Cannabinoid receptor 1 blockade attenuates metabolic inflammation and gut microbial dysbiosis during high-fat diet-induced obesity.

Abstract

Abstract The endocannabinoid (eCB) system regulates a variety of physiological processes including inflammation and metabolism. Obesity is characterized by overactivation of the eCB system, chronic low-grade inflammation, metabolic dysfunction, and gut microbial dysbiosis. Blockade of cannabinoid receptor 1 (CB1) ameliorates obesity, however CB1-mediated immune-microbial interactions have not been extensively explored. In the current study, antagonists and genetic ablation of CB1 were used in a mouse model of diet-induced obesity to determine the role of CB1 in modulating inflammation, metabolism, and the gut microbiome. As expected, CB1−/− mice were resistant to high-fat diet (HFD)-induced weight gain and metabolic inflammation was significantly less in CB1−/− mice when compared to wild-type (WT) controls. Lamina propria lymphocytes from CB1−/− mice did not display a Th1 induction after HFD feeding whereas WT mice fed HFD had elevated CD4+T-bet+ cells compared to WT mice fed low-fat diet. Decreased colonic inflammation indicated CB1-dependent alterations in the gut microbiome may contribute to a decreased obese phenotype. Similarly, WT obese mice treated with the CB1 antagonist AM251 experienced weight loss, decreased inflammation, and improvement in metabolic parameters. Interrogation of the gut microbiome by 16S metagenomics revealed CB1-dependent alterations in abundance of bacteria belonging to the Clostridiales order. In addition, functional predictions by PICRUSt analysis revealed decreased abundance of operational taxonomic units belonging to bacterial metabolism and membrane transport pathways. Together these data suggest CB1 regulates metabolism by shaping the immune response and gut microbial community.