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Given the gut microbiota’s contribution to pathogenesis of autoimmune diseases, microbiota characteristics could potentially be used to predict disease susceptibility or progression. Although various gut commensals have been proposed as risk factors for autoimmune disease development, predictions based on microbiota composition alone remain unreliable. Here, we evaluated a common approach to identify a potential microbial risk factor from complex communities, followed by in-depth evaluation of its risk factor properties using an autoimmune neuroinflammation disease model in mice harboring several distinct, defined microbiota compositions. We found that the relative abundances of commensal taxa across distinct communities are poorly suited to assess the disease-mediating property of a given microbiota. Instead, the presence of certain microbial risk factors allowed us to determine the probability of severe disease, but failed to predict the individual disease course. We investigated multiple other microbiota-associated characteristics by applying 16S rRNA gene sequencing, metatranscriptomic and metabolomic approaches, as well as in-depth analysis of host immune responses and intestinal barrier integrity-associated readouts. By leveraging gnotobiotic mouse models harboring six defined compositions, we identified the IgA coating index ofBacteroides ovatusas a reliable individual disease risk predictor before disease onset, due to its ability to reflect autoimmunity-mediating properties of a given gut microbial network within a specific host. In summary, our data suggest that common taxonomic analysis approaches should be refined by taxonomic network analyses or combined with microbiota function-related readouts to reliably assess disease predisposition of a given host−microbiota combination.

Alterations in the gut microbiome, including diet-driven changes, are linked to the rising prevalence of food allergy, yet little is known about how specific gut bacteria incite breakdown of oral tolerance. Here, we show that depriving specific-pathogen-free mice of dietary fiber leads to an increase of the mucolytic bacterium Akkermansia muciniphila, which is associated with a surge in the colonic type 2 immune cells and IgE-coated commensals, and microbiota-mediated gut mucosal barrier dysfunction. These changes manifest into exacerbated sensitization to food allergens, ovalbumin and peanut. To demonstrate the causal role of A. muciniphila, we employed a tractable synthetic human gut microbiota in gnotobiotic mice. The presence of A. muciniphila within the microbiota, combined with fiber deprivation, resulted in stronger anti-commensal IgE coating and type 2 immune responses, which worsened symptoms of food allergy. Our study supports a mechanistic link between diet and a mucolytic gut microbe in regulating food allergy.

Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, diet and gut bacteria are thought to be prominent features contributing to IBD, but little is known about the precise mechanisms involved. Here, we show that low dietary fiber promotes bacterial erosion of protective colonic mucus, leading to lethal colitis in mice lacking the IBD-associated cytokine, interleukin-10. Diet-induced inflammation is driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of some bacteria. Surprisingly, an exclusive enteral nutrition diet, also lacking dietary fiber, reduced disease by increasing bacterial production of isobutyrate, which was dependent on the presence of a specific bacterial species, Eubacterium rectale. Our results illuminate a mechanistic framework using gnotobiotic mice to unravel the complex web of diet, host and microbial factors that influence IBD.

BACKGROUND & AIMSHost-secreted gastrointestinal mucus plays a key role in the expulsion of intestinal nematode parasites. A balance between mucin secretion by the host and the gut microbial mucin foraging is essential to maintain the intestinal homeostasis, yet little is known about how changes in the mucin–microbiome interactions affect worm infection. Here, we aimed to examine how increased mucin foraging activity by the microbiome changes the course of the parasitic infection by modulating the host immune responses.METHODSWe employed a gnotobiotic mouse model containing a 14-member synthetic human gut microbiota that facilitates functional interpretations, including diet-driven manipulation of the microbiota toward mucin foraging. We infected the mice with a robust murine nematode, Trichuris muris, that closely resembles human infection with Trichuris trichiura. We investigated the temporal dynamics of worm infection including worm burden and the host immune responses, and connected these readouts to the microbial changes and metabolic activity toward mucin foraging.RESULTSThe microbial mucin foraging was further increased during worm infection only in mice with pre-enhanced mucin degrading capacity. The elevated mucin foraging coincides with a shift in host immune responses from susceptible (chronic, Th1 type) to resistant (acute, Th2 type), which promotes worm clearance. The relative abundances of mucin-generalist bacteria drammatically increased during worm clearance, but not during worm retention.CONCLUSIONSThese results point to a mechanism whereby skewing the metabolic activity of the microbiome toward mucin glycoproteins promotes resistance to worm infection. Our study documents a clinically-relevant, novel link in the microbiome–parasite–host immune axis, which is important prerequisite knowledge in treating parasitic infections.