels of serum vitamin D can lead to vitamin D intoxi cation, characterized by hypercalcemia and/or hyperphosphatemia impairing renal, cardiac, parathyroid, and brain functions.

- Karen Yeung

VITAMIN D

IMMpress Vol. 10 No. 2 2022 11

While there is a role for supplements in correcting nutri tional deficits, their importance for the general healthy pop ulation is less clear. The impact of nutritional supplements on preventing disease in healthy adults are conflicting, with some studies linking specific supplements to benefits in over all health, while others showing minimal or even negative outcomes.Nutritional supplements are classified by Health Canada as a sub-category of drugs under the umbrella term “natural health products” (NHPs), but are subject to different regu lations than other drug products. Unlike prescription and non-prescription drugs that are required by the Food and Drug Regulations to be labelled in plain language, NHPs are not required to follow a standardized labelling format. In consistent and inadequate access to information about NHPs can result in adverse reactions to other drugs or NHPs taken concurrently, unsafe dosing, or allergic reactions, especial ly as NHPs can be purchased without medical consultation or prescriptions. In 2011, the Canadian Institute for Health Information estimated that 12% of emergency hospitaliza tions were related to preventable medication errors, including improper NHP usage. Of note, one of the major reasons for hospitalization was accidental overdose.

Whether it be ingested or generated from sun exposure in the skin, vitamin D remains inactive until it reaches the liver. To be used in the body, vitamin D must be activated through two enzy matic steps, the first of which is in the liver and the second is in the kidneys, into calcitriol and 25-hydroxyergocal ciferol. These two compounds make up the biologically active forms of vitamin D that can be used to promote healthy tissue function and growth in humans.

Biology of Vitamin D

Vitamin D describes a group of fat-soluble chemical compounds that promote normal growth and devel opment, with vitamin D2 and D3 being the most important for humans. While essential vitamins cannot be synthesized by humans, vitamin D can be. The major natural source of vitamin D is a chemi cal reaction dependent on sun exposure that results in its synthesis in the lower layers of the

Alternativeskin.sources

Impact of Vitamin D on Health and Disease:

Despite these controversial findings, the vitamin D receptor and the enzyme involved in producing the active form of vitamin D are widely expressed in tis sues not involved in calcium, phosphate, or magnesium transport. As such, the importance of vitamin D in health and disease likely extend beyond skeletal health. Furthermore, many diseases in humans are reportedly associated with low serum vitamin D levels, as such, it is important to investigate whether vita min D plays a causal role in the devel opment of specific diseases.

Until we better understand the role of vitamin D in disease development, it is important that vitamin D be used wisely and provided to populations of people that are not taking enough to maintain a healthy nutritional status.

The impact of vitamin D on ex tra-skeletal tissues and organs are more controversial. Vitamin D deficiency has been shown to increase the risk and/or severity of various infectious diseases, including tuberculosis, HIV, and more

12 IMMpress Vol. 10 No. 2 2022

of vitamin D in clude certain foods, such as mushrooms, fatty fish and some milks that are for tified with vitamin D, as well as man ufactured supplements. Despite this, a large proportion of the world popula tion (~7%) do not take or have access to normal doses of vitamin D. When considering the potential health benefits of vitamin D, this raises several concerns that will be discussed in this article.

A D-lightful Vitamin: the importance of vitamin D for a healthy individual

recently COVID-19. There is also strong evidence that supports a causal asso ciation between low serum vitamin D levels and increased risk of autoimmune diseases, particularly multiple sclerosis. However, vitamin D supplementation provides only a modest decrease in can cer mortality and no effects on the inci dence of cardiovascular events.

- Baweleta Isho

One of the most well-known benefits of vitamin D is its role in calcium ho meostasis and metabolism to maintain skeletal health. In addition to calcium absorption, vitamin D also improves the intestinal absorption of nutrients such as phosphate and magnesium, which are necessary in the blood for improved metabolism and bone health. It is well understood that children deficient in vi tamin D can experience nutritional rick ets, a disease that results in bone pain, delayed motor development and bend ing of the bones. Further, supplementa tion with vitamin D and calcium in old er adults have been shown to decrease risk of hip fractures and other fractures by approximately 20%

Treat inflammation the natural way: the natural alternatives to ibuprofen

Over-the-counter and prescription non-steroidal anti-in flammatory drug (NSAID) medications like ibuprofen and aspirin are frequently used for joint- and spine-related in flammatory pain. Most NSAIDs work by reversibly inhib iting the activity of cyclooxygenase (COX)-1 and COX-2, the enzymes that produce pro-inflammatory prostaglandins (PGs). PGs are hormone-like substances with diverse roles in the human body, principally the processes that lead to the classic signs of inflammation: redness, swelling and pain. However, recent studies suggest that NSAIDs can lead to se rious side effects such as myocardial infarction, gastrointes tinal bleeding and ulcers, and stroke. Therefore, although NSAIDs can be effective, natural anti-inflammatory supple ments may provide a safer, yet potent alternative treatment for inflammatory pain relief. Natural products have served mankind for thousands of years - traditional herbal rem edies have been the main source of medicine for treating many different diseases throughout history, and modern medicine, in many cases, has advanced due to the use of natural products as lead compounds for the pharmaceutical industry. Since COX-2-mediated PG synthesis and free rad ical production are responsible for numerous inflammatory conditions, it is widely believed that phytochemicals with potent COX-2 inhibitory effects will demonstrate signifi cant analgesic and anti-inflammatory activity. This article will introduce some of the natural anti-inflammatory agents and foods that produce similar anti-inflammatory activity like classical NSAIDs, but with less side effects.

Curcumin

Omega-3 fatty acids

For most people, coffee is the first drink consumed in the morning to help them get through the day. Recently, many studies suggested that coffee can also fit into a healthy life style and act as an anti-inflammatory agent – largely due to the fact that it is rich in antioxidants, such as hydrocinnam ic acids and polyphenols, that neutralize excess free radi cals to reduce inflammation. One study showed that regular coffee drinkers had lower circulating levels of inflammatory markers compared to non-regular coffee drinkers, which may partially mediate the inverse associations of coffee with cancer and other chronic diseases. However, contradictory effects have also been reported. Some people may have in creased inflammation after coffee consumption. Therefore, a deeper understanding of potential impacts of coffee intake on individuals is needed.

IMMpress Vol. 10 No. 2 2022 13

Coffee

Although natural herbal medications may help alleviate side effects from NSAIDs, there may be potential adverse in teractions between some of the commonly used herbal med ications and analgesic drugs. Therefore, if you are interested in taking herbal medication, it is still important to consult with physicians before taking these herbal remedies to de termine the best anti-inflammatory medication for you.

- Tianning Yu

Fish oils contain omega-3 polyunsaturated fatty acids (PUFAs). Many of the biological functions of PUFAs are moderated via lipid mediators produced by fatty acid oxy genases such as COXs, lipoxygenases, and cytochrome P450 monooxygenases. The anti-inflammatory effect of omega-3 PUFAs is believed to occur by binding to oxygenases to re duce the formation of pro-inflammatory lipid mediators. Thus, fish oil warrants consideration for effective treatment for arthritis, especially rheumatoid arthritis.

Curcumin is a natural substance present in turmeric, the spice that gives curry its characteristic yellow color. Cur cumin acts as an anti-inflammatory by inhibiting COX-2 expression, thereby blocking the synthesis of PGs. Some clinical studies have shown that curcumin’s anti-inflam matory properties may help many inflammatory diseases, from arthritis to ulcerative colitis. One study on curcum in maintenance therapy for ulcerative colitis showed that 2 grams of curcumin a day in combination with prescription medication had significantly better clinical efficacy in the prevention of relapse in patients with quiescent ulcerative colitis. Thus, although it may not help during an active in flammation flare-up, curcumin seems to be a promising and safe way to prolong disease remission.

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Cravings to Extremethe

as the consumption and craving of non-food items over a period longer than a month, pica is a disorder that many may find overly bizarre and unrelatable. This disorder may also be best known to the public from its heavy coverage on the TLC show, My Strange Addiction, which follows individuals with com pulsive and “unusual” behaviours, such as pica. However, these widely documented cases of the compulsive eating of objects such as toilet pa per, cosmetics, and air freshener, may arise from reasons more complex than just liking their taste or texture.

Furthermore, association studies of individuals that exhibit pica be haviour have found that this disor der is correlated with anemia, low hemoglobin, and iron and zinc defi ciencies, making the cause (or causes) behind this disorder more compli cated than it might initially appear.

In some places, pica behaviour may be normalized, such as in the state of Georgia in the United States of America, where consumption of ka olin, or white clay, by African-Amer ican women is considered a cultural practice. Kaolin is also consumed widely in Africa and is thought to relieve nausea and gastrointestinal symptoms caused by early pregnancy.

While pica behaviour is largely seen in pregnant women, children, and people with developmental disorders, it has also been associated with psy chological stress stemming from famil ial and parental issues and emotional trauma. Other proposed causes of pica include gastrointestinal distress and obsessive-compulsive spectrum disor der, with the consumption of non-food items acting as a method to soothe or reduce physical or mental discomfort.

Defined

And while it might seem obvious, the consequences of pica can be quite severe. Consumption of materials such as broken glass can cause internal in juries while ingestion of dirt in areas where pesticides or other toxic envi ronmental pollutants can be found can lead to poisoning. However, treat ment of pica can be quite complex,

Lotito passed in 2007 at age 57 of natural causes, almost 30 years after consuming the Cessna, with no cas

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cats, eels, and lizards, and in a stay at a hospital, he was caught attempting to drink blood from bloodletting patients and to eat corpses from the morgue. He was even suspected in the disap pearance of a 14-month-old baby and was quickly removed from the hospi tal as a result of this.

In children, pica is often treated by alerting the parents and ensuring that the child is under heavier supervision to prevent any attempts to eat nonfood items. Another strategy involves ig noring the behaviour if the motivation is to seek attention, or to find an alternative to the non-food item if the patient ingests this item for a sen sory reason. Other treatments include therapy, the prescription of psychiatric medicine, and taking certain nutri tional supplements because, as previ ously stated, pica is shown to be as sociated with iron or zinc deficiencies.

[...pica is a serious and sometimes life-threatening condition that should be regarded with empathy and understanding.]

When he later died of tuberculosis, it was found that Tarrare’s esophagus was incredibly wide and that his body was full of pus. This aligns with the fact that in life, he was known for his largely distended mouth and abdomen and terrible odour that reportedly worsened after he ate. In his time, it was impossible to determine any underlying causes for his unusual appetite so we only know him now as one of the most bizarre and harrow ing stories of pica and polyphagia.

craft over the course of two years! And while it may seem difficult, or even impossible to chew or swallow all the materials found in an airplane, Lotito has a strategy to indulge his odd cravings—he breaks them apart into bits that he can swallow and drinks

However, these two cases are an anomalous extreme and patients with pica should not be viewed as exhibits in a freak show, which the television pro gram My Strange Addiction has long been criticized as doing. Instead, it is important to recog nize, that although potentially strange to those unfamiliar with it, pica is a serious and sometimes life-threaten ing condition that should be regard ed with empathy and understanding.

[...this disorder is correlated with anemia, low hemoglobin, and iron and zinc deficiencies, making the cause more complicated than it might initially appear.]

The range of pica behaviour can be as harmless as chewing ice cubes or chips to such extremes as regularly in gesting the material of bikes, television sets, and even planes in the case of Michel Lotito of France, also known as Monsieur “Mouth” Mangetout or Mr. Eat-All in En glish. From a young age, Lotito found that he preferred to ingest non-food materials and medical examination revealed that he had un usually strong stomach acids and thick gastrointestinal tract linings, which helped facilitate his pica behaviour.

and it is important to determine the cause of a patient’s pica behaviour.

- Faustina Lau

mineral oil to ensure everything goes down smoothly. With this routine, Lotito was awarded with the record for the ‘strangest diet’ in the Guin ness Book of Records. He even re ceived a plaque in commemoration of this, however, quite fittingly, he ate it.

Lotito went on to become an en tertainer with his act being the con sumption of absurd items, even once consuming an entire Cessna 150 air

es of pica so extreme since. However, more bizarre historical accounts of pica and unusual appetites include the story of a man known as Tarrare, who lived in the late 1700s. While Tarra re exhibited regular pica behaviours, such as ingesting corks and stones for entertainment, his other consumption habits were objectionable at best and abhorrent at worst. Tarrare would swallow whole, live animals, such as

GENE-UINE DISGUSTWHYDO WE DISLIKE CERTAIN FOODS

hydoweeatwhat weeat?Peopleenjoy eatingfoodsthatare notjustappealingtotheirtaste buds,butmoreimportantly, thatarenotunappealingto them.Whetherit’sdisgustover thetasteofcilantroorintolerancetoafoodgroupaltogether, thesciencebehindfoodpreferencesiscomplex.Factorsincludingallergies,genetics,socioeconomicalinfluences,and eventhegutmicrobiomehave beenimplicatedindetermining whatweeat.Geneticsspecificallyremainsapoorlyunderstoodcontributortodiet,althoughrecentresearchhas shedlightontoseveralgenetic variationsinindividualsthat canplayaroleindetermining whichfoodsweprefertoconsume.

-MatthewWong

Cilantroisn’ttheonlyexamplewhereanindividual’s senseofsmellcanaffecttheir dietarychoices.Asparagusis knowntoleaveafoulodour inurineafterconsumption,a by-productofasparagusic acidmetabolismthatgeneratespungentsulfuriccompoundsasawasteproduct. Yuck!However,somepeople areinluck.SNPsinolfactory receptorgenesonchromosome1havebeenassociated withthecuriousinabilityto smellasparagusinurine,a conditionknownasasparagus anosmia.Over50%ofCaucasianspossessalteredolfactoryreceptorsthatevadethe

putridstenchleftbehindby asparagus,possiblyinfluencingone’sdecisiontoinclude thesegreenstalksintheirdiet.

thepresenceofaldehydesin cilantroleaves.Peoplethat possessasinglenucleotide polymorphism(SNP)mutationinasetofolfactoryreceptorgenestendtoexperience thisphenomenonmorefrequently,suggestingthatvariantsoftheseolfactoryreceptorsareresponsibleforthe disagreeabletasteofcilantro duetodifferentialbindingto aldehydes.

Alongwithoursenseof smellandtaste,theabilityto metabolizefoodisalsoanimportantdeterminantinwhat weeat.Enzymesthataidin thedigestionofcommon foods,suchasdairyoralcohol,areoftenfoundlackingor dysfunctionalinsomepopulations.Forexample,SNPsin theregulatoryregionofthe lactasegene,whichistypically downregulatedafterinfancy, arepostulatedtocontributeto theretentionoflactaseinto adulthoodandtheabilityto consumedairyproductswithoutintestinaldiscomfort.This phenomenonismorecommon inpopulationswithpastoral ancestorsthatdrankanimal milk.Similarly,SNPvariants ofalcoholdehydrogenase (ADH)andaldehydedehydrogenase(ALDH)contribute toalcoholtolerance.Acetaldehyde,aby-productofalcohol metabolismviaADH,results innauseaandflushingasit

buildsupinthebody.Individualswith“fast”ADHvariants orinactiveALDHvariants (whichnormallybreaksdown acetaldehyde)tendtodrink lessalcoholduetothebodily discomfortcausedbythis toxicby-product.

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Althoughthefoodsand drinksweconsumeareheavilyinfluencedbytheenvironmentweareraisedin,itis clearthatourgeneticmakeup canplayasignificantrolein ourdietarydecisions.Gene variantscancausecertain foodstobeunpleasant–ifa mealtastesnastyorgivesyou theruns,chancesareyou won’teatitagain.However,at whatlevelgenesdetermine whatweenjoyeatingstillrequiresfurtherresearch.Asscientificgroupscontinuetoinvestigatethegeneticsbehind foodpreferences,itwillbeinterestingtouncoverhow muchofourdietisdirectlyaffectedbyourbiologicalcode.

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- Meghan Kates

Metabolic Disorders:

When

Finally, an analysis of metabolism cannot be completed without a consideration of the powerhouse of the cell, mito chondria. The possible errors in mitochondrial metabolism are legion and have been grouped into a general classifica tion of ‘mitochondrial disorders’ that are associated with a vast range of conditions including cardiovascular disorders, neurodegenerative disorders, cancer, obesity and many more. Most often, these disorders present in the body in tissues with high energy demand including the central nervous system, heart muscles, and skeletal muscles. Symptoms vary depend ing on the tissue of presentation. These disorders result from mutations in genes encoded within the mitochondria itself, or mitochondrial genes encoded in the nucleus.

“... metabolism is an extraordinarily complicated, diverse, and vital series of reactions ...”

Overall, metabolism is an extraordinarily complicated, di verse and vital series of reactions in the body that allow for proper functioning of cells. However, this complexity intro duces many areas for errors and dysfunction that can lead to severe, sometimes fatal clinical effects.

Diabetes is a result of some of the most common defects in the body’s ability to use energy. Broadly, this con dition involves defects in system ic metabolism due to progressive dysfunction in the pancreas’ ability to create insulin, a hormone involved in regulating blood glucose levels. However, errors in metabolism can also occur at the cellular level. Metabolic defects often stem from genetic mutations that can impair breakdown, accumulation and usage of components involved in cellular function.

Critical Missteps in Metabolism

Gaucher’s disease is an important example of such ge netic mutations. It is an autosomal recessive condition in which individuals have a mutation in the gene GBA that is responsible for creating a protein involved in breaking down an important component of the cell membrane, called glyco sphingolipids (GSLs). Therefore, errors in this protein lead to accumulation of GSLs in cells, often in a type of immune cell called macrophages. This accumulation in macrophages can lead to heterogeneous clinical presentation, affecting a vari ety of organ systems. One type of Gaucher’s disease can lead to enlarged spleen and liver, bone disease, errors in blood coagulation and sometimes lung, renal and cardiac dysfunc tion. Gaucher disease can also be fatal a few weeks after birth when the central nervous system is affected. Treatment in volves rendering the protein functional in macrophages in fused into the patient, using synthesized protein, or reducing the synthesis of the GSLs.

considering metabolism, what may first come to mind is the breaking down of dietary compo nents to make energy for us to perform our daily tasks. However, metabolism is an intricate, complicated pro cess that involves many chemical reactions in the body that modify, break down, store, and use a variety of molecules. Correct functioning of these reactions is important for all body systems and the ease of our daily actions. When these processes go wrong, severe consequences may occur.

Another genetic metabolic disorder is hemochromatosis which involves an excess of iron in the body that is often caused by defects in proteins responsible for acquiring or reg ulating iron. Iron is needed for the normal function of cells, but excess amounts can be toxic and lead to free-radical in duced tissue damage that causes clinical disease. The most common mutation is in one particular locus of the homeo static iron regulator (HFE) gene. Despite how common this mutation is in hemochromatosis, there is still great variety in disease severity. Symptoms appear gradually as indi viduals accumulate iron over time and can be par ticularly severe in the liver, joints, anterior pituitary and pancreas. It can therefore lead to liver dysfunction, car diac issues, diabetes mellitus, etc. Treatment involves taking blood from patients at regular intervals to reduce the amount of iron in the body.

“Several groups, including ours, have found certain metabolites [like pantoth enate] to be enriched in the pre-treatment blood of patients who would respond to immunotherapy. So, I think another trans lational aspect would be to increase the lev els of metabolites in patients prior to im munotherapy to see if this could increase response.”

pantothenate/coenzyme A metabolism, which are precursor substrates of the Krebs cycle.

An Interview with Dr. Michael St. Pau l

Venturing into the field of metabo lism Michael’s first exposure to immu nology research was during his master’s degree at the University of Guelph. His the sis involved identifying methods to enhance innate immunity against avian influenza vi rus using chickens as an animal model. After graduating however, a different field piqued his interest.

In 2012, Michael joined the Department of Immunology as a PhD student under the su pervision of Dr. Pamela Ohashi. At first, his project had nothing to do with metabolism. Michael was comparing the anti-tumor capa bilities between different CD8+ T cell subsets and demonstrated that IL22-producing cyto toxic CD8+ T cells (Tc22) were very effective at controlling murine tumor growth.

Those findings were published a few months ago in Cell Metabolism. Compared to other CD8+ T cell subsets, Tc22 cells have enhanced oxidative phosphorylation (OXPHOS), an important pathway in the mitochondria that generates ATP. This was attributed to greater

“The role of the immune system in cancer treatment was beginning to be appreciat ed and I was interested in identifying ways in which we could make T cells kill tumor cells better.”

“The most exciting aspect is that metabolic pathways can have profound implications on T cells, and by flipping various meta bolic switches it is possible to drastically alter T cell phenotype and function.”

Manipulating Metabolism:

“We were seeing hints there were metabol ic differences in [Tc22 cells], and further investigation led us to uncover some inter esting metabolic findings.”

For example, enhancing OXPHOS in T cells increases persistence and effector func tions. When asked about the potential clinical implications of T cell metabolism research, Michael believes the focus will be on adop tive cell therapy products. This immunother apy involves expanding tumor-reactive T cells in vitro, then infusing them back into cancer patients. There’s an opportunity during the expansion process to add small molecule in hibitors, cytokines, co-stimulatory molecules, or even genetically modify the T cells to boost their metabolic function. Moreover, Michael believes there’s another method that could prove useful.

Nutrient-limited, hypoxic, and acid ic-the microenvironment of solid tumors is like a battlefield for effector T cells. What can be done to allow T cells to survive such a hostile climate and ex ert their anti-tumor functions? I caught up with a recent alumnus of the de partment, Dr. Michael St. Paul, to talk about T cell metabolism, cancer immu notherapy, and his journey as a scientist.

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“Not really. Ramen still makes up 50% of my diet.”

Michael and Sam gave crucial input to each other’s proj ects, resulting in multiple co-authored papers and a lifelong friendship.Towrap

up, I asked Michael if studying metabolism made him more conscientious about his own lifestyle choices.

A new chapter

- Stephanie Wong

Lessons learned

Michael’s PhD journey also demonstrates the value of col laboration. He worked closely with many fellow lab members and external researchers, but none closer than Dr. Sam Saibil. Sam is an alumnus from the Ohashi Lab and is currently a clinician-scientist appointed at the Department of Immunol ogy. The pair were often seen in deep intellectual conversa tions, whether it was at the lab bench or over a cup of coffee.

Michael is now a Post-Doctoral Fellow in Dr. Tak Mak’s lab at Princess Margaret Hospital. His research has shifted away from metabolism but he is still interested in improving T cell anti-tumor functions. Currently, his project involves finding novel tumor antigens and exploring how tumors evade T cells using cancer patient specimens. For now, Michael is open to working in academia or industry. Regardless of the path he chooses, he intends to stay in the field of cancer immunology and immunotherapy.

“My biggest takeaway was honing my ability to ask a good scientific question. Dr. Pam Ohashi was amazing and encouraged us to ask our own research questions. Half of the time, the questions I thought of ended up not being very good but going through that process myself and learning from those experiences was really beneficial and helped me to become a better scientific researcher.”

Touché, Michael.

Michael successfully defended his thesis during the height of the pandemic in 2020. I asked Michael to reflect on the high lights of his PhD experience.

“Sam is incredibly knowledgeable in the field of metabo lism, immunology, and cell therapy. So by bouncing ideas off each other and discussing the latest papers we were able to come up with some pretty cool ideas together; some of which have led to some unexpected findings.”

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In contrast to Western diets, Mediterranean diets are en riched in vegetable-derived protein, vitamins and unsaturat ed (healthy) fats. This diet has been associated with anti-in flammatory effects, a decreased rate of chronic diseases and increased longevity.

We can usually name the broad goals of a diet — weight loss, gut cleansing, or “healthy eating.” Yet, oftentimes, we are unaware of how these diets affect our bod ies on a cellular level and impact how the cells get energy, function and behave. This article will focus on how diets affect our immune system specifically.

The Western diet is perhaps the most thoroughly re searched diet. It is a modern-day diet rich in refined sug ars, salt, processed meats, and saturated fats derived from animals while containing low fibre, vitamins, and minerals. Research from various disciplines has shown that the popu larization of the Western diet and lifestyle accounts for the drastic increase in chronic inflammation and non-communi cable diseases worldwide, including most heart diseases and cancers.AWestern

The Western diet also affects gut microbiota composition, causing microbial imbalances in the gut. This, in turn, sab otages gut-dependent processes and contributes to increased cardiovascular risks and autoimmune diseases.

Mediterranean Diet

As part of the adaptive immune system, lymphocytes, in cluding T cells and B cells, are also impacted by obesity. The balance between two T cell subsets, Th1 and Th2, is bro ken when the body is in an obese state, rendering the body more susceptible to inflammation. B cell concentration also increases under obesity, worsening insulin resistance.

How Are Diets Changing Our Immune Systems?

“I am on a diet.” is probably one of the most commonly heard sentences these days. With or without a specific aim in mind, most of us have tried to be on a particular “diet” regimen. Diets, in nutrition, are defined as the sum of food consumed by a person. Nowadays, it often implies the intake or avoidance of particular food.

diet meal impacts both branches of the immune system: adaptive and innate immunity. Macrophages, a type of innate immune cell, are involved in engulfing and degrad ing infected cells and foreign pathogens. These cells are par ticularly susceptible to the stress induced by animal-derived fats in a Western diet. Obesity caused by excessive caloric intake also alters the natural localization of innate immune cells, which correlates to increased systemic inflammation.

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Western Diet

So far, it seems like all the “healthy” diets mentioned have been shown to reduce the level of inflammatory responses in the body, on top of other pro-immune effects. However, as we will learn throughout this issue of IMMpress, gut micro biota composition and balance are essential for maintaining health. Sudden changes in diets can often cause drastic chang es in the gut microbiota population and behaviour, leading to unpredictable or undesirable effects. We should always keep in mind that there is no one-size-fits-all diet, and we should all ensure we understand the impact of a diet before jumping into one.

Studies have also investigated the effects of fasting during Ramadan, the month of fasting for Muslims. Over the month of Ramadan, the level of proinflammatory cytokines, the concentration of circulating leukocytes and the cell prolifera tion rates in the body were all significantly reduced compared to before Ramadan. This suggests that IF practiced during Ramadan effectively reduced the level of inflammatory pro cesses in the body.

Fasting as a dietary option has gained popularity over the years, with the duration ranging from a couple of hours a day to multiple days as a “system cleanse.” The 16/8 intermittent fasting (IF) regimen is the most popular version of fasting. Dieters restrict their eating period to only an 8-hour window, for example, from 8 am to 4 pm, and refrain from eating for the remaining 16 hours of the day.

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However, so far, no studies have attempted to uncover if or how a paleo diet alters immunity on a cellular level.

IF also promotes a cellular activity called autophagy, a natural degradation method to remove dysfunctional compo nents of the cells. Autophagy plays an essential role in regu lating the activation and responses of specific T cells. IF also reduces biomarkers of inflammation in the body and decreas es fat mass, which correlates to lower levels of proinflam matory cytokines. Combining the effects of both reducing inflammation and promoting T cell activation, IF has been suggested as a possible defence mechanism against SARSCoV-2 infections.

The paleolithic diet, or the cavemen diet, is a diet that attempts to resemble what human hunter-gatherer ancestors ate during the Paleolithic era. This diet avoids any processed food, grains, legumes, vegetable oils and most dairy prod ucts and emphasizes the intake of fruits, vegetables, meat and fish. In fact, derivatives of paleo diets have been adopted and advocated for to alleviate the symptoms of some immune dis eases.The

modified paleolithic Wahls diet is one of the two di ets promoted for multiple sclerosis (MS). Despite the precise pathogenesis of MS being unknown, numerous studies have shown that the Wahls diet promoted mobility and improved symptoms of MS, including fatigue.

- Evey Zheng

A recent study showed that people going on a 14% caloric restriction over two years had a drastic increase in the gener ation of new immune cells and overall decreased proinflam matory gene expressions.

A study demonstrated that macaques on a Mediterranean diet, compared to those on a Western diet, had lower expres sions of proinflammatory genes in monocytes, the precursors of macrophages. The diet also inhibited a specific type of monocytes, M1 monocytes, and their downstream M1 mac rophages, known to be associated with chronic diseases.

Unsaturated fats, found in olive oil and nuts in the Med iterranean diet, can, in fact, dampen the deleterious effects caused by saturated fats and promote the functionality of innate immune cells. Fibres, another component enriched in the Mediterranean diet but lacking in the Western diet, are also crucial in regulating immune functions. Certain fibres have been found to promote the differentiation of a subset of T cells called regulatory T cells, essential for preventing autoimmune diseases. Moreover, a diet high in vitamins and fibres has also been shown to ameliorate intestinal inflamma tion and restore bacterial composition in mouse models.

Paleo Diet

According to the Autoimmune Association, the Autoim mune Paleo (AIP) diet is suitable for people with autoimmune or inflammatory conditions such as psoriasis, celiac disease and inflammatory bowel syndrome. AIP diet also focuses on eating more vegetables and fish, aligning with the paleo diet principles, while avoiding food that people with autoimmune diseases commonly react to.

Eating Less or Not Eating at All

IMPACTOFTHEGUTMICROBIOTA ONIMMUNOTHERAPYRESPONSES

hottopicnowadaysis discussionssurrounding themicrobesinourgut andthenumeroushealth benefitstheyprovide. Whatisn’tasfrequentlydiscussed, however,ishowgutmicrobialcompositioncanimpactanindividual’sresponsetocancertreatments.

Consideredanimportantscientific breakthrough,immunotherapyactsto stimulatethebody’simmunesystemto recognizeandkillcancercells.Several typesofimmunotherapiesexist,includingimmunecheckpointblockade (ICB),adoptiveTcelltransfers,and cancervaccines,tonameafew.Eachof thesetreatmentsworksdifferently. ICB,forexample,targetscheckpoint moleculesthatactas“brakes”ofthe immunesystem,resultinginimmune cellactivation.Unfortunately,lessthan 30%ofpatientsbenefitfromICB. Whyexactlythishappensiscomplex butsomeofthediverseclinicalresponsestoICBcanbeattributedtodifferencesinthegutmicrobiome.

patientswithadvancedepithelialtumorswasattributedtobetterresponsestoatypeofICBtreatment.On theotherhand,thepresenceofcertain bacteriacanalsonegativelyinfluence immunotherapyresponses. Ruminococcusbromii isabacteriumthat breaksdowncomplexsugarsinthegut anditsabsenceisassociatedwithbetteroutcomesinlungcancerpatients.

Thegutmicrobiomeiscomposed oftrillionsoftinyorganismssuchas bacteria,fungi,parasites,andviruses andtheirpresenceorabsencecanpredictapatient’sresponsetoICB.Researchersstudythefecalcomposition ofpatientsonICBtogainkeyinsights intotheirgut’sbacterialdiversity,or lackthereof.Forexample,theabundanceofthebacterialspecies Akkermansiamuciniphila infecalsamplesof

Eventhoughthegutmicrobiota modulatesresponsestoimmunotherapies,itsunknownhowtheydothis.

Finally,notunlikeothercancertherapies,therearevarioustoxicitiesassociatedwithimmunotherapy.Amajor sideeffectofICBiscolitis,orcoloninflammation.Hereagain,thepresence ofaGram-negativeanaerobe, Bacteroidetes,helpedtodampentherisk ofdevelopingcolitisinpatientsonICB.

-AmmarahNaseer

Patientsundergoingcancertreatmentsareoftenprescribedantibiotics astheyaremoresusceptibletoinfections.Whilehelpfulinpreventinginfections,antibioticscanalsoreduce thenumberofbeneficialgutbacteria, resultinginreducedimmunotherapy treatmenteffectiveness.Cancerpatientswhohadantibioticsadministeredwithin60daysofimmunotherapyfaredworsethanthosethat weren’tgiventheantibacterialdrugs. Antibioticsareadouble-edgedsword andcliniciansneedtobecognizantof bothdosageanddurationtoproperly treatpatientsreceivingICB.

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microbiota has been im plicated in a range of disorders including metabolic diseases, irritable bowel syn drome, and neurological disorders. To assess a causal link between the gut mi crobiota and disease, germ-free mouse models are commonly used where the mice are transplanted with feces from human donors. In a study conducted by Gérard et al. fecal microbiota trans plant from donors with non-alcoholic fatty liver disease (NAFLD) into mice caused them to gain more weight and have increased fatty liver deposits when compared to mice transplanted with healthy donor feces. These results con firm that the gut microbiota plays a role in the development of NAFLD and can inform the creation of therapeutic strat egies that target the microbiome.

Anmodels.altered

“Ours bodies are spaceships for mi crobes” is Dr. Allen-Vercoe’s micro biology lab motto at the University of Guelph. Amusing, yet completely on point. If earth is a rock hurtling through space harboring an extensive network of ecosystems, we can think of ourselves as a microcosm of the same phenom ena. A single human body carries 39 trillion microbial cells, outnumbering human cells at a ratio of 10:1. Micro bial communities inhabit the deserts of our skin, the wetlands of our mucosal surfaces, and the rainforests of our gut. Collectively, these communities con stitute the human microbiome – with which we live in symbiosis. Our micro biome helps us digest food, regulate our immune system, and protects us from pathogens.Mostof the bacteria in our microbi ome are unculturable and thus it took until the invention of DNA sequenc ing in 1977 for us to begin to under stand the vastness and complexity of these microbial communities. The last two decades have seen an explosion of microbiome research. Sequencing has become cheaper and computers expo nentially more powerful, thereby in creasing our knowledge of the symbi otic relationship between humans and microbes radically. While sequencing the first human genome in 2001 took upwards of $2.7 billion and 15 years to complete, today sequencing a human genome costs around $1400 and takes less than a week.

We can look at which bacteria are present in the microbiome by sequenc ing the 16S ribosomal gene which is only present in bacteria. This method is quick and inexpensive but lacks in formation relating to other microbes (Archaea and Eukaryotes) and the

Since the coining of the term “mi crobiome” in 2001, scientists have only scratched the surface of our relationship with microbes. Yet, ongoing research in this field is continuing to show a deep interconnectedness between humans and the natural world. Future advanc es in omics technologies will allow a deeper understanding of how microbes influence us, and we will be able to har ness their power to help treat a plethora of diseases. It’s an exciting time to be a microbiologist..

- Marie-Christine Perry

functional capacity of the microbiome. To study this, scientists apply “omics” style analyses like metagenomics, me tatranscriptomics, and metabolomics. Metagenomics tells us the collection of genes present, metatranscriptomics re veals the genes being expressed and me tabolomics identifies metabolites pro duced by microbes. By combining these omics analyses, multi-omics approaches can help us to discover associations be tween the presence of specific bacteria, gene expression, and the production of certain bacterial by-products. When combined with human disease data, we can use this data to uncover patterns between the functional capacity of the microbiome and disease states. These findings generate hypotheses which must be validated using biologically-rel evant

In some cases, the complete replace ment of the microbiota has been shown to be curative against disease. The standard of care for recurrent C. dif

ficile infection is now fecal microbiota transplant, with a success rate between 80-90%. However, the need for healthy fecal donors and the inherent variation of the microbiome from person-to-per son highlights the need for standard ized microbiome therapeutics. One company, NuBiyota, which spun out from Dr. Allen-Vercoe’s lab, is work ing to address this issue. The team at NuBiyota is working to create defined Microbial Ecosystem Therapeutics (METs) constructed from healthy do nor isolates. NuBiyota uses “Roboguts” – bioreactors that mimic the human co lon, to culture defined communities of microbes. These communities are pro cessed and can then be administered orally in capsule form. In the future, microbial therapeutics have the poten tial to treat disorders ranging from dia betes to generalized anxiety.

BlastingResearchMicrobiomeisOff

IMMpress Vol. 10 No. 2 2022 23

IBD is a heterogeneous group of disorders (including Crohn’s disease and ulcerative colitis) characterized by chron ic inflammation along the intestinal tract and is suggested to be caused by a combination of genetic and environmen tal factors that leads to an inappropriate immune response to the gut microbiota. Conventional IBD treatment options, primarily anti-inflammatory and immunosuppressive drugs, have been designed to alleviate symptoms, prevent further complications, and restore damage to the intestinal mucosal layer. Although there are many medication options available, there is still a serious proportion of individuals with IBD who fail to respond or lose their response to medication. Adverse reactions to medication can also occur in some patients, es pecially in those who have other comorbidities. In Canada, approximately $1.28 billion is spent annually on IBD care as Canadians experience one of the highest rates of IBD.

BeforeRestoringFMT

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the Balance of the Gut Microbiota: How Our Feces Can Help Fight Inflammatory Bowel Disease

ytLowBacterialDiversi

Everyone has heard of kidney, heart, or other organ transplantations but many people may be surprised to discover that transplanting intestinal microbes is emerging as a promising new treatment option for sever al gastrointestinal, metabolic, and neurological disorders. Microbes in the intestinal tract, or the gut microbiota, play a pivotal role in both metabolic and immune function. Al though everyone has a unique composition of microbes in the intestines, a healthy gut is highlighted by microbial diversity and stability. An imbalance in the composition of bacterial species in the gut is associated with the pathogenesis of many disorders, such as inflammatory bowel disease (IBD).

Fecal microbiota transplantation (FMT) is designed to re store this balance by replenishing the gut with bacteria iso lated from the feces of healthy donors. Fecal samples contain billions of live bacteria that originate directly from the gut and can be administered to recipients either through direct intestinal infusions or through oral capsules. There are other treatment options that can influence the gut microbiota, such as prebiotics or probiotics, however, these methods only sup port the growth of specific species of bacteria. FMT is advan tageous since it can provide a wide variety of bacterial species spanning the entire ecosystem of a healthy individual’s gut microbiota. FMT has been demonstrated to successfully cure 90% of people who have a recurrent infection from a bac terium, Clostridioides difficile. FMT is now emerging as an exciting potential treatment option for IBD.

FMT differs from other IBD therapeutics as the intended outcome for treatment is to ultimately cure IBD. Currently, the effectiveness of FMT for IBD treatment remains unclear. There has only been a limited number of controlled clinical trials testing FMT treatment for IBD. Although the results of these studies have been conflicting and treatment outcomes have not been as remarkable as for treating C. difficile, sever al groups have identified that more patients have undergone clinical remission after FMT compared to the placebo. Nota bly, in one study, remission success rates were higher in IBD patients who had a greater enrichment of the transplanted bacteria.

ytIncreasedBacterialDiversi

FMT donor selection is determined by donor health, age, BMI, and fecal weight. Although FMT doesn’t require specif ically matched donors like organ transplantation, identifying donor samples with particular bacterial species compositions may be beneficial. For example, higher concentrations of E. hallii and R. inulivorans following FMT have been associat ed with greater remission outcomes. Additionally, a decline in members of Lachnospiraceae family and the Bacteroidetes phylum can be seen in the IBD microbiota in the absence of FMT treatment. Moreover, the heterogeneity of IBD suggests that a personalized approached may be necessary to fully cap ture the potential of FMT for IBD

FMTtreatment.incorporating fecal samples from multiple donors is another way that can po tentially amplify FMT effectiveness. It was recently demon strated that FMT using fecal microbes from multiple donors increased bacterial diversity in IBD patients and improved patient outcomes compared to FMT that used a singular donor per recipient. Another option that can potentially im prove the success rate of FMT is to administer antibiotics and deplete some residents of the gut microbiota prior to transplantation. The combination of antibiotics and FMT has been identified to improve remission rates, however, the process of determining which antibiotics to use has yet to be

While in the short-term FMT appears to be relatively safe, the long-term safety of FMT has yet to be fully evaluated and some long-term adverse events have been reported, includ ing depression (2%), arthritis (7%), and allergic bronchitis (2%). Despite the uncertainty surrounding the safety and ef fectiveness of FMT, approxi mately 20% of ulcerative colitis patients and 80% of patients with Crohn’s disease will re quire intestinal surgery in their lifetime which should be con sidered when evaluating the potential benefits of FMT.

After FMT

“FMT differs from other IBD therapeutics as the intended outcome for treatment is to ultimately cure IBD.”

IMMpress Vol. 10 No. 2 2022 25

standardized. FMT optimization is still in its infancy and po tentially incorporating donor personalization, multiple donor selection, and antibiotic use makes FMT an attractive thera py for further development.

Ultimately, FMT appears to be a promising treatment op tion for IBD, although we still need a better understanding of the causes and mechanisms behind the pathogenesis of IBD to harness the full potential of FMT treatment for IBD. It will be interesting to see whether FMT will become the primary treatment option for IBD in the next decade or if the excite ment will eventually diminish.

- Daniel Zangrando

different times of the day results in different disease outcomes. This effect was attributed to the functions of macrophages, a specialized immune cell that is crucial in detection and de fense against pathogens, which was regulated by a circadian clock gene. This temporal effect suggests that regulating our circadian rhythms may be beneficial in bolstering our immu nity, particularly for those with higher risk of infections. In line with this, sleep deprivation can also affect response to certain vaccines, resulting in lower levels of antibody titers.

last few decades of research has revealed that sleep supports our immune systems, playing a crucial role in both innate and adaptive immunity. Our sleep-wake cycles are regulated by circadian oscillations, natural processes that are driven by exposure and response to light. Accumulat ing evidence suggests that many of our immune cells follow intrinsic clocks as well, where their activity, migration, and functions are regulated by core circadian genes. It has been shown that during sleep, serum levels of proinflammatory cytokines peaks, while numbers of immune cells flow and ebb. Sleep disturbances (due to interrupted sleep or altered sleep patterns) disrupts this clockwork, resulting in a shift in increased cytokine production during waking hours rather than during sleep. This shift is accompanied by a decreased anti-viral responses, potentially conferring increased sus ceptibility to infectious disease. In fact, human studies have found that a lack of sleep is associated with higher risk of in fections. Partial sleep deprivation is associated with reduced T cell frequencies and natural killer cell activity, both crucial cells in fighting against pathogens. Moreover, sleep was re ported to affect T cell migration and improve T cell activity.

Understanding the cross-talk between circadian clock and our immune system will undoubtedly reveal insights into the mechanisms that govern these interactions and how regu lation of sleep contributes to these systems. The next time you contemplate whether or not to go to bed, remember that curtailing sleep, unfortunately, does have long term conse quences.

sleep and immunity

- Siu Ling Tai

Not only does sleep affect immunity, but immune respons es can also affect your quality of sleep. Higher levels of in flammation are correlated with changes in sleep duration and disrupted sleep patterns. Exposure of mice to influenza virus leads to changes in sleep architecture – decreases in rapid eye movement (REM) sleep – and longer sleep continuity. During infection, many proinflammatory cytokines are released, in cluding interleukin (IL)-1β. Administration of this cytokine directly into the cerebrospinal fluid of rabbits and rats was shown to increase the duration of non-REM sleep, otherwise known as deep sleep, impacting sleep pattern.

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A s a kid, my father always emphasized the importance of sleep. Little did I know, as I hid under my blankets, reading a novel with a flashlight, that I was weakening my immune system.The

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These changes in response to sleep deprivation are con served across species, suggesting an important regulatory role of the circadian system in immunity. Although the mech anisms and evolutionary factors for this response are not yet fully understood, studies have shown that infecting mice at

A Brief Introduction to

Finally, parasites are a large group of organisms that can be single-celled, like protozoa, or multi-cellular like ringworms. The commonality between these organisms is that they typ ically live, reproduce, and thrive at the cost of their hosts, as well as usually residing in or on them. Parasitic proto zoa, such as members of the Cryptosporidium genus cause diarrheal diseases and even death in very young or immu nocompromised people. Another, much larger parasite, the tapeworm, is typically ingested and absorbs nutrients from its hosts, growing up to 15 metres on occasion!

Bacteria are single-celled organisms that are found all throughout our planet, from the coldest of poles to the deep est of hydrothermal vents. Some have even been found to originate from outer space! However, one of the most widely known habitats for bacteria is the human body. And while it may be alarming to learn that these tiny microorganisms exist in areas like your mouth, gut, and all over your skin, you should be relieved to know that the majority of these bacteria are not harmful in the least. In fact, some might even provide benefits to you, like helping you digest certain foods or produce vitamins for your body to use. Some very prom inent bacteria include Yersinia pestis, the causative agent of the Black Plague, and Clostridium botulinum , the producers of the deadly botulinum toxin, which is also used for medical and cosmetic procedures.

said cell. Unlike bacteria, viruses can’t reproduce outside of the cells of other beings, and they don’t provide the bene fits of bacteria, like vitamin production or food digestion. In fact, viruses have been shown to be the causative agents of some of the world’s worst diseases, like AIDS, Ebola, and COVID-19. Like bacteria, they exist in great quantities on and in the human body, although thankfully, the majority of them are incapable of infecting your cells.

ith health and infectious disease concerns sweep ing the world over the past few years, it might be concerning to learn that causes of disease can be anywhere and everywhere in our lives. However, it’s also im portant to know that many similar harmless microorganisms are just as, if not more, abundant than harmful microorgan isms, and while it might take many years to learn all about every single one, here is just a quick breakdown on the main categories of these agents of disease.

- Faustina Lau

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Viruses, on the other hand, are not cells at all. They’re simply nucleic acids, like DNA or RNA, pack aged in protein, and some times bits of their host cells that they’ve taken infectingafter

While it might be daunting to know that the world is full of disease-causing organisms, and that you’re practically crawl ing with microbes, it may be reassuring to be able to differen tiate between them and know that many of these tiny things are harmless. But as usual, always remember to wash your hands and cook your food thoroughly to ensure limited con tact with harmful, disease-causing microbes!

sue. Obesity is a complex metabolic condition that is chronic, debilitating and deeply intertwined with the increased risk and occurrence of several metabolic disorders. Weight loss and weight management for people who are obese becomes imperative not because they need to look shapely and meet societal beauty standards but because they need to avoid un necessary, and sometimes deadly health complications.

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The Secrets of Resting Metabolism

While it is rather simple to determine your calorie intake, it is significantly more challenging to determine your resting metabolic rate. Resting metabolic rate, or RMR, is the total

sedentary and consuming fast food are habits that have stealthily entered our fast-paced Western lifestyles and are common contributors to obesity. In response, most of us have either aimed to become healthier or at least known someone who has pursued this goal for themselves. Technological and social advancements have increased our risk of developing a range of diseases and disorders, while simultaneously increasing our awareness of the need for healthy living. Availability of healthy food alternatives at gro cery stores, podcasts on healthy living, YouTube tutorials on home exercises and health-tracking apps are some instances of how healthy living is now more accessible than ever before. The age-old idea of a healthy mind in a healthy body is also picking up traction once again as we become more conscious of mental health issues being commonplace in our society. All of this converges at one question: how do we make ourselves healthier?But,before we get ahead of ourselves, how do we deter mine if we are indeed healthy? For a long time, a person’s body mass index, or BMI (kg/m 2), and their waist to hip cir cumference ratio have been primary measures of their body weight status and are still popularly used to categorize people as underweight, overweight or obese. While these indicators are extremely useful, they only scratch the surface of the is

Being

A notion that is common to any kind of weight loss pro gram is creating a caloric deficit. This simply means — con sume fewer calories than you burn. Crudely put — “Eat less, exercise more.” This sounds like a sure, easy formula for suc cess. However, it does not always translate into weight loss for everyone. There are many questions to be answered. For starters, how many calories do you burn every day? This is called the total daily energy expenditure or TDEE. While an average adult burns 1800-2100 kCal/day, this number is an average estimate and can vary from individual to individu al. Knowing the number of calories that you burn every day would help determine how many calories you would want to consume each day such that you lose weight.

“Fat to Fit” While you Sit?

While all of this may seem too excessive and unnecessary, obesity is indeed quite complex by design. There are several genetic and environmental factors at play. A key environmen tal factor that has historically been overlooked, but has now been speculated to regulate the RMR, is the gut microbiota.

calories burned by your body when you are completely at rest. This is the energy your body requires to keep itself func tioning and is the major portion (60-75%) of your TDEE. Each physical action requires energy and hence, burns calo ries. Deliberate physical exercise generally contributes only 15-30% of your TDEE unless you are an endurance athlete or an Olympic swimmer who undergoes regular rigorous training.There

will. People aiming for weight loss usually follow a regimen that is a combination of dietary interventions and physical activity. While short-term physical activity has been shown to increase your RMR, the effect of long-term physical activ ity on RMR is more convoluted. Put simply, the RMR can be most closely correlated to the lean mass or fat free mass (FFM) in the body. As one exercises or cuts down on their calories, their overall body weight decreases, and so does their FFM. A reduction in FFM translates to a reduction in RMR, which is undesirable. Hence, it is optimal to design your workouts and nutritional plans such that you lose weight while the in evitable loss of FFM is minimized. Reducing the ratio of car bohydrates to proteins in your diet and weight training have been shown to help achieve this goal.

A public health perspective published in 2015 consolidat ed data from the existing scientific literature to conclude that “no single value of the RMR is appropriate for all adults”. The average estimates available online are likely an overesti mation of one’s actual RMR. Several factors including age, sex, body weight and height can impact your RMR. Many mathematical equations have been devised over the years to calculate this ever-elusive magical number of the RMR. Two of the popular ones are the Harris and Benedict equation and the Mifflin-St Jeor Equation. We do not need to worry about the complexity of their names or their mathematical nature as several free online calculators are readily available and can give us relatively accurate measures of our RMR and TDEE.

are several questions around the RMR that have long puzzled researchers, doctors and fitness enthusiasts alike. How widely does the resting metabolic rate vary from person to person? Can it be increased through long-term physical activity? Does your gut microbiota impact your rest ing metabolic activity? How significant is this impact?

RMR is calculated based on several factors. Interestingly, while one has no control over factors such as their age, sex, or height; physical activity is a factor that can be regulated at

HealthyUnderweightWeightOverweightObesity BMI Weight Status Below 18.5 18.5 - 24.9 25 - 29.9 30 and Above

mice treated with risperidone, an antipsychotic drug, showed drug-dependent weight gain. Fur ther probing into this apparent obesity of the mice revealed the underlying reduction in their resting metabolic activity. There was a whopping 16% reduction in the RMR of these mice which was later confirmed to be caused by a shift in their gut microbiota. This 16% reduction is roughly equiva lent to a human adult consuming an extra cheeseburger every day. This study was repeated in humans and a similar effect was observed. This was also attributed to microbiota as a reduction was observed in the ratio of Bacteroidetes to Fir micutes, two types of bacterial phyla commonly found in the gut. The microbiota in our gut, thus, may be actively involved in regulating our resting metabolism.

- Manjula Kamath

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The gut plays a central role in metabolism and is home to a plethora of microbes that are important for our surviv al. In mice, depletion of the gut microbiota has been shown to reduce the amount of weight loss achieved upon calorie restriction. It has been shown to cause an attenuation in the metabolic rate, a reduction in lean mass (or FFM) and an increase in fat mass. Conversely, calorie restriction has been shown to cause a shift in the microbiota towards more probi otic, healthy bacteria such as Lactobacillus and Bifidobacte rium along with a concomitant decrease in harmful bacteria such as AnotherHelicobacter.studyinvolving

Our bodies work in mysterious ways – from the food on your plate to the microbes in your gut, everything is a part of your weight loss journey. While there is no shortcut for hard work in life, sometimes shifting your perspective can help make the goal look more achievable. Obesity is not a “lazy fat person” problem. Being “fat” and “lazy” may both be symp toms of this multi-faceted issue, but the cause lies deeper – it may be your lifestyle, it may be your genes and it very well may be the invisible microbes in your gut!

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The use of fermentation quickly expanded to oth er foods: bread made by Egyptians in 3500 BCE, pickles made by Mesopotamians in 2000 BCE, kombucha made by the Chinese in 200 BCE, and fermented corn drinks like tejuino made in pre-Hispanic Mexico. It wasn’t un til 1856 when Louis Pasteur discovered forces he called “ferments”, what we know today as the catalytic action

of yeast metabolism, that we began to understand fermen tation as a process of life, not death. Further advances in microbiology helped to turn fermentation into an indus trial process. New techniques in food science have refined the composition of microbes used in fermentation and led to entirely new food products like the Impossible Burger.

There is some evidence to suggest that fermentation in creases the vitamin content of some foods. Tempeh, a tra ditional Indonesian food made from fermented soybeans, is enriched for vitamin B12 , a vitamin predominantly found in animal products, making it an excellent option for people with plant-based diets who have an increased risk of vitamin B12 deficiency. Yoghurt has additional folate (vitamin B9) compared to unfermented milk, and often possesses different riboflavin (vitamin B2) levels. Whether the riboflavin content is higher or lower than unfermented milk depends on the mi crobial abundance and diversity in the starter culture that’s used.

Once a necessary method of food preservation, many now know “fermented” as a word used by food compa nies to promote their products. But do fermented foods have any real health benefits? The answer is: possibly.

Depending on your tastes, you may find that many of your favourite foods are products of fermenta tion. Wine, cheese, bread, beer, and chocolate are just a few of these products that humans have enjoyed for thousands of years thanks to this simple chemical pro cess. What started as a food preservation technique has now become a trendy way to modify the taste, texture, and health benefits of all types of food and beverages.

As early as 10,000 BCE, humans took advantage of the spontaneous fermentation that occurred in milk from early domesticated animals, creating nutrient-dense and long-last ing dairy products. The discovery of beer residues from this time period led scientists to find the world’s first brewery in a cave in Israel. Other fermented beverages were being brewed as well, such as a nine-thousand-year-old drink made by a Neolithic culture in China using fruit, rice, and honey.

Some studies have focused on the antihypertensive and antidiabetic properties of fer mented foods. Whole wheat sourdough bread has been de veloped using a specific strain

Fermentation involves the conversion of sugars to alcohols and organic acids using microbes like bacteria and yeasts. For example, the yeast used in winemaking turns the sugar in grape juice into ethanol and carbon dioxide as a by-product.

Consuming fermented foods could be beneficial by improving the nutritional value of the food, or by mod ulating the gut microbiome to prevent disease. Analyz ing the nutritional properties of fermented foods is rel atively straightforward, however, very few randomized clinical trials (RCTs) have investigated whether con suming fermented foods improves disease resistance.

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- James Pollock

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Many fermented food products are advertised as probi otic foods that improve gastrointestinal health by modifying the gut microbiome. While these labels are good for mar keting, they are somewhat misleading. A 2021 statement by the International Scientific Association for Probiotics and Prebiotics (ISAPP) called much of the information on fer mented foods presented by social media “exaggerated or inaccurate”. This is due to the lack of evidence presented by the food industry that their fermented products have consistent probiotic properties. For this to be the case, live microorganisms that can colonize the gut need to be suf ficiently present in the product. However, with the many types of fermented foods available with different manufac turers and different starter cultures, these conditions are not always present in fermented foods. Furthermore, any probiotic effect from fermented foods is not clinically prov en to have health benefits to the consumer, as results from the RCTs on fermented foods and probiotics are mixed.

The explosion of interest in fermented foods can be at tributed to the food industry’s marketing of these products as superfoods and consumers’ growing interest in improving their diet by natural means. While early studies on the nu tritional benefits and probiotic characteristics of fermented foods are promising, most of the claims peddled by food man ufacturers are overstated. Research still needs to move beyond chemical analysis of fermented foods and animal models to wards the analyses of existing health databases and place bo-controlled RCTs with well-characterized microbe strains and nutrient compositions. But just like scientists, consum ers are still getting to know how the microbiome works, and with more research fermented foods may one day be recommended as their own food group as part of a healthy diet.

of Lactobacillus that produces functional antihyperten sive peptides, while other studies have shown that sour dough has a lower glycemic index than other breads.

The best-described health benefit of fermented foods, though, is the antioxidant activity that fermentation en hances. Oxidative damage has been linked to many age-and diet-related diseases like Alzheimer’s disease and stomach cancer, but the body can shield itself from this damage us ing enzymes like peroxidases and other compounds like vi tamin C and carotenoids. Several studies have found that fermented foods, especially fermented milk, have higher an tioxidant activity than similar unfermented products. Several factors affect the antioxidant potential of fermented milk, including the milk origin (goats’ milk has greater poten tial than camels’ or cows’ milk when fermented), fat con tent (fat-free yoghurt has greater potential than semi- and full-fat yoghurts), and fermenting microbe strain (some species of lactic acid-producing bacteria confer greater potential than others). Similar antioxidant effects are de scribed in fermented quinoa and fermented apple juice.

The main issue when it comes to studying the health benefits of fermented foods is the inherent mosaicism that makes up the category of fermented food. These foods have different manufacturers, animal and plant origins, industrial processes, and, most diverse of all, the microorganisms used in the fermentation process. It’s difficult to precisely con trol the abundance and diversity of these microbes, which in turn affects the beneficial effects of the final product.

The second symposium focused on im mune system development and layered immunity. Co-chair Dr. Padmaja Sub barao (University of Toronto) began by discussing her work on characterizing the trajectory of infant asthma and al lergy development. She showcased how the power of deep datasets and machine learning can provide insights into the heterogeneity of childhood asthma and can lead to improved diagnostics and therapeutics. She also discussed how the microbiome can influence immune system development, mediating the de velopment of traits associated to asthma progression. Next, Dr. Petter Brodin (Imperial College London & Karolins ka Institute) presented his work on how the immune system evolves early in life along with the microbiome. He spoke on the sensitive interplay between com mensal bacteria and immune cell pro files of newborns, showing that preg nancy length influenced the epigenetic signatures and compositions of immune

Anti-Tumor Immunity

However, under the right contexts, TET deficiency can also prove bene ficial for cancer patients. One such scenario involved an individual under going chimeric antigen receptor (CAR) T cell immunotherapy to treat an ad vanced form of chronic lymphocytic leukemia, where insertion of the CAR transgene led to the disruption of one of the TET2 alleles. Serendipitously, this

The conference’s first symposium fo cused on both the pro- and anti-tumor igenic immune responses to cancer. Dr. David Brooks, (University of Toronto) who served as a co-chair, began by discussing the dichotomy of how Type I interferons (IFN-I) can drive pro-in flammatory responses in immune cells but are suppressive for cancer cells. He showed that immune cells, notably T cells, responded differently to IFN-I due to variations in chromatin accessi bility signatures and that these varia tions could predict the success of PD-1 blocking immunotherapy. Dr. Thorn sten Mempel (Massachusetts General Hospital) then spoke about the cellular interactions within the tumor microen vironment that regulate T cell function. He showed how two distinct trajecto ries of tumor-infiltrating regulatory T cells initiated IFN-γ expression, cor relating the degree of expression to the success of checkpoint inhibitor therapy response.

Layered Immunity

Dr. Brent Johnston (Dalhousie Uni versity) continued the discussion by showcasing the therapeutic potential of natural killer T cell (NKT) activation in immunotherapy. He spoke on how NKT cells can work in combination with oncolytic virotherapy and check point inhibitor therapy to enhance ther apeutic outcomes. Lastly, Dr. Daniela Quail concluded the session by talking about the inflammation and cancer me tastasis associated with obesity, finding that obesity led to neutrophil accumu lation in metastatic sites, burdened the surrounding tissue, and allowed for in creased access to tumor cells.

The conference started off with keynote speaker Dr. Anjana Rao (La Jolla Insti tute for Immunology) who shared her insight into how pathways regulating methylation and demethylation impact ed oncogenesis. Dr. Rao and her team found that across multiple cell types that included T cells, regulatory T cells, and myeloid cells, loss-of-function of the TET dioxygenase family—enzymes notable for their role in DNA demeth ylation—altered methylation signatures to promote aberrant cell lineage specifi cation and cancer development.

CSI 2022 34 IMMpress Vol. 10 No. 2 2022

After a two-year hiatus of in-per son conferences, the 34th annual Canadian Society for Immunol ogy (CSI) meeting reunited immunol ogists in the port city of the Canadian Atlantic, Halifax, Nova Scotia, on June 17-20th. Situated at the beautiful Mar riott Harbourfront Hotel, the three-day conference was packed full with dis cussions of exciting and novel research, workshops, and a chance for trainees to present their own work. We want to thank the local organizing committee chair Dr. Andrew Makrigiannis from Dalhousie University and his team for the incredible and safe in-person con ference.

Dr. Rao’s lab found that the altered methylation patterns caused by TET2 dysfunction impacted the differentia tion state of the CAR T cells and their proliferative capacity, resulting in a life saving therapeutic outcome. This work showcased the potential in targeting the epigenome and the clinical significance that is achievable when we understand the molecular mechanisms.

Keynote

patient already harbored a loss-of-func tion mutation within the second allele, ablating TET2 activity within the CAR T cells and resulted in anti-tumor activ ity accompanied by complete remission.

Finally, we thank the organizers, staff, and sponsors for making the 34th CSI meeting possible. A huge thank you goes out to the local organizing committee from Dalhousie University and Memorial University including Dr. Andrew Makrigiannis (Chair), Dr. Jea nette Boudreau, Dr. Sherri Christian, Dr. Francesca Di Cara, Dr. Thomas Issekutz, Dr. Brent Johnston, Dr. Jean Marshall, Dr. Channakeshava Sokke Umeshappa , and Dr. Jun Wang.

We would like to thank all who gen erously donated and the CSI 2022 spon sors: Platinum sponsor – BD Bioscienc es; Gold sponsor – Biolegend; Silver sponsors – 10X GENOMICS, Cytek, Miltenyi Biotec, and STEMCELL Tech nologies; Bronze sponsors: Adaptive Biotechnologies, Luminex, and Qiagen; Cinader Award Sponsor – Akoya Bio sciences; Educational Sponsor – CIHR - Institute of Infection and Immunity; General sponsors – Cedarlane, Journal of Leukocyte Biology, Kyowa Kirin, Lu micks, and Paraza Pharma Inc.

Dr. Ana Cvejic (University of Cam bridge) continued the discussion with a talk on human fetal blood development at a single-cell level. She presented the impact of the epigenetic landscape on hematopoietic stem cells and multipo tent progenitor differentiation, showing the importance that DNA motif acces sibility has on cell fate choice, and iden tifying the patterns of transcriptional accessibility that influence erythroid or myeloid/lymphoid lineage differen tiation. Dr. James E. Gern (Universi ty of Wisconsin) then spoke about the approaches used to understand child hood asthma at a population level. He described that the conclusions drawn from single cohorts of data is compli cated when compared to different pop ulations from varying environments. Instead, using a collaborative approach containing multiple cohorts, he collect ed powerful datasets from an extensive population across the United States to find that race, socioeconomic factors, and genetic polymorphisms all contrib ute to an increased risk of asthma de velopment. Finally, co-chair Dr. Kathy McCoy (University of Calgary) spoke about how the maternal microbiome can influence the development of the neonatal immune system. She described that the susceptibility of children to childhood illnesses including neurode velopmental disorders and asthma is correlated to the microbiome transmit ted from the mother during birth.

Congratulations to Dr. Brad Nelson (BC Cancer, University of Victoria & University of British Columbia) for re ceiving the Bernhard Cinader Award to honor his brilliant scientific contri butions and his leadership within the immunology community. The John D. Reynolds Award was received by our own Dr. Juan Carlos Zúñiga-Pflücker (University of Toronto) for his contin ued service and excellence to the CSI.

- Philip Barbulescu

Primary Immune Deficiencies

The co-chair of the seminar, Dr. Hélène Decaluwe (University of Mon treal) discussed T cell exhaustion and the immeasurable value of clinical work studying patients as a way to better un derstand the immune system and im munodeficiencies. In severe combined immunodeficiency (SCID) patients for example, CD4 T cell abundance in fluenced the degree of T cell exhaus tion post-transplantation, allowing the group to use exhaustion scores as a biomarker for T-cell reconstitution in future transplantation therapies. Next, Dr. Aleixo Muise (University of Toron to) showcased how studying extreme phenotypes in patients with Inflamma tory Bowel Disease (IBD) can identify underlying genetic problems and pro vide insights into human biology. He found that certain patients who pos sessed gain-of-function mutations with in the Spleen Tyrosine Kinase gene had immune dysregulation and inflamma tion, allowing his group to develop nov el treatment options for IBD patients. Finally, the co-chair Dr. Stuart Turvey (University of British Columbia) report ed on a new human immune deficiency. He presented that complete deficiencies in the NFAT family of transcription factors of activated T cells, specifically NFAT1, impacted joint contractures, osteochondromas, and B cell malignan cy.

Awards & Acknowledgements

IMMpress Vol. 10 No. 2 2022 35

cells towards that of tolerance or resis tance against commensal bacteria.

Congratulations for the huge success on a long-awaited, in-person CSI con Seeference!you year in Orford, Quebec for CSI 2023!

localization, culminating in the abroga tion of proper thymus development. Dr. Liana Falcone (University of Montreal & IRCM) then highlighted the role of the microbiome in causing inborn errors of immunity, specifically in Chronic Granulomatous Disease (CGD). Using CGD mouse models, her lab found that colitis susceptibility is influenced by the microbial signature established at birth.

The third and final symposium of CSI looked into primary immune deficien cies and the dysregulation and inflam mation associated with developmental defects in the thymus. Dr. Georg Hol länder (University of Oxford) began the symposium by sharing his work on key timings of thymic development and how molecular defects can affect it, ob serving that the mouse and human thy mus have very different developmental windows. By creating a Δ550 variant of the FOXN1 transcriptional factor, his group highlighted the importance of FOXN1 on transcription, with the de fect leading to its reduced activity and

The Investigator Award was given to Dr. Kathy McCoy (University of Cal gary), the New Investigator Award was given to Dr. Matthew Macauley (Uni versity of Alberta), and the New Inves tigator Travel Awards were received by Dr. Deanna Santer (University of Man itoba), Dr. Jean-Francois Lauzon-Joset (University of Laval), and another of our own, Dr. Matthew Beuchler (Uni versity of Toronto). Additionally, cheers and congratulations to all travel and poster award winners this year!

Photo Credits: University of Toronto

Archives.

Department of Immunology University of Toronto 1 King’s College Circle Toronto, ON M5S 1A8 Canada

Exhibition on food research (c196-)