Blockade of CB1 cannabinoid receptor alters gut microbiota and attenuates inflammation and diet-induced obesity

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.

Cannabinoid receptor types 1 and 2 and peroxisome proliferator‐activated receptor‐α: distribution in the skin of clinically healthy cats and cats with hypersensitivity dermatitis

“…A delicate balance between CBR1 and CBR2 signalling is essential for skin health . CBR1 has been associated with both decreased and increased inflammation whereas CBR2 overactivation in a decreased immune response, as recently reported . Why CBR1 should be overexpressed in the hyperplastic epidermis and not found in the dermal infiltrate, whereas CBR2 is overexpressed in both skin compartments, is unclear but might reflect different pathways regulating inflammation.…”

Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol

“…Obesity is associated with chronic low-grade inflammatory state and excessive fat accumulation (120). The expression of CB 1 and CB 2 receptors, other eCBome molecular targets (i.e., TRPV1,GPR55) and ECs enzymes level in the visceral and subcutaneous adipose tissue has been found (121,122).…”

Cannabinoids and the Microbiota–Gut–Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders

“…LPS stimulates eCB release and prebiotic treatment normalizes ECS tone in the GI (Muccioli et al, ). In another study, antagonizing CB1 attenuated cytokine release, reduced intestinal permeability (as measured by plasma LPS), and altered the relative abundance of several gut bacteria, increasing Akkermansia muciniphila and decreasing Lachnospiraceae and Erysipelotrichaceae (Mehrpouya‐Bahrami et al, ) . Given the role of CB1 antagonists in GI‐related inflammation, it is possible that phytocannabinoids may be a useful therapeutic treatment for intestinal hyperpermeability due to chronic inflamed states, such as in the context of chronic alcohol use (Fig.…”