Dietary manganese intake modulates the intestinal levels of N-acylethanolamines and microbial taxa in a sex-specific manner in mice with diet-induced obesity

Obesity is characterized by low-grade inflammation, changes in the gut microbiota, and increased tone of the expanded endocannabinoid system (eCBome). The gut is a complex ecosystem that serves as an interface between the diet and its ultimate conversion to nutrients and energy for all cells of the organism. Manganese (Mn) is an essential micronutrient from the diet required for normal cell function and physiological processes. Moreover, it is an indispensable trace mineral for some microbial species since it is a cofactor in several metabolic enzymes. Therefore, we aimed to identify possible interactions between gut microbiota composition and the eCBome during dietary variations of Mn in the context of diet-induced obesity. Female and male mice were fed Mn-depleted and Mn-enriched diets in combination with Low Fat-Low Sucrose (LFLS) or High Fat-High Sucrose (HFHS) diets for 28 days to assess intestinal microbiota and eCBome levels. Interestingly, Mn-enriched diets enhanced the circulating levels of N-docosapentaenoyl-ethanolamine (DPEA) and anandamide (AEA), while they reduced the intestinal concentrations of N-linoleoyl-ethanolamine (LEA), N-oleoyl-ethanolamine (OEA) and other N-acylethanolamines. Besides we found a strong sex-effect of Mn on the intestinal levels of 2-monoacylglycerols (2-MAGs) in females. Furthermore, other endocannabinoid-like molecules involved in the immune response were impacted by dietary Mn enrichment, such as N-palmitoyl-glycine and N-oleoyl-L-serine. Concomitantly, Mn enrichment also promoted segment-specific changes in the relative abundance of several taxa in intestinal microbiota following the HFHS diet. Microbial families such as Peptostreptococcaceae, Muribaculaceae, and Erysipelotrichaceae responded differentially to dietary variations in Mn. Interestingly, when stratified by the sex of the animals, Mn enrichment led to a reduction in the relative abundance of the Erysipelotrichaceae and Oscillospiraceae. This study hints at potential interactions between the eCBome, an endogenous cross-functional lipid signaling system, and several intestinal taxa during dietary Mn variations within HFHS-induced dysmetabolic processes, with a potential impact on the capacity of the host to adapt to these latter. These results will eventually contribute to identifying members of the gut microbiome and/or mediators of the eCBome useful for improving metabolic health.