Effects of host endocannabinoid signaling on Enterobacteriaceae infection

PROJECT SUMMARY The Escherichia coli species encompass innocuous commensals, resident pathobionts, and invading pathogens. In the gut, the proliferation of E. coli and other Enterobacteriaceae, and their potential to induce or contribute to disease, is dependent on the reduction or complete loss of colonization resistance. Host, microbial, and environmental factors can all contribute to lowering colonization resistance to facilitate Enterobacteriaceae expansion, which represents a common hallmark of microbiome dysfunction in many chronic diseases including Crohn’s disease. Supported by our extensive preliminary data, this proposal will define a novel mechanism by which a host signaling network – the endocannabinoid system – lowers colonization resistance by releasing otherwise unavailable nutrients that stimulate proliferation of gut E. coli pathobionts and Enterobacteriaceae pathogens. Using mouse models of enteric infection and of pathobiont- exacerbated Crohn’s disease, as well as a combination of host and bacterial genetics, targeted metabolomics, gnotobiology, and pharmacological manipulations, this proposal outlines an innovative approach to: 1) evaluate the temporal and spatial effects of host endocannabinoid activity on Enterobacteriaceae niche formation in the gut and consequent effects on disease; and 2) define the nutrients and bacterial metabolic pathways that support Enterobacteriaceae expansion stimulated by increased host endocannabinoid activity. These studies are particularly pressing considering the ongoing efforts to develop the endocannabinoid system as a therapeutic target for managing debilitating symptoms that are commonly reported in chronic inflammatory diseases.