Role of CB 1 receptors in the gastrointestinal tract after microbiota depletion and natural recolonization

The endocannabinoid system is involved in the control of gastrointestinal motility and function, with increasing evidence of its interactions with gut microbiota. We investigated if cannabinoid (CB) ₁ receptors participate in the enteric nervous system (ENS) response to microbiota depletion and natural microbial recolonization. We characterized enteric neurons and glia in the ileum and colon of CB ₁ receptor knockout mice (CB ₁ -KO), showing their ENS is identical to wild type (WT) mice. Next, WT and CB ₁ -KO mice were treated for 2 weeks with antibiotics followed by 2 or 4 weeks of natural microbial recolonization, compared to mice on water or continuous antibiotic treatment. CB ₁ -KO mice lost significantly more body weight than WT mice during antibiotic treatment, and both genotypes had slower whole gut transit with antibiotic treatment. Compared to WT mice, CB ₁ -KO mice had faster whole gut transit, but slower colonic motility after recolonization. Gut microbiota diversity was similarly affected by antibiotic treatment in both genotypes. CB ₁ -KO mice showed the same ENS neuronal and glial density as WT mice in all populations, with neuronal loss after antibiotic treatment and recovery after natural microbial recolonization. Altogether, this study reveals new insights in the interactions between the endocannabinoid system and gut microbiota in gastrointestinal function.