Host integration of commensal and pathogenic bacterial-derived signals

PROJECT SUMMARY Enteric bacterial infections remain one of the greatest public health challenges worldwide and deciphering the mechanisms that protect against infection will enable development of new treatments. Intestinal tissues are in constant direct contact with diverse beneficial and pathogenic microbes, highlighting the need for orchestrating complex microbial signals to sustain protection against infection. Intestinal epithelial cells (IECs) reside at the direct interface between intestinal pathogens, beneficial commensal bacteria, and intestinal immune components. However, despite continuous exposure to diverse microbes, the mechanisms regulating how IECs integrate microbial-derived signals to mount protective host responses to pathogens are not well understood. The goals of this proposal are to interrogate how specific commensal bacterial-derived metabolites are sensed by IECs to protect against pathogenic infection. Employing Citrobacter rodentium, a murine model of human enteropathogenic Escherichia coli infection, our studies have identified that microbiota-derived products protect against intestinal damage and enteric bacterial infection. Our epigenetic analyses for this project led to identification of new commensal bacterial-derived metabolites that can directly regulate IECs and prime host defense against pathogenic bacterial infection. Employing an exciting array of transgenic animals, pathogenic and commensal bacterial strains, and human intestinal organoids, three specific aims are proposed that will (i) decipher how the host calibrates intestinal barrier function by sensing newly-identified commensal bacterial- derived metabolites, (ii) investigate metabolite-dependent regulation of enteric infection, and (iii) interrogate how metabolism of dietary components by commensal bacteria prime the epigenome and enhance host response to pathogenic bacteria. Defining pathways that integrate commensal and pathogenic signals will provide a framework to test the therapeutic potential of manipulating commensal bacterial-derived metabolites to promote antibacterial immunity.