Project Summary The overall goal of this proposal is to understand how host metabolic adaptations during infection promote co- operative defenses between a host and enteric pathogens to drive asymptomatic carriage and the eventual evolution of commensalism. The proposed studies utilize a natural in vivo host-pathogen involving a enteric bacterial pathogen that causes infectious colitis. In previous work, the Ayres lab discovered that host micronutrient metabolic adaptations during infection with enteric pathogens, regulates host carbohydrate metabolism leading to a phenomenon the Ayres lab calls “metabolic bribery”. This involves the allocation of carbohydrates to the niche of the pathogen (intestine) to increase availability for the pathogen to metabolize. The Ayres lab discovered that the metabolism of these specific carbohydrates by the pathogen suppressed pathogen virulence and disease, indicating this micronutrient regulation of host and pathogen macronutrient metabolism acts as an anti-virulence mechanism. In the new proposal, the Ayres lab presents exciting data demonstrating that micronutrient metabolism coordinates interactions between host glucose and lipid metabolism to suppress virulence and promote cooperation with enteric pathogens. The proposed studies will investigate the mechanisms by which dietary micronutrients regulate macronutrient metabolism to suppress pathogen virulence to yield asymptomatic carriers of the pathogen. The proposed studies will focus on understanding how micronutrient metabolism orchestrates glucose and lipid processes in the body to suppress pathogen virulence. The proposed studies will then examine the interplay between the adaptive immune response and micronutrient mediated cooperative defenses, elucidating how these two systems cooperate to mediate healthy host-pathogen interactions and protect from infectious colitis. Finally, the proposed studies will utilize this novel host-pathogen/micronutrient system to elucidate the mechanisms that drive the evolution of pathogen attenuation towards commensalism and persistence within the microbiota. This work will contribute to a better understanding for gastrointestinal mucosal adaptive immunology, mechanisms of acute and chronic gastrointestinal inflammation and colitis, the effects of gastrointestinal microbes and microbial metabolism on gastrointestinal health and disease, including the effects of pathogenic bacterial pathogens.