The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids

Exercise is known to elicit a feeling of euphoria, referred to as a “runner’s high”, which recent studies indicate is the result of activation of the endocannabinoid system. 1,2 Endocannabinoids (ECs), such as anandamide (AEA), 2-arachidonoylglycerol (2-AG), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA) are lipid mediators that bind to specific receptors and elicit cell signaling. The EC system modulates systemic energy metabolism, inflammation, pain, and brain biology3 and is comprised of ECs, its receptors, most notably the G-protein coupled receptors CB1, CB2, and the enzymes that produce and degrade ECs. The role of this system in modulating inflammation, muscle strength and energy metabolism is now widely documented in humans and in other mammals. 

In addition, there is a vast body of evidence suggesting that the gut microbiome and exercise are interconnected to regulate metabolism and homeostasis, independent of diet Specifically, exercise has been shown in both animal model and human studies to increase the relative abundance of butyrate-producing microbes and thereby increase the production of butyrate, a short chain fatty acid with systemic anti-inflammatory benefits. 

Separately, the gut microbiome and the EC system have also been connected to metabolic regulation and homeostasis. For over a decade now it has been known that specific gut microbial strains modulate the expression of cannabinoid and μ-opioid receptors in intestinal cells. Extensive work in animal models has shown that gut microbes also counteract obesity-induced overactivity of the EC system in the mouse colon, with subsequent reduction of gut permeability to lipopolysaccharide(LPS) (i.e. decreased metabolic endotoxaemia) and increased adipogenesis. Accordingly, prebiotics, probiotics and antibiotics affect the intestinal EC system. These effects of the microbiota appear to be mediated in part by the modulation of EC inactivating enzymes, which also metabolize EC-related mediators with activity at non-cannabinoid receptors. Furthermore, dysregulation of the EC system has been connected to digestive disorders such as inflammatory bowel disease, irritable bowel syndrome, as well as obesity. These conditions involve both a dysregulated microbiota (dysbiosis) and altered short chain fatty acids (SCFAs) levels. 

To date the mechanisms and the extent to which the anti-inflammatory effects of gut microbial production of (SCFAs) are mediated or induced by changes in the EC system have not been explored. Moreover, the links between changes in specific bacterial strains and EC levels in response to dietary or other interventions are lacking in humans. In this study they have investigated the cross-sectional links between ECs and gut microbiome composition in two cohorts and further investigated the relationship between changes in ECs and gut microbiome in response to an exercise intervention.

In the current study they explore the functional interactions between the endocannabinoid system and the gut microbiome in modulating inflammatory markers. Using data from a 6 week exercise intervention (treatment n = 38 control n = 40) and a cross sectional validation cohort (n = 35), they measured the associations of 2-arachidonoylglycerol (2-AG), anandamide (AEA), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) with gut microbiome composition, gut derived metabolites (SCFAs) and inflammatory markers both cross-sectionally and longitudinally. At baseline AEA and OEA were positively associated with alpha diversity (β(SE) = .32 (.06), P = .002; .44 (.04), P < .001) and with SCFA producing bacteria such as Bifidobacterium (2-AG β(SE) = .21 (.10), P < .01; PEA β(SE) = .23 (.08), P < .01), Coprococcus 3 and Faecalibacterium (PEA β(SE) = .29 (.11), P = .01; .25 (.09), P < .01) and negatively associated with Collinsella (AEA β(SE) = −.31 (.12), P = .004). 

Additionally, they found AEA to be positively associated with SCFA Butyrate (β(SE) = .34 (.15), P = .01). AEA, OEA and PEA all increased significantly with the exercise intervention but remained constant in the control group. Changes in AEA correlated with SCFA butyrate and increases in AEA and PEA correlated with decreases in TNF-ɑ and IL-6 statistically mediating one third of the effect of SCFAs on these cytokines. 

Their ur data show that the anti-inflammatory effects of SCFAs are partly mediated by the EC system suggesting that there may be other pathways involved in the modulation of the immune system via the gut microbiome.

 

Sherry