The precise etiology of inflammatory bowel disease (IBD) remains unknown. Despite 100 genetic polymorphisms associated with IBD, host genetics does not fully explain disease risk, leading to the postulate that environmental factors such as diet and gut microbes play critical, causal roles in IBD progression. Using a gnotobiotic mouse model, in which germ-free wild-type and interleukin 10 (IL-10) knockout animals are colonized with synthetic human gut microbial communities composed of fully sequenced and metabolically characterized commensal bacteria, we have begun to elucidate the mechanistic interactions between dietary fiber, the gut microbiota and the colonic mucus barrier, which serves as a primary defense against encroachment by intestinal bacteria. During dietary fiber deficiency, the gut microbiota resorts to host-secreted mucus glycoproteins as a nutrient source, leading to erosion of this protective layer. Dietary fiber deprivation, together with a fiber-deprived, mucus-eroding microbiota, promotes severe, often lethal, spontaneous colitis in mice lacking IL-10, a cytokine for which loss of function is associated with early and very early onset IBD. In contrast, both isogenic wild-type mice and colonized IL-10 knockout mice fed high fiber do not experience disease, revealing that inflammation precipitates develops in a diet, microbiota and host genotype specific fashion. Selectively removing mucus-degrading species from the synthetic microbiota abrogates disease in IL-10 knockout, fiber-deprived mice, providing an additional link to microbial causation.
