Features

Exploring the brain-gut connection in mental health

An interview with Dr. Margaret Hahn

By Sally Wu

Trillions of living microorganisms reside in pockets of bustling communities in the human body. An array of bacteria, viruses, fungi, and other microbes collectively form microbiomes—the microbial inhabitants that contribute to human health and well-being. Ongoing efforts by scientists to characterize the functions of microbes, specifically the gut microbiome, have discovered its tremendous impact on metabolism, the immune system, the heart, and other important physiological functions.1 We are only now beginning to understand and acknowledge the importance of having a healthy gut microbiome and its role in health and disease. More recently, studies have suggested that the gut microbiome may also affect mental health.2 Dr. Margaret Hahn (along with Dr. Daniel Mueller), their team at the Centre for Addiction and Mental Health (CAMH), and their collaborators at the Farncombe Institute at McMaster University are leading translational studies to investigate the complex interplay between the gut and the brain. Their research aims to better understand the underlying mechanisms of the metabolic burden observed in patients with schizophrenia.

Dr. Hahn completed her undergraduate studies in biochemistry and immunology at McGill University. She has always had an interest in metabolic pathways and how these may interact with the immune system. As she completed her MD at the University of Calgary, Dr. Hahn reminisced that “while I enjoyed medical school and seeing patients, I’ve always had the interest to discover novel things and to improve the care of patients. I always felt like the way to do that was through research.” As the “brain was a more undiscovered frontier…that has more potential for discovery and to further the care of patients”, she decided to complete her residency in psychiatry. She later completed her Doctoral degree at the Institute of Medical Science at the University of Toronto. “Thanks to Dr. Gary Remington who managed to convince me that on top of all these years of studies that a PhD was a good idea.” Dr. Hahn laughed and continued, “In the long run, it was a good idea because it gave me the background in not only psychiatry but [also] allowed me to focus on the metabolic comorbidity in schizophrenia.”

As the Director of the Mental Health and Metabolism Clinic at CAMH, Dr. Hahn expressed that “working as a clinician in this field has highlighted the lack of ability to improve patient outcomes in so many domains. This includes the huge gaps in physical care and addressing the high cardiovascular mortality rates that represent the leading cause of death in schizophrenia patients and other severe mental illnesses, [surpassing] suicide.” Even before patients with schizophrenia are prescribed antipsychotics, they present with premorbid metabolic dysregulation, particularly insulin resistance and dysglycemia.3 To make matters worse, antipsychotics additionally induce adverse metabolic side effects, such as insulin resistance, weight gain, and contribute to the very high prevalence of type 2 diabetes in patients.4 A potential culprit of this observed metabolic dysregulation is the gut microbiome.

“There is a really complex interplay between the brain and body. We tend to treat each system separately. One of the systems that is linked to mental illness and most certainly a key aspect of metabolism is the gut microbiome,” Dr. Hahn explains.

A few years ago, Dr. Hahn and Dr. Daniel Mueller along with other scientists in different areas of research at CAMH had the good fortune to receive a donation from the Farncombe family to ignite a collaboration between CAMH and the Farncombe Family Digestive Health Research Institute at McMaster University (Drs. Elena Verdu and Premysl Bercik) to conduct one of the first pilot projects examining the gut microbiome and mental health in Canada. Their interest and passion in the metabolic health of

DR. MARGARET HAHN

MD, PhD, FRCPC Director of the Mental Health and Metabolism Clinic | Clinician-Scientist in the Schizophrenia Division at the Centre for Addiction and Mental Health | Associate Professor at the University of Toronto | Kelly and Michael Meighen Chair in Psychosis Prevention

Photo Credit: CAMH

patients led them to create a proposal suggesting that the gut microbiome may contribute to the increased risk of pre-morbid metabolic dysfunction, as well as antipsychotic-induced metabolic dysregulation in patients with psychosis spectrum illnesses. This proposal has grown into a project that first started in humans but has now (through a successful Pilot and Feasibility funding competition from the Banting and Best Diabetes Centre) taken a backward translational approach into rodent models. In humans, antipsychotic-naïve patients are followed over twelve weeks to investigate the effects of pre-and post-antipsychotic treatment on metabolic functions. Basic metabolic panels are completed, and stool samples are collected. Weight and body mass index are also recorded to monitor for antipsychotic-induced weight gain, which occurs in a subset of individuals. The pre-antipsychotic treatment stool samples from the individuals who go on to gain weight are then transplanted to germ-free mice to examine the causality of these metabolic side effects. “The hope is that in the future we can find which gut microbiome signatures predispose patients to these metabolic side effects. Then we can intervene with probiotics in a subset of patients—a type of personalized medicine.”

“Taking a step back, our research focuses on schizophrenia, but all mental illnesses have a very large metabolic burden. The gut microbiome may explain some but not all of the interactions between the body and brain,” says Dr. Hahn.

When asked to share the most important thing that the public should understand about the gut microbiome and mental health, Dr. Hahn emphasized that “you can’t separate physical and mental health, and the gut microbiome could represent a link between the two. Going forward, we can’t work in silos. Our field needs multidisciplinary collaborations from different specialties to address different aspects of a complex multisystemic illness in order to move to novel interventions. You can’t have a good quality of life or functional outcomes if you don’t have good mental and physical health.” At the end of it all, Dr. Hahn exuded gratitude and appreciation for her team, collaborators, mentors, study participants and the generosity of her funding sources and the Farncombe family, all of whom make this work possible and rewarding.

References

1. Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol. 2015; 31(1):69-75. 2. Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh

S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry. 2016: 21(6):739-748. 3. Papanastaiou E. The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review. Ther Adv Psychopharmacol. 2013: 3(1):33-51. 4. Rajkumar AP, Horsdal HT, Wimberley T, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a danish population-based cohort study. Am J

Psychiatry. 2017: 174(4):686-694.

Unravelling the Complexity of

Inflammatory Bowel Disease

By Kyla Trkulja

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal (GI) tract that affects millions of people worldwide.1 IBD includes conditions such as Crohn’s disease and ulcerative colitis, and is one of the most prevalent GI diseases with accelerating incidence in newly industrialized countries.1 In this condition, chronic inflammation of the GI tract causes an influx of immune cells that produce cytokines and free radicals that damage the intestinal epithelium, causing painful ulcers and symptoms such as abdominal pain, diarrhea, bloody stools, and weight loss.1

The exact cause of IBD remains largely unknown, but is thought to be a complex combination of genetic susceptibility, composition of the intestinal microbiome, environmental factors, and abnormalities in the immune system.1 The lack of a clear etiology makes this disease very difficult to treat; in fact, for decades, treatment focused only on controlling the symptoms instead of the underlying disease.2 Thankfully, recent advances in the past 20 years have generated treatments aimed at helping patients achieve remission, allowing patients to achieve a better quality of life.2 However, the complexity of the disease results in patients presenting clinically different from each other, known as heterogeneity; this makes it difficult to find an optimal therapy that works for all patients.2

One researcher working to help overcome this issue is Dr. Mark Silverberg, a clinician-scientist at Mount Sinai Hospital. He has been involved in many of the treatment advances made in IBD, and continues to research new treatments and ways to tailor them appropriately to patients. He was a student at the University of Toronto for many years, where he completed his medical education, gastroenterology residency, and PhD studying the genetics of IBD. Dr. Silverberg has been taking care of patients with IBD for over 20 years and has led many clinical trials and research studies to improve disease management. His research looks for causes of IBD, treatments, and ways to develop tools that allow clinicians to predict a patient’s clinical course with the disease based on their genetic and bacterial signatures.

Dr. Silverberg was inspired to study IBD by his mentors during his training. He worked under a clinician-scientist who he said, “was probably the first person that got me excited about the area that I ended up pursuing.” During his PhD, genetics of complex diseases was just starting to become a “hot topic” as a result of the ongoing Human Genome Project, and researchers thought that finding genes for chronic diseases was going to be the key to curing them. “That was why I started in the research field and in looking for genetic variants that lead to inflammatory bowel disease,” Dr. Silverberg explained.

However, as research unveiled that chronic diseases involve both genetic susceptibility and environmental contributions, Dr. Silverberg realized that focusing on genetics alone was not going to be the answer to the problem. “So, I started to shift into more of the environmental side. In particular, I was always interested in diet and food and its effect on disease and in particular, on the microbiome,” he described. Over the next several years, he pivoted his work to combine his knowledge of genetics with the environmental aspect of IBD, inspiring his research in biomarkers related to disease severity, clinical markers related to treatment outcomes, and the microbiome and its effect on prognosis.

An example of this can be seen in one of his recent projects, where his team examined gene expression and microbiome profiles in patients with

DR. MARK SILVERBERG

MD, PhD, FRCPC Clinician-Scientist & Gastroenterologist, Mount Sinai Hospital | Professor, Department of Medicine, University of Toronto | Founder & Director, Toronto Immune and Digestive Health Institute

Photo Credit: Dr. Silverberg

IBD. This knowledge was used to better understand whether the treatment target for IBD should be bowel healing, as seen during a colonoscopy, or histological healing, as seen by looking at the patient’s tissue sample under a microscope. Gene expression and microbiome patterns in IBD patients who only healed in one of these two ways were compared to that of IBD-free individuals. Their results showed patients with histological healing had gene expression and microbial patterns that were similar to healthy individuals without the disease. The project “proved from a biomarker standpoint, from a biologic standpoint… that histologic healing is a better target,” Dr. Silverberg explained. With a clearer idea of the optimal treatment goal for IBD patients, doctors will be able to better monitor and care for their patients.

Despite the challenges of precision medicine in IBD, Dr. Silverberg still has hope that progress will be made on this front. “It’s a very heterogeneous disease… personalized medicine and precision medicine is probably going to be critical in making better progress in treatment and understanding etiology,” he said. To get there, Dr. Silverberg says, “the next few years will focus on gut bacteria and how its composition will define precision medicine. By finding relationships between the microbiome and the type of IBD a patient has, how aggressive it is, what parts of the bowel are affected, and whether they respond to different therapies, better precision medicine targets will hopefully be achieved.” Part of Dr. Silverberg’s success in this field has been due to his role as a clinicianscientist. He describes the role as challenging, as “you need to stay up to date and be progressive when you have clinical responsibilities, and to try to compete for grants and write papers at the same time as making sure you answer your patients’ questions and help them when they’re not doing well. So, it’s a tricky balance.” However, the challenges of the role are what allow his work to be so groundbreaking; as Dr. Silverberg describes, “a lot of our research questions and approaches all derive from clinical problems that we face. It’s the questions that we see in the office and with patients that drive our excitement to do the research to solve it.” Through his dual role and hard-working, innovative team, knowledge on underlying causes and optimal treatments for IBD will continue to advance.

References

1. Guan Q. A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease.

J Immunol Res. 2019 Dec 1;2019:7247238. doi: 10.1155/2019/7247238.

2. Jeong DY, Kim S, Son MJ, et al. Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review. Autoimmun

Rev. 2019 May;18(5):439-454. doi: 10.1016/j. autrev.2019.03.002.

From Obesity to Diabetes

Role of Gut Microbiome Nutrient Sensing Molecules in Modulating Weight Gain and Glucose Metabolism

By Nayaab Punjani

By the year 2040, it is estimated that 600 million people will develop diabetes.1 Even more will have pre-diabetes, which is marked by blood glucose levels that exceed the normal range and is influenced by various lifestyle factors. For example, obesity puts individuals at risk for this condition, and if left untreated, may progress to type 2 diabetes (T2D).1 With the obesity and diabetes epidemics exacerbated by increasingly sedentary lifestyles, a greater understanding of the underlying factors controlling glucose metabolism and weight gain is key. This is what Dr. Tony Lam’s lab aims to examine, through their study of the role of nutrient sensing molecules and the gut microbiome.

Beginning with his Ph.D. at the University of Toronto, Dr. Lam investigated how “nutrients such as fatty acids could affect insulin action in the liver, and eventually affect glucose homeostasis.” He continued in this field during his post-doctoral appointment in New York City by examining the role of the hypothalamus in modulating glucose levels. He explains, “the end result for me is always the same: how glucose and energy homeostasis is achieved and how [it] is disrupted in the context of diabetes type 2, as well as obesity.” Following this work, Dr. Lam began investigating independently and concluded that one of the initial points of nutrient processing and absorption following a meal occurs at the site of the upper small intestine. This led him to study nutrient processing in the gastrointestinal (GI) tract and the complex interactions with diet, glucose homeostasis, obesity, diabetes, and the gut microbiome.

Dr. Lam explains, “nutrients such as glucose and fatty acids, once ingested from the meal, will trigger various signaling pathways within the upper small intestine. It will tell the body to lower glucose levels and food intake. In the context of diabetes and obesity, this control is disrupted. We want to find out how this control is disrupted and how it can be restored.” His research highlights the role of the gut microbiome in altering gut nutrient sensing molecules. He studies the impact of sodium glucose cotransporter 1 (SGLT1), which is present in the upper small intestine and acts to lower glucose levels. High fat diets inhibit the activity of SGLT1 and disrupt the microbiome by decreasing levels of healthy bacteria, such as Lactobacillus, required in nutrient sensing.2 In order to mediate these impacts, Dr. Lam’s lab has also examined the role of metformin, a medication used to treat T2D, to regulate glucose levels in the rodent gut microbiome. His research has demonstrated that metformin helps to restore Lactobacillus and SGLT1mediatiated glucose sensing in rodents.2

DR. TONY LAM

Professor, Departments of Medicine and Physiology | Cross appointed with the Institute of Medical Science | Associate Director, Banting & Best Diabetes Centre, University of Toronto | Canada Research Chair, Tier 1, in Diabetes and Obesity Research, University of Toronto | Jon Kitson McIvor Endowed Chair in Diabetes Research, TGHRI | Senior Scientist, Toronto General Hospital Research Institute (TGHRI)

Photo Credit: Mikaeel Valli

Dr. Lam also illustrates the role of the enzyme acyl-CoA synthetase 3 (ACSL3) in pre-absorptive fatty-acid sensing in the upper small intestine. Pre-absorptive ACSL3-mediated fatty acid sensing is involved in moderating glucose tolerance. Rodents fed high fat diets were observed

to have decreased Lactobacillus levels and disrupted ACSL3. However, healthy microbiome transplantation restored ACSL3 fatty acid sensing and thus glucose homeostasis, along with Lactobacillus levels.3 These studies demonstrate the regulatory role of these nutrient sensing molecules and the impact of high fat feeding on their activity.

Dr. Lam has also explored other applications of these nutrient-sensing molecules beyond, and in relation to, the gut microbiome. His lab recently discovered that changes in the gut microbiome result in altered production of secondary bile acids. Once these secondary bile acids are absorbed into the blood through the small intestine, cross the blood-brain-barrier, and bind to bile acid receptors, this may induce insulin resistance and affect glucose homeostasis. Increased production of these bile acids occurs in T2D as well as during shortterm high fat feeding. Interestingly, healthy microbiome transplantation into the upper small intestine results in reduced production of these bile acids and improved glucose regulation.4

Based on his current findings, Dr. Lam has various next steps for his research. This includes further investigating the impact of the microbiome on bile acids, the receptors involved in this interaction, and eventually how this alters the gene expression of nutrient sensing molecules. This would be followed by determining the cells impacted in maintaining glucose homeostasis, as well as the therapeutic potential of metformin in helping mediate altered nutrient sensing and restoring the gut microbiome.

In addition to his research, Dr. Lam works closely with the Banting and Best Diabetes Centre (BBDC) as the Associate Director. The goal of the BBDC is to promote diabetes research in part through various funded summer and graduate studentships as well as post-doctoral fellowships. These applications are examined through a rigorous peer-review process involving ten faculty members and chaired by himself, providing fair grounds for selection. He mentions, “[these stipends are] not just going into one single lab or person, it is benefiting the whole Toronto community at all levels.” The BBDC also conducts a seminar series, inviting key researchers in the fields of diabetes and obesity, with plans of offering this in-person beginning in January 2022.

For students planning to pursue research in the diabetes field, Dr. Lam offers various suggestions. The first is to apply for BBDC summer studentships. These paid positions provide students with the opportunity to get hands-on experience in a lab for 12 weeks, allowing you to determine whether you would like to continue pursuing this research field for graduate studies. There are also undergraduate courses taught by various faculty members, such as Dr. Lam’s PSL425 course, which focus on studying metabolism.

Dr. Lam summarizes the application of his work to everyday life: “the general public should be aware of the fact that there are many molecules that could be activated or inhibited by nutrients that we take in each day—each meal. These signaling pathways could eventually affect glucose levels as well as weight in the body.” Furthermore, he reflects on how sedentary lifestyles result in excess calories that could greatly influence these nutrient-dependent molecules. From alterations to the gut microbiome composition, to nutrient metabolism, we must be cognizant of the types of foods that we consume and their effect on our body. References

1. Boles A, Kandimalla R, Reddy PH. Dynamics of diabetes and obesity: Epidemiological perspective. Biochim Biophys Acta BBA - Mol

Basis Dis. 2017 May 1;1863(5):1026–36. 2. Bauer PV, Duca FA, Waise TMZ, et al. Metformin Alters Upper

Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing

Glucoregulatory Pathway. Cell Metab. 2018 Jan 9;27(1):101-117.e5. 3. Bauer PV, Duca FA, Waise TMZ, et al. Lactobacillus gasseri in the

Upper Small Intestine Impacts an ACSL3-Dependent Fatty Acid-Sensing Pathway Regulating Whole-Body Glucose Homeostasis.

Cell Metab. 2018 Mar 6;27(3):572-587.e6. 4. Zhang S-Y, Li RJW, Lim Y-M, et al. FXR in the dorsal vagal complex is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats.

Gut. 2021 Sep;70(9):1675–83.

Lets play hide and seek with the immune system: Understanding the cause and effect of Helicobacter pylori infection on gastrointestinal health

By Vritika Batura

Host-pathogen interactions are highly dynamic processes, that can include adhesion, invasion and resolution.1 The process begins with the pathogen infecting its host and ultimately ends with the host initiating an appropriate immune response to clear the infection and build immunity for future encounters.1 But what happens when the pathogen hides from the host? What mechanisms are at play? Is the host able to resolve the infection? That’s the tale of Helicobacter pylori, a gram negative spiral shaped bacterium, that infects 50% of the world population.2

Dr. Nicola Jones garnered interest in studying H. pylori during her fellowship in Paediatric Gastroenterology at The Hospital for Sick Children (Sickkids). She joined the lab of Dr. Philip Sherman to do research as part of the fellowship training with the goal of ultimately returning to the clinic as a full-time clinician. However, the intellectually stimulating environment in the Sherman lab allowed her to look at scientific problems in a new way, where she was able to combine patient care with microbiology and molecular genetics. This motivated her to pursue a PhD in this field and was the start of her journey towards becoming a well-established clinicianscientist in Gastroenterology and the Director of Integrated Physician Scientist Training Program at the University of Toronto. Her current appointments speak to her merit as a dedicated clinicianscientist and are reflective of her success and commitment to both research and patient care. During her PhD, she started exploring host-pathogen interactions. The Nobel prize winning discovery of H. pylori by J Robin Warren and Barry Marshall had gained much attention at the time. It was evident that the bacteria was highly pathogenic and had an active role in chronic gastritis.3 Dr. Jones recalls, “I really wanted to understand how the infection evades the immune system or the host responses so that you get chronic infection for life with most people not developing any complications and only ten percent developing peptic ulcer disease and less than one percent developing gastric cancer. How does this happen?”

H. pylori is a genetically diverse bacterial species and is considered the most significant risk factor for gastric cancer.2 Studies have shown that eradicating the bacteria through therapy can reduce the risk of gastric cancer.4 Current therapy to treat H. pylori infection involves the use of aggressive antibiotic treatment but antibiotic resistance is a major hurdle in H. pylori eradication.2 The real question then became, how does the bacteria acquire this resistance? Dr. Jones mentioned that during her PhD, she noticed the presence of vacuoles in gastric cells infected with H. pylori. It was later found that these vacuoles were induced by a bacterial toxin called the vacuolating cytotoxin (VacA), and these vacuoles formed a niche that permitted survival of H. pylori inside of the cells.⁵ Interestingly, with the use of an animal model her lab showed that mice infected with strains of H. pylori that secreted the toxin had bacteria detected within gastric cells but mice infected with strains that did not secrete vacA, did not have intracellular bacteria.⁶ This finding of intracellular bacteria during infection with VacA+ but not VacA- H. pylori was also seen in gastric biopsies obtained from patients. Subsequent studies showed that antibiotic treatment of mice infected with VacA- H. pylori resulted in complete eradication of the infection, whereas intracellular bacteria persisted in mice infected with VacA+ H. pylori.⁶ Dr. Jones explains, “Having this intracellular niche actually protects the bacteria from eradication therapy and potentially host responses. It’s a place for the bacteria to hide from clearance.”

How does this bacterial strain form these vacuoles and hide inside the cells? Dr. Jones research delineated that it inhibits a specific calcium channel, TRPML1, that is involved in endosomal trafficking.⁷ Her recent paper highlighted the mechanism that is at play by H. pylori (vacA+) strain. VacA inhibits the channel and disrupts endolysosomal trafficking resulting in the formation of these large vacuoles (dysfunctional lysosomes) that ultimately provide safe haven for the bacteria to hide from host immune responses.⁶ She is now looking into a potential drug that would activate this channel. Treatment with a small molecule TRPML1 agonist (ML-SA1), causes resolution of the large vacuoles in VacA+ infected gastric epithelial cells and human gastric organoids, resulting in formation of normal functional lysosomes and ultimately bacterial killing.⁶ Targeting TRPML1 could be a novel treatment to get rid of the niche that allows the bacteria to

escape antibiotics and the host immune response. This could be a potential treatment to be used as part of eradication therapy and would hopefully decrease antibiotic resistance.

When asked how H. pylori infection leads to increased risk of gastric cancer, she explained that H. pylori forms these vacuoles only in certain cell types, specifically parietal cells. Parietal cells are the acid secreting cells of the stomach and are long-lived gastric cells. “Smart for the bacteria to hide in these cells where they can live happily for a long time and every so often get out in the lumen and infect other cells.” She mentions that if during H. pylori infection, gastric acid secretion is inhibited, it can increase the risk of gastric cancer development. Other risk factors include chronic inflammation, gastric atrophy (loss of parietal cells) and intestinal metaplasia. She hopes that studying the effects of the intracellular bacteria can shed light on mechanisms involved in gastric cancer development.

But is H. pylori all bad? She explained that studies have shown an inverse relationship between H. pylori infection and inflammatory bowel disease (IBD) and asthma. In fact, some animal studies have shown that exposure to H. pylori in young animals can provide protection against IBD and asthma. Hence, there are conflicting schools of thoughts: one believes that H. pylori must be eradicated as its pathogenic and the other believes that it might have some health benefits.

Dr. Jones believes that being a clinicianscientist provides unique opportunities to contribute to her field of gastroenterology by beginning to understand the pathophysiology of H. pylori infection. She says, “As a clinician-scientist you have a unique lens; you can identify what the clinical problems are, which allows you to ask relevant questions and then hopefully discover pathways or novel treatment options that ultimately have a positive impact on patients.” It was the opportunity, support and mentorship provided to her during her fellowship and PhD, which allowed her to pursue this direction. She considers this a privilege and has dedicated part of her career to the development of new clinician-scientists as an advocate and mentor.

DR. NICOLA JONES

MD, PhD | Professor, Department of Pediatrics, University of Toronto | Professor, Department of Physiology, University of Toronto | Professor, Institute of Medical Science, University of Toronto | Director, Integrated Physician Scientist Training Program, Faculty of Medicine, University of Toronto | Staff Gastroenterologist, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children | Senior Scientist, Cell Biology, Sickkids Research Institute

Photo Credit: Dorsa Derakhshan

Gastric organoids stained with lysosome markers (LAMP1 and Cathepsin D) to show the effect of H. pylori infection with strain containing vacuolating cytotoxin A (vacA+, bottom panel) and missing vacA (vacA-, top panel). Use of ML-SA1 (a molecular compound) resolved the vacuoles in VacA+ H. pylori infected cells. Image adapted from Capurro et al. 2019. Nat Microbiol. References

1. Jo, E-K. Interplay between host and pathogen: immune defense and beyond. Exp. Mol. Med. 2019;51(12), 1–3. 2. Miller, AK, Williams, SM. Helicobacter pylori infection causes both protective and deleterious effects in human health and disease.

Genes & Immunity. 2021;22(4):218-26 3. Robin Warren, J., Marshall, B. Unidentifed curved bacilli on gastric epithelium in active chronic gastritis. The Lancet. 1983;321(8336), 1273–1275. 4. Mégraud, F, Bessède, E,Varon, C. Helicobacter pylori infection and gastric carcinoma. Clin. Microbiol. Infect. 2015;21(11), 984–990. 5. Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat. Rev. Microbiol. 2005;3(4), 320–332. 6. Capurro, MI, Greenfield LK, Prashar A, et al. VacA generates a protective intracellular reservoir for Helicobacter pylori that is eliminated by activation of the lysosomal calcium channel TRPML1.

Nat Microbiol. 2019;4(8), 1411–1423