The human fecal endocannabinoidome mediator profile is mainly defined by the fecal microbiota and diet.

BACKGROUND: The endocannabinoid system and its extension, the endocannabinoidome (eCBome), are involved in numerous biological processes, notably energy homeostasis, across virtually all tissues. While the circulating eCBome mediator profile is associated with dietary intakes and metabolic status, an important knowledge gap resides in the identification of the precise determinants of these mediators in the gut lumen. We aimed at establishing the profile of eCBome mediators in human feces and investigating their association with circulating eCBome mediators, dietary intakes, metabolic status and gut microbiota composition. METHODS: N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2-MAGs) were profiled by LC-MS/MS in plasma and feces of a cross-sectional cohort (n = 195) and a short term dietary intervention trials (n = 21) with comprehensive dietary intakes and gut microbiota measures. RESULTS: Six NAEs and seven 2-MAGs were identified in fecal samples, but some, especially omega-3 derived mediators, were undetectable in the majority of samples. Fecal NAEs, and to a lower extent 2-MAGs, were positively albeit weakly correlated with the circulating levels of eCBome mediators. Fecal 2-AG, PEA and DHEA levels were positively associated with visceral adiposity and with some parameters of the metabolic profile. Dietary intakes of foods rich in fibers were associated with lower fecal levels of several eCBome mediators, while intakes of unsaturated fatty acids were associated with fecal 2-OG and 2-LG. Interestingly, gut microbiota diversity and composition were a strong correlate of the fecal eCBome profile. CONCLUSION: The fecal eCBome profile is associated with gut microbiota composition and dietary intakes, more than with the circulating profile. These results strengthen the hypothesis of an interrelation between the gut microbiome and eCBome signaling involved in the regulation of numerous host biological processes.

Influence of diet on acute endocannabinoidome mediator levels post exercise in active women, a crossover randomized study.

The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat.

The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2­MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC-MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2­MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2­MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.