Endocannabinoids inhibit induction of virulence in enteric pathogens

Endocannabinoids are host-derived lipid signaling molecules that modulate gastrointestinal (GI) physiology and immunity 1 2. Recent findings have demonstrated that bacterial lipases metabolize endocannabinoids such as 2-arachidonoyl glycerol (2-AG) 3 4, suggesting possible endocannabinoid modulation of bacterial function. Here we show that 2-AG inhibits key virulence programs encoded by the locus of enterocyte effacement (LEE) pathogenicity island that are required for successful intestinal colonization by attaching/effacing (A/E) pathogens 5. Consistent with these findings, mice with elevated 2-AG levels are resistant to ¬Citrobacter rodentium infection. As in mammalian systems, we further show that 2-AG counteracts adrenergic signaling through the bacterially-encoded receptor QseC 6, resulting in reduced activation of the LEE. The long chain fatty acid transporter FadL is also required for bacterial responsiveness to 2-AG. QseC and FadL are encoded within the core genomes of Enterobacteriaceae, introducing the potential for broader endocannabinoid effects on bacterial function. Indeed, we demonstrate that 2-AG attenuates the virulence potential of Salmonella Typhimurium. Thus, by using several well-studied enteric pathogens as model organisms, we have established that bacteria respond transcriptionally, behaviorally and physiologically to endocannabinoids. More broadly, our findings suggest that the antagonistic relationships between adrenergic and endocannabinoid signaling pathways is conserved in both eukaryotic and prokaryotic systems.