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Episode 37: Targeting the gut microbiome in inflammatory bowel disease, with Prof. Harry Sokol MD PhD

/in Podcast, Season Three /by Laura

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The ISAPP hosts discuss the microbiome in inflammatory bowel disease (IBD) with leading expert Prof. Harry Sokol MD PhD, who is Professor of Gastroenterology at Saint Antoine Hospital and has positions with Sorbonne University and the Micalis Institute, INRAE in Paris, France. Sokol talks about the specific gut bacteria that seem to be important in IBD, as well as the challenge of targeting the gut microbiome for therapeutic effects.

Key topics from this episode:

  • Dr. Sokol says that while more and more gastroenterologists see the gut microbiome as relevant to disease diagnosis, prognosis, and treatment, the microbiome is not yet an important part of clinical practice. Fecal microbiota transplantation is widely used for recurrent C. difficile infection, but its utility in chronic disease is not established.
  • Earlier in his research career, he started with the ‘global description’ strategy of surveying the gut microbiome of patients with IBD using the available scientific tools. More recently, Dr. Sokol has focused on ‘candidate microorganisms’ to target such as Faecalibacterium prausnitzii, or F. prau.
  • How do scientists know F. prau is important for IBD? First, those with IBD have less of these bacteria. And patients with Crohn’s disease who have the lowest amounts in their gut microbiomes have the highest chance of disease relapse. Furthermore, these bacteria are human-specific and are found at a very high prevalence in healthy individuals – it makes up between 5 and 10% of the average person’s gut microbiome. A recent prospective study (GEM) also found that F. prau was one of the bacterial species that decreased even before the onset of inflammation and disease. Now Dr. Sokol and others are exploring the therapeutic uses of these bacteria.
  • The ultimate goal with IBD is to use treatments that target the microbiome alongside treatments that target the host.
  • A decrease in F. prau within the gut microbiome is not specific to IBD; it’s also seen in people with IBS and diarrhea. These bacteria may have multiple effects in the body.
  • Dr. Sokol’s group worked on CARD9, an IBD susceptibility gene. The gene’s effect on phenotype occurs through the microbiome, because in mice, fecal microbiota transplantation (FMT) was enough to transfer the susceptibility to colitis. The microbiota also transferred an immune defect in IL-22 production, related to an alteration in tryptophan metabolism in the microbiome. Normally some bacteria in the microbiota use tryptophan to produce indoles, which lead to the production of IL-22, but this process was altered in the mice that received the FMT.
  • This tryptophan metabolism in the microbiome is altered in IBD as well as other diseases. It’s one of the major functions of the gut microbiome, similar to short-chain fatty acid production and bile acid metabolism.
  • As for F. prau, challenges remain with growing and scaling up production for industrial use, but currently Dr. Sokol and collaborators have a method that works. Perhaps eventually they will zone in on the molecules produced by the bacteria, but then again the bacteria may be more effective because it may address different mechanisms of action and different targets simultaneously.

Episode abbreviations and links:

Additional resources:

About Prof. Harry Sokol MD PhD:

Harry Sokol is Professor in the Gastroenterology department of Saint-Antoine Hospital (APHP, Sorbonne Université, Paris, France). the co-director of the Microbiota, Gut & Inflammation team (INSERM CRSA UMRS 938, Sorbonne Université, Paris), group leader in Micalis institute (INRAE) and coordinator of the “Paris Center for Microbiome Medicine” (www.fhu-pacemm.fr/). He is an internationally recognized expert in the inflammatory bowel disease (IBD) and gut microbiota fields, in which he has published more than 330 papers in major journals. He is the current president of the French group of Fecal Microbiota Transplantation, and the head of the APHP Fecal Microbiota Transplantation Center. His work on the role of gut microbiota in IBD pathogenesis led to landmark papers, including the identification of the pivotal role of the commensal bacteria Faecalibacterium prausnitzii in gut homeostasis and IBD. Currently, his work focuses on deciphering gut microbiota–host interactions in health and disease to better understand their role in pathogenesis and develop innovative treatments. Harry received two grants from the European Research Council (ERC) in 2016 and 2022, and he is a member of the International Organization for the Study of IBD (IOIBD). Since 2020, he is recognized as a Highly Cited Researcher (Clarivate, Web of Science). Harry Sokol is currently Associate Editor for Gastroenterology. Harry Sokol co-founded Exeliom biosciences (https://www.exeliombio.com/).

Find Harry on X/Twitter: @h_sokol

Episode 35: Investigating gut microbiome links to chronic diseases, with Dr. Purna Kashyap MBBS

/in Podcast, Season Three /by Laura

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In this episode, the ISAPP hosts discuss the gut microbiome’s role in chronic diseases with Dr. Purna Kashyap MBBS, from Mayo Clinic in Rochester, Minnesota, USA. Dr. Kashyap talks about how to discover the complex factors that trigger and perpetuate chronic diseases such as inflammatory bowel disease, zeroing in on the gut microbiome as a contributor to different aspects of gastrointestinal (GI) tract physiology.

Key topics from this episode:

  • Dr. Kashyap became interested in some of the initial studies linking the gut microbiome to chronic diseases around 2007-2008, and subsequently began to study the molecular mechanisms that underlie changes in GI tract physiology.
  • How can scientists figure out causality in chronic diseases and the role of gut microbes? Dr. Kashyap sees causality as an ongoing cascade of events in the GI tract, with no single causal factor. Both the initial triggers and the perpetuating factors can be considered part of what causes these diseases.
  • Microbes can help perpetuate a certain state in the host because once they establish themselves they serve to make the environment more conducive to their survival. In chronic diseases, the factor that triggers the microbial community configuration may not be as important as the factor(s) that perpetuate it on an ongoing basis.
  • The gut microbiome is changeable but not easy to change. Scientists need to know how the microbial community sustains itself and intervene there to change the community.
  • Even small microbiome studies can be informative if you look at who responds to the intervention and why. This information can be valuable for informing which treatments might work for which subgroups of people.
  • Dr. Kashyap encourages combining three types of research: large-scale studies on microbial metabolites and potential drug targets; clinical studies on the metabolites present in various subgroups; preclinical models studying the effects of individual metabolites.
  • Diet, microbes, and host uptake all contribute to the physiological effects of different metabolites. And for example, if a metabolite is low, knowing which microbes are present is not enough information to explain why it’s low.
  • In gastroenterology, clinicians primarily care about the gut microbiome in relation to the new treatments it makes possible. Now that FDA-approved treatments exist (standardized fecal microbiota transplants for recurrent C. difficile), clinicians may start paying more attention.
  • Does Dr. Kashyap recommend interventions to patients based on their gut microbiomes? A high-fiber diet is good for the gut microbiome and also for overall health, so he advises patients to adhere to dietary recommendations for their daily fiber intake.

Episode abbreviations and links:

Additional resources:

Why researchers need to understand more about the small intestinal microbiome. ISAPP blog.

About Dr. Purna Kashyap:

Dr. Purna Kashyap is practicing gastroenterologist and Professor of Medicine and Physiology, the Bernard and Edith Waterman Director of the Microbiome program, and Director of the germ-free mouse facility in the Center for Individualized Medicine at Mayo Clinic, Rochester, MN. The NIH funded Gut Microbiome laboratory led by Dr. Kashyap is focused on delineating the complex interactions between diet, gut microbiome, and host gastrointestinal physiology.  The laboratory uses germ-free mouse models in conjunction with measures of gastrointestinal physiology in vitro and in vivo to investigate effects of gut microbial products on host gastrointestinal function. In parallel, they use a systems approach incorporating multi-omics, patient metadata, and physiologic tissue responses in human studies, to aid in discovery of novel microbial drivers of disease. The overall goal of the program is to develop novel microbiota-targeted therapies. Dr. Kashyap has published nearly 100 peer reviewed articles including journals like Cell, Cell Host Microbe, Science Translational Medicine, Nature Communications, and Gastroenterology. He was inducted to American Society of Clinical Investigation in 2021. He has previously served on the scientific advisory board of American Gastroenterology Association Gut Microbiome Center, and on the council of American Neurogastroenterology and Motility Society. He now serves on the council and the research committee of AGA, in an editorial role for Gut Microbes and as an ad hoc reviewer on NIH study sections.