Deficiency of cannabinoid receptors enhances host susceptibility to bacterial infection

Host resilience to bacterial infection depends on tightly regulated immune responses, which can be shaped by metabolic cues, including the contribution from bioactive lipids. The endocannabinoid system (ECS), a lipid signaling network known for its neuromodulatory roles, also influences immunity; however, the receptor-specific contributions of cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) in host-pathogen interactions remain incompletely defined in this context. Using receptor-deficient mouse models, we investigated how CB1R and CB2R modify immune responses to <i>Salmonella</i> Typhimurium. CB1R-deficient (CB1R-KO) mice exhibited heightened systemic inflammation, impaired bacterial clearance, and reduced survival in systemic infection, associated with dysregulated macrophage polarization and diminished neutrophil recruitment. In contrast, CB2R-KO mice showed increased susceptibility in both systemic and mucosal infection models, marked by a pro-inflammatory macrophage profile, enhanced neutrophilia, and microbiota dysbiosis. Shotgun metagenomic analysis revealed a reduced abundance of specific protective commensals and altered microbial metabolic pathway profiles in CB2R-KO mice, suggesting a role for CB2R in maintaining mucosal immune-microbiota homeostasis. Collectively, these findings highlight non-redundant roles for CB1R and CB2R in regulating immune dynamics and salmonellosis disease severity, and they point to the ECS as a potential target for host-directed immunomodulatory therapies.IMPORTANCEEffective immunity against bacterial pathogens requires a delicate balance between microbial clearance and the containment of inflammatory damage encountered during many infections. The molecular pathways that regulate this equilibrium remain incompletely defined, and the involvement of bioactive lipid signaling mechanisms also needs to be better described. Here, we show that the endocannabinoid receptors CB1R and CB2R play non-redundant roles in host defense against <i>Salmonella</i> infection. CB1R deficiency results in exacerbated systemic inflammation, defective bacterial clearance, and dysregulated macrophage polarization. In contrast, CB2R deficiency leads post-infection to gut dysbiosis and has been found to negatively affect the outcome for the host in both systemic and mucosal infection with <i>Salmonella</i>. By describing cannabinoid receptor-specific contributions to immune regulation and microbiota dynamics, our findings reveal a previously underappreciated axis of host-pathogen interaction. This study broadens our understanding of lipid-mediated immune modulation and identifies CB1R and CB2R as potential targets for therapies aimed at restoring immune homeostasis and improving infectious disease outcomes.