Objective:

To establish the profile of endocannabinoidome (eCBome) mediators in human feces and investigate their association with circulating eCBome mediators, dietary intakes, metabolic status, and gut microbiota composition, emphasizing the interplay between these factors.

Key Findings:

• Six NAEs and seven 2-MAGs were identified in fecal samples, with some omega-3-derived mediators undetectable in most samples, highlighting dietary influences.
• Fecal NAEs and 2-MAGs showed weak positive correlations with circulating eCBome levels, suggesting limited direct relationships.
• Certain fecal eCBome mediators were positively associated with visceral adiposity and metabolic parameters, indicating potential health implications.
• Dietary fiber intake was linked to lower fecal levels of several eCBome mediators, while unsaturated fatty acids were associated with specific 2-MAGs, underscoring dietary impacts.
• Gut microbiota diversity and composition strongly correlated with the fecal eCBome profile, suggesting a significant interplay.

Interpretation:

The fecal eCBome profile is more influenced by gut microbiota composition and dietary intakes than by circulating eCBome levels, suggesting a complex interplay between diet, gut microbiota, and eCBome signaling in metabolic regulation, with potential implications for health.

Limitations:

• The study's cross-sectional design limits causal inferences.
• The sample size for the dietary intervention was relatively small.
• Potential biases in self-reported dietary intakes may affect results.

Conclusion:

The findings highlight the significant role of diet and gut microbiota in shaping the fecal eCBome profile, which may have implications for understanding metabolic and intestinal health.