Dysbiosis and Anti-commensal Immunity Following Acute Gastrointestinal Infection is Influenced by Host Genetics

The gastrointestinal (GI) tract represents one of the primary sites for pathogen entry. During GI infection the inflamed mucosal tissue and pathogen virulence genes can cause changes in the diversity of the microbiota, allowing the outgrowth of opportunistic commensal species even after the pathogen is cleared. Here we show that TLR1-deficiency during acute GI infection by Yersinia enterocolitica shifts the host immune response from a TH17 to a neutrophil-dominant response. This shift is accompanied by an outgrowth of a sulfate-reducing Proteobacteria species, chronic inflammation and development of systemic anti-commensal immune responses. Yersinia, similar to Salmonella, can utilize tetrathionate generated by neutrophils for respiration. Both a Yersinia mutant that cannot utilize tetrathionate or depletion of neutrophils were able prevent the bloom of Proteobacteria and systemic anti-commensal antibody responses. These data indicate that the increased neutrophil response in TLR1-deficiency produce tetrathionate that is utilized by Yersinia thereby producing different metabolites and by-products which allow the expansion of sulfate-reducing Proteobacteria. These data demonstrate that dysbiosis can be a consequence of pathogenic bacterial metabolism, which is affected by the genetic context of the host immune response.