The Human Fecal Endocannabinoidome Mediator Profile Is Mainly Defined by the Fecal Microbiota and Diet.

CONTEXT: 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.

OBJECTIVE

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 liquid chromatography coupled to tandem mass spectrometry in plasma and feces of a cross-sectional cohort (n = 195) and a short-term dietary intervention trial (n = 21) with comprehensive dietary intakes and gut microbiota measures.

RESULTS

Six NAEs and 7 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-arachidonoyl-glycerol, N-palmitoyl-ethanolamine, and N-docosahexaenoyl-ethanolamine 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-oleoyl-glycerol and 2-linoleoyl-glycerol. 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.