Host inflammation drives adaptive evolution in gut bacteria

About This Grant

Host inflammation drives adaptive evolution in gut bacteria Summary Inflammatory bowel disease (IBD) has long been associated with compositional and metabolic changes in the gut microbiota, yet extensive research efforts have failed to identify a single pathogenic microorganism as the causative agent. Here, I hypothesize that gut inflammation facilitates adaptations in commensal bacteria that further exacerbates disease in IBD. Exposure to gut inflammation exposes bacterial strains to reactive oxygen species (ROS), creating a hostile environment that drives microbial adaptation. I will use the human commensal Bacteroides fragilis as a model system, as this gut-resident bacteria is known to promote anti-inflammatory responses during steady-state. Although traditionally considered a strict anaerobe, B. fragilis has a unique ability to tolerate and even utilize nanomolar concentrations of oxygen. In addition, it can acquire metabolic adaptations due to the strong selective pressures of oxidative stress which enable its persistence in the intestine despite the extreme inflammatory environment. Whether these subsequent changes alter its metabolic output and host interactions remains unexplored. Thus, there is a critical need to understand how the inflamed gut environment shapes commensal bacteria metabolism. We hypothesize that gut inflammation induces specific adaptive responses in B. fragilis, altering its immunomodulatory functions and metabolic output to worsen IBD symptoms. The goal of this proposal is to elucidate how gut inflammation drives adaptations in B. fragilis, and whether these adaptations contribute to disease progression in IBD. To achieve this goal, I will evolve B. fragilis strains using in vitro and in vivo models of inflammation, characterize the transcriptional and metabolic responses of B. fragilis to inflammatory conditions, and assess the functional changes in evolved B. fragilis strains and their subsequent impact on gut inflammation. The findings of this study will significantly advance our understanding of microbial dynamics in IBD, with broad implications for microbiology, immunology, and the development of therapeutic strategies targeting the gut microbiota.