Cannabinoid signaling via the host CB1 receptor promotes intestinal dysbiosis

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Inflammatory bowel diseases (IBD) are chronic, relapsing, immune-mediated diseases influenced by host genetics, environmental factors and the gut microbiota. Intestinal inflammation alters gut microbiota composition and function to disrupt its symbiosis with the host (dysbiosis). Increased Escherichia coli is a common signature of gut dysbiosis in human IBD and murine colitis models and is thought to contribute to colitis development. The endocannabinoid (EC) system has emerged as a promising therapeutic target for human IBD because of its reported anti-inflammatory effects. ECs are lipid hormones that activate host cannabinoid receptors to modulate gut physiology and immunity. Host EC activity is regulated by biosynthetic and degradative enzymes that modulate tissue EC levels and by signaling at host cannabinoid receptors (e.g. CB1, CB2) . Inhibiting EC degradation, or agonism of CB1 or CB2, attenuates disease in chemically-induced colitis models. The host EC system also influences microbiota composition and directly modulates bacterial functions. However, it remains unknown whether cannabinoid modulation of the gut microbiota occurs in IBD and whether these interactions impact disease severity. Moreover, the therapeutic potential of cannabinoids in genetic models of IBD remains understudied. Using the Il10 KO mouse model of IBD, our initial studies demonstrate that inhibiting degradation of the EC 2-AG exacerbates colitis and and promotes dysbiosis as characterized by the expansion of intestinal E. coli. Moreover, we show that inhibiting 2-AG degradation increases gut E. coli in non-inflamed WT mice, which is counteracted with CB1 receptor blockade Our central hypothesis is that cannabinoid signaling at the host CB1 receptor promotes the outgrowth of intestinal E. coli, thus exacerbating inflammation in IBD-susceptible hosts. The objective of this proposal is to establish host cannabinoid signaling as a novel mediator of intestinal dysbiosis by completing the following Aims. Aim 1: Determine the contribution of the host CB1 and CB2 receptors in promoting the outgrowth of intestinal E. coli. Aim 2: Evaluate the effects of host cannabinoid signaling on intestinal dysbiosis and consequent inflammation in IBDsusceptible Il10 KO mice. Aim 3: Characterize the effects of host CB1 receptor signaling on the intestinal metabolome.