EvoBacNiche · Diet-driven evolution in a human gut commensal bacterium: impact on niche adaptation and host physiology

Gut microbiota perturbations are associated with increased severity of human pathologies including metabolic disorders and infectious diseases. Diet influences host physiology in a microbiota-dependent manner. In mice, a diet low in fiber and high in fat and simple sugars (western diet: WD) lowers bacterial diversity, alters microbiota functions, and increases host susceptibility to infection and inflammation. This susceptibility is associated with decreased mucus layer thickness that presumably depends on the activity of mucus-degrading species. Within-host evolution experiments show WD-dependent selection of mutations targeting degradative pathways of mucin-derived glycans in the intestinal commensal Bacteroides thetaiotaomicron (B.theta). Mutations targeting an uncharacterized starch utilization-like system gene showed the strongest frequency fluctuations between standard and western diet. However, the functional consequences of these mutations remain uncharacterized. We hypothesize that WD-selected mutations contribute to spatial niche acquisition, reduction of mucus layer thickness, and increased host susceptibility to pathogen infections. To address this, I will construct isogenic B.theta mutants carrying diet-selected mutations. The mutants will be tested for their ability to degrade mucin-derived glycans in vitro, in a gut-on-chip and in animal models. Their initial spatial distribution will be monitored in mice with a conventional microbiota fed either a standard or western diet. Long-term niche establishment along the gastrointestinal tract and near the mucosal surface, and host susceptibility to inflammation and Citrobacter rodentium infection, will be evaluated in gnotobiotic mice within a community of human-associated bacteria under the two dietary regimens. This study thereby aims to identify molecular mechanisms by which diet impacts host-microbiota interactions at the mucosal surface and to assess their effects on host health and disease.