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See detailEXCESSIVE MICROBIAL MUCIN FORAGING INDUCED BY DIETARY FIBER DEPRIVATION MODULATES SUSCEPTIBILITY TO INFECTIOUS AND AUTOIMMUNE DISEASES
Wolter, Mathis UL

Doctoral thesis (2022)

The gastrointestinal (GI) mucus layer is a protective and lubricating hydrogel of polymer-forming glycoproteins that covers our intestinal epithelium. This mucus layer serves as an interface between the ... [more ▼]

The gastrointestinal (GI) mucus layer is a protective and lubricating hydrogel of polymer-forming glycoproteins that covers our intestinal epithelium. This mucus layer serves as an interface between the intestinal epithelium and environment as well as a as first line of defense against the potentially harmful microorganisms. While the GI mucus layer closer to the gut epithelium is highly condensed and acts as a physical barrier for invading microorganisms, further away from the epithelium, proteolytic degradation makes it loose. This looser part of the mucus layer serves as an attachment site and a nutrient source for some commensal gut bacteria. The molecular mechanisms that drive the mucus–microbe interactions are emerging and are important to understand the functional role of the gut microbiome in health and disease. Previous work by my research group showed that a dietary fiber-deprived gut microbiota erodes the colonic mucus barrier and enhances susceptibility to a mucosal pathogen Citrobacter rodentium, a mouse model for human Escherichia coli infections. In this PhD thesis, I studied role of the gut mucus layer in the context of various other infectious and autoimmune diseases by inducing the natural erosion of the mucus layer by dietary fiber deprivation. In order to unravel the mechanistic details in the intricate interactions between diet, mucus layer and gut microbiome, I leveraged our previously established gnotobiotic mouse model hosting a synthetic human gut microbiota of fully characterized 14 commensal bacteria (14SM). I employed three different types of infectious diseases for the following reasons: 1) attaching and effacing (A/E) pathogen (C. rodentium), to better understand which commensal bacteria aid in enhancing the pathogen susceptibility when a fiber-deprived gut microbiota erodes the mucus barrier; 2) human intracellular pathogens (Listeria monocytogenes and Salmonella Tyhimurium) to investigate, whether like the A/E pathogen, erosion of the mucus layer could affect the infection dynamics; and 3) a mouse nematode parasite – Trichuris muris, which is a model for the human parasite Trichuris trichiura – to study how changes in the mucin–microbiome interactions drive the worm infection, as mucins play an important role in worm expulsion. In my thesis, I used various combinations of 14SM by dropping out individual or all mucin-degrading bacteria from the microbial community to show that, in the face of reduced dietary fiber, the commensal gut bacterium Akkermansia muciniphila is responsible for enhancing susceptibility to C. rodentium, most likely by eroding the protective gut mucus layer. For my experiments with intracellular pathogens (L. monocytogenes and S. Tyhimurium, I found that dietary fiber deprivation provided protection against the infection by both L. monocytogenes and S. Typhimurium. This protective effect against the pathogens was driven directly by diet and not by the microbial erosion of the mucus layer, since a similar protective effect was observed in both gnotobiotic and germ-free mice. Finally, for the helminth model, I showed that that fiber deprivation-led elevated microbial mucin foraging promotes clearance of the parasitic worm by shifting the host immune response from a susceptible, Th1 type to a resistant, Th2 type. In the context of autoimmune disease, I focused on inflammatory bowel disease (IBD). Although IBD results from genetic predisposition, the contribution of environmental triggers is thought to be crucial. Diet–gut microbiota interactions are considered to be an important environmental trigger, but the precise mechanisms are unknown. As a model for IBD, I employed IL-10-/- mice which are known to spontaneously develop IBD-like colitis in conventional mice. Using our 14SM gnotobiotic mouse model, I showed that in a genetically susceptible host, microbiota-mediated erosion of the mucus layer following dietary fiber deprivation is sufficient to induce lethal colitis. Furthermore, my results show that this effect was clearly dependent on interaction all three factors: microbiome, diet and genetic susceptibility. Leaving out only one of these factors eliminated the lethal phenotype. The novel findings arising from my PhD thesis will help the scientific community to enhance our understanding of the functional role of mucolytic bacteria and the GI mucus layer in shaping our health. Overall, given a reduced consumption of dietary fiber in industrialized countries compared to developing countries, my results have profound implications for potential treatment and prevention strategies by leveraging diet to engineer the gut microbiome, especially in the context of personalized medicine. [less ▲]

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