Microbiota in Non-Infectious Disorders

A second focus of our research group is to understand what mechanisms contribute to microbiota changes in the inflamed intestine in the absence of a bacterial pathogen. During non-infectious inflammatory disorders affecting the intestinal mucosa such as IBD, an enrichment of commensal Proteobacteria (i.e. Enterobacteriaceae) by unknown mechanisms has been described.

Our central hypothesis (see central model) is that oxidized compounds, such as tetrathionate or nitrate, are generated as a byproduct of the inflammatory response. These terminal electron acceptors can be utilized by facultative anaerobic Proteobacteria (i.e. Enterobacteriaceae) in the gut to efficiently edge out bacteria that rely on fermentation to generate energy for growth.

To study the mechanisms driving this dysbiosis, we are using E. coli as a model organism in several animal models of non-infectious diarrhea. We were able to demonstrate that commensal E. coli strains as well as IBD-associated adherent invasive E. coli strains gain a substantial growth benefit through anaerobic nitrate respiration in the inflamed gut, but not in the healthy intestine. Nitrate production in vivo requires the host enzyme inducible nitric oxide synthase (iNOS). Thus the inflammatory host response selectively enhances growth of commensal Enterobacteriaceae by generating electron acceptors for anaerobic respiration.

The overall picture that is emerging from our studies is that microbiota changes in the inflamed gut, in particular the outgrowth of Enterobacteriaceae, is driven by changes in the bacterial metabolism and competitive growth.