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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 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.