https://doi.org/10.1038/s41598-017-15154-6">
 

Blockade of CB1 Cannabinoid Receptor Alters Gut Microbiota and Attenuates Inflammation and Diet-Induced Obesity

Pegah Mehrpouya-Bahrami, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Kumaraswamy Naidu Chitrala, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Mitra S. Ganewatta, Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
Chuanbing Tang, Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
E Angela Murphy, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Reilly T. Enos, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Kandy T. Velazquez, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Jamie McCellan, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Mitzi Nagarkatti, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA.
Prakash Nagarkatti, Department of Pathology, Microbiology, and Immunology, School of Medicine, Columbia, SC, USA. prakash@mailbox.sc.edu.

Abstract

Obesity is characterized by chronic low-grade, systemic inflammation, altered gut microbiota, and gut barrier disruption. Additionally, obesity is associated with increased activity of endocannabinoid system (eCB). However, the clear connection between gut microbiota and the eCB system in the regulation of energy homeostasis and adipose tissue inflammation and metabolism, remains to be established. We investigated the effect of treatment of mice with a cannabinoid receptor 1 (CB1) antagonist on Diet-Induced Obesity (DIO), specifically whether such a treatment that blocks endocannabinoid activity can induce changes in gut microbiota and anti-inflammatory state in adipose tissue. Blockade of CB1 attenuated DIO, inflammatory cytokines and trafficking of M1 macrophages into adipose tissue. Decreased inflammatory tone was associated with a lower intestinal permeability and decreased metabolic endotoxemia as evidenced by reduced plasma LPS level, and improved hyperglycemia and insulin resistance. 16S rRNA metagenomics sequencing revealed that CB1 blockade dramatically increased relative abundance of Akkermansia muciniphila and decreased Lanchnospiraceae and Erysipelotrichaceae in the gut. Together, the current study suggests that blocking of CB1 ameliorates Diet-Induced Obesity and metabolic disorder by modulating macrophage inflammatory mediators, and that this effect is associated with alterations in gut microbiota and their metabolites.