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 36: Uncovering the mechanisms of sorbitol intolerance, with Dr. Jee-Yon Lee MD PhD

/in Podcast, Season Three /by Laura

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This episode features Jee-Yon Lee MD PhD, assistant project scientist at the University of California Davis, USA, speaking about a recent paper on the mechanisms of sorbitol intolerance and the contributions of the gut microbiota. Dr. Lee explains how gut microbes in the large intestine can drive sorbitol intolerance, and how their research group designed a probiotic intervention to ameliorate it in a mouse model.

Key topics from this episode:

  • Dr. Lee joined Baumler lab in 2017 to study how ecological causes such as diet or chronic disease can change host cell metabolism, thereby changing the gut microbiota, and also the effect of the gut microbiota on chronic diseases.
  • Sorbitol is a sugar alcohol used as an artificial sweetener. It cannot be absorbed or catabolized in the small intestine so it reaches the large intestine and draws water into the lumen through osmosis. Large amounts cause diarrhea, but normally small amounts do not. 
  • Some people are sensitive to small amounts of sorbitol and are said to have sorbitol intolerance. Where does the intolerance originate? Possibly the inability of bacteria in the large intestine to catabolize sorbitol using enzymes.
  • Sorbitol intolerance (causing diarrhea) can be transient, such as after taking antibiotics. 
  • What is happening in sustained sorbitol intolerance? Clinically, a recent history of taking antibiotics plus a high-fat diet is associated with diarrhea as well as low-grade inflammation. A mouse model showed that a high-fat diet plus antibiotics led to low-grade inflammation, which may be at the root of sorbitol intolerance.
  • Clostridia are the main bacteria catabolizing sorbitol in the gut. Overall, a high-fat diet plus antibiotics together drive the gut ‘dysbiosis’, and contribute to the chronic depletion of mitochondrial function in the colonic epithelium. This makes the colonic environment less hypoxic, sustains the depletion of Clostridia, and thereby induces sorbitol intolerance.
  • From this, Dr. Lee helped design a probiotic intervention. They selected 3 strains of bacteria and tested them with the high-fat diet and antibiotics mouse model. All of them protected the host from sorbitol intolerance in slightly different ways.
  • Decreased sorbitol dehydrogenase activity may be a biomarker of sorbitol intolerance; currently there’s no way to diagnose this intolerance clinically, so patients typically cut out the substance to discover their intolerance.

Episode abbreviations and links:

About Dr. Jee-Yon Lee MD PhD:

Jee-Yon Lee is an Assistant Project Scientist in Dr. Andreas Baumler’s lab at UC Davis, focusing on studying host-microbial interactions and their impact on human health and non-communicable diseases. She earned her MD and PhD from Yonsei University College of Medicine and served as a family medicine physician in South Korea until 2017. She joined Dr. Andreas Baumler’s lab in 2017 as a visiting scholar and completed her postdoctoral research there. Dr. Lee’s long-term research goal is to elucidate the ecological causes of dysbiosis, its consequences on the development of human diseases, and to find potential therapeutics targeting the microbiome.

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.

Episode 34: New evidence on the virome in gut-brain communication and stress, with Nathaniel Ritz and Thomaz Bastiaanssen

/in Podcast, Season Three /by Laura

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In this episode, the ISAPP hosts discuss a new study on how the gut virome affects the host during stress, with Nathaniel (Nate) Ritz from the Institute for Systems Biology in Seattle, USA and Thomaz Bastiaanssen from APC Microbiome Ireland. The guests give an overview of the microbiota-gut-brain axis, then delve into a new study they led on the virome and its effects on stress responses in mice.

Key topics from this episode:

  • The gut and the brain communicate in various ways, and the microbiota play a role in some of these modes of communication. Various studies use animal models to look at mechanisms that might be applicable to humans.
  • Why would the microbiota affect the human brain? Because we evolved with a ‘background’ of microbes and have relied on them as we evolved. For example, gut microbes produce metabolites the human body is unable to produce by itself.
  • The newly published paper is titled “The gut virome is associated with stress-induced changes in behaviour and immune responses in mice”.
  • Most microbiota-gut-brain axis research to date has looked at the bacterial component of the microbiome, but this misses the bigger context. The virome is the collection of viruses in the gut, mostly consisting of bacteriophages (which infect bacteria in the gut). This study focused on the virome and how it influenced the gut bacteriome as well as host behavior.
  • Bioinformatics challenges exist when working with the virome for several reasons. For one, distinguishing the biology of a bacteriophage from its host can be challenging.
  • The study used a fecal virome transplant: taking a fecal sample, removing the cellular organisms and small particulates so that the bacteriophages were left over, and then concentrating them and administering them. The researchers took this entire virome from a mouse, then transferred it back to the same individual mouse while it was undergoing stress.
  • After stress, differences were seen in the mouse gut bacteriome and virome. The mice had higher anxiety- and depression-like behaviour, plus changes in their immune systems. But after the fecal virome transplant, some of their behaviours were improved.
  • Do the viruses impact the host nervous system directly, or do they only affect the host by way of the bacteriome? This is not fully known, but there appears to be very little interaction of the bacteriophages with the host. 
  • Analysis of the gut bacteriome or virome must respect the compositional nature of the data. The types of measurements used to analyze the microbiome and virome are confounded by compositional effects, and in the field this is not respected as much as it should be.
  • The next step after this study is to explore the changes in microbiome function in the mice, perhaps pinpointing which bacterial groups need to be changed to normalize the mouse behaviours.

Episode links:

About Nathaniel Ritz:

Dr. Nathaniel Ritz completed his PhD in Prof. John Cryan’s lab at APC Microbiome Ireland where he studied the role of the bacteriome and the virome in social and stress-related disorders. His interests lie in elucidating microbiota-host interactions and establishing microbiota causality within the microbiota-gut-brain axis. Nathaniel has recently moved to Seattle, Washington, USA, to join the lab of Dr. Sid Venkatesh as a postdoctoral fellow at the Institute for Systems Biology to further unravel the mechanisms underpinning microbe-host interaction. Outside of the lab, Nathaniel is an avid rock climber, dog walker, and partner to fellow scientist Dr. Minke Nota. More details and current position can be found at https://venkatesh.isbscience.org/

About Thomaz Bastiaanssen:

Dr. Thomaz Bastiaanssen is the lead bioinformatician in Prof. John F. Cryan’s microbiota-gut-brain axis group in Cork, Ireland. He is interested in the ecological dynamics governing host-microbe communication and how this complex interplay can impact human well-being. He will soon transition to a new role at Amsterdam UMC, the Netherlands, where he will continue to study the microbiome gut-brain axis. Besides working on multi-omics analyses, he enjoys horror stories, tabletop games and spending time with his wife, son, and corgi. His website can be found at: https://thomazbastiaanssen.github.io/

Episode 33: From probiotic mechanisms to applications, with Prof. Graciela Lorca PhD

/in Podcast, Season Three /by Laura

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This episode, we discuss how to advance from probiotic mechanisms to human applications, with Prof. Graciela Lorca PhD at the University of Florida in Gainesville, USA. Prof. Lorca talks about her experiences seeking out the mechanisms of action of a probiotic – including which molecules from bacteria may have beneficial effects – and bringing a probiotic through drug trials for use in Type 1 diabetes. They also discuss probiotic responders versus nonresponders and how dietary intake may provide clues about who will respond to an intervention.

Key topics from this episode:

  • Prof. Lorca’s lab is primarily concerned with discovering the mechanisms of action of specific probiotics, including the molecules they produce that can have beneficial effects on a host.
  • Knowing how a probiotic works allows scientists to select strains that are likely to be effective for a certain application.
  • Prof. Lorca’s lab found that L. johnsonii produces extracellular vesicles (EVs) and that a few proteins carried in these EVs may be important markers of where and how they affect the host. She triggered antibodies against these proteins, allowing them to be tracked in the host.
  • EVs are small protrusions from the bacterial membrane, and only some bacteria produce them. Evs have complex cargo, which mostly represents the metabolic state of the cell.
  • Prof. Lorca studied bacteria that appeared to affect autoimmunity in animal models. In humans, administering these bacteria changed immune markers; this intervention is now in a Phase II trial with humans who have Type 1 diabetes. The bacteria may be acting in the small intestine, but they don’t colonize permanently.
  • Extensive data on safety were required to advance the probiotic through to a Phase II trial. Although administering EVs could be an even safer approach, they are difficult to purify from bacteria. Prof. Lorca continues to investigate the bioactive components of these EVs to perhaps administer only those components.
  • Prof. Lorca is also interested in responders versus nonresponders to a probiotic intervention. One of her clinical trials showed that people had either high lactic acid bacteria (LAB) or low LAB at baseline. For those with high levels of LAB, the levels didn’t change much over time. But for those with initially low levels of LAB, the levels increased over time. The latter responded better to treatment. Furthermore, people with high LAB were shown to consume a diet with more long-chain fatty acids, which LAB can utilize. Overall, dietary intake may be a key part of uncovering responders and nonresponders.
  • Over the next ten years in this field, Prof. Lorca believes we will be able to increasingly personalize probiotics according to someone’s genetics and dietary intake. Regulatory aspects are complicated but continue to evolve.

Episode links:

Additional resources:

About Prof. Graciela Lorca PhD:

Dr. Graciela Lorca is currently a Professor in the Department of Microbiology and Cell Science at the University of Florida. She completed her Licentiate in Genetics studies at the National University of Misiones and later received her doctoral degree in Food Technology at the National University of Tucuman in Argentina. She completed her postdoctoral studies at the University of California San Diego in Molecular Microbiology and at the University of Toronto in Structural Biology and Gene Regulation. Since joining the Department of Microbiology and Cell Science at the University of Florida in 2007, Dr. Lorca has focused on the identification of environmental signals that modulate host-microbe interactions. Using multiomic approaches, her laboratory is investigating the bacterial components such as extracellular vesicles that target host pathways involved on those beneficial interactions in vitro and in vivo. Furthermore, Dr. Lorca’s laboratory is currently conducting human trials to evaluate the use of Lactobacillus johnsonii Type 1 Diabetes patients. Dr. Lorca currently teaches a graduate and undergraduate level Probiotics course. She is also in charge of the new concentration on Microbiome in health and disease within the Online Master program at Department of Microbiology and Cell Science.