Infection-Induced Intestinal Dysbiosis Is Mediated by Macrophage Activation and Nitrate Production.

Oral infection of C57BL/6J mice with results in a marked bacterial dysbiosis and the development of severe pathology in the distal small intestine that is dependent on CD4 T cells and interferon gamma (IFN-γ). This dysbiosis and bacterial translocation contribute to the development of ileal pathology, but the factors that support the bloom of bacterial pathobionts are unclear. The use of microbial community profiling and shotgun metagenomics revealed that infection induces a dysbiosis dominated by and an increased potential for nitrate respiration. experiments using bacterial metabolic mutants revealed that during this infection, host-derived nitrate supports the expansion of in the ileum via nitrate respiration. Additional experiments with infected mice indicate that the IFN-γ/STAT1/iNOS axis, while essential for parasite control, also supplies a pool of nitrate that serves as a source for anaerobic respiration and supports overgrowth of Together, these data reveal a trade-off in intestinal immunity after oral infection of C57BL/6J mice with , in which inducible nitric oxide synthase (iNOS) is required for parasite control, while this host enzyme is responsible for specific modification of the composition of the microbiome that contributes to pathology. is a protozoan parasite and a leading cause of foodborne illness. Infection is initiated when the parasite invades the intestinal epithelium, and in many host species, this leads to intense inflammation and a dramatic disruption of the normal microbial ecosystem that resides in the healthy gut (the so-called microbiome). One characteristic change in the microbiome during infection with -as well as numerous other pathogens-is the overgrowth of or similar bacteria and a breakdown of commensal containment leading to seeding of peripheral organs with gut bacteria and subsequent sepsis. Our findings provide one clear explanation for how this process is regulated, thereby improving our understanding of the relationship between parasite infection, inflammation, and disease. Furthermore, our results could serve as the basis for the development of novel therapeutics to reduce the potential for harmful bacteria to bloom in the gut during infection.