Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease

Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals. [Display omitted] •Dysbiosis and chronic immune activation follow acute infection of TLR1−/− mice•Altered microbiota confers inflammatory potential and susceptibility to tissue injury•Microbiota alterations depend on enteric pathogen’s use of tetrathionate respiration•Targeted probiotic therapy prevents microbiota alterations and chronic inflammation The relationship between host genes, pathogens, and chronic inflammatory conditions is not well understood. Kamdar et al. demonstrate that altered immune responses against an enteric bacterial infection, shifts bacterial metabolism altering microbiota composition, generating anti-commensal immunity and development of chronic inflammation.