Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

Abstract

Cannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.

Exploring the gut microbiota: lifestyle choices, disease associations, and personal genomics

“…A systematic review and meta-analysis has also found inconsistent results regarding cannabis’ impact on the gut microbiome across studies, highlighting the need for more comprehensive research to decipher the precise mechanisms and consequences of cannabis on gut microbiota ( 83 ). Furthermore, cannabis consumption has demonstrated potential benefits in ulcerative colitis patients, such as altering endocannabinoid tone and inducing mucosal healing, but the involvement of gut microbiota in these effects remains unclear ( 84 ). Other recreational drugs, such as cocaine and methamphetamine, have been linked to negative changes in gut microbial composition ( 85 , 86 ).…”

Emerging mechanisms by which endocannabinoids and their derivatives modulate bacterial populations within the gut microbiome

“…To our knowledge, similar studies focused on MAGs have not yet been published. Considering that altered gut endocannabinoid tone and microbiome dysfunction are both associated with numerous disease states including obesity, cardiovascular diseases, metabolic dysfunction, and neurological diseases [ 14 , 24 , 35 – 39 ], it will be interesting to learn whether the direct effects of NAEs and other endocannabinoid-like molecules on bacterial growth contribute to the pathogenesis of these complex diseases.…”

“…Numerous studies have correlated compositional changes to the gut microbiome with altered host endocannabinoid tone [20][21][22][23][24][25][26][27]. These ecological changes to the microbial community are likely driven by multiple factors including the indirect effects of host cannabinoid signaling on the gut environment and the direct effects of endocannabinoids on endogenous bacteria.…”

“…Included research articles were located using the following search terms in the PubMed database: endocannabinoid + bacteria; endocannabinoid + gut microbiome; N- acylethanolamide + bacteria; 2-arachidonoyl glycerol + bacteria; anadamide + bacteria. The mechanisms by which the gut microbiome modulates the host endocannabinoid system and the consequent effects on disease development have been reviewed in a companion article for this special issue [ 24 ].…”

“…Moreover, endocannabinoid tone in intestinal tissues is significantly altered in germ free mice compared to conventional mice colonized with a microbiome, suggesting that microbes somehow impact the degradation and/or biosynthesis of NAEs and MAGs [18,19]. Conversely, pharmacological and genetic interventions that alter host endocannabinoid activity is correlated with an altered gut microbiome [20][21][22][23][24][25][26][27]. Together, these findings suggest that incompletely defined reciprocal relationships exist between the host endocannabinoid system and the gut microbiome.…”