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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\u2010induced obesity. Female and male mice were fed Mn\u2010depleted and Mn\u2010enriched diets in combination with Low Fat\u2010Low Sucrose (LFLS) or High Fat\u2010High Sucrose (HFHS) diets for 28\u2009days to assess intestinal microbiota and eCBome levels. Mn\u2010enriched diets enhanced the circulating levels of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010docosapentaenoyl\u2010ethanolamine (DPEA) and anandamide (AEA), while they reduced the intestinal concentrations of other\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acylethanolamines, particularly in the caecum. Besides, we found a strong sex effect of Mn on the intestinal levels of 2\u2010monoacylglycerols (2\u2010MAGs), which were lower in females. Other endocannabinoid\u2010like molecules involved in the immune response were impacted by dietary Mn enrichment, such as\n                    <jats:italic>N<\/jats:italic>\n                    \u2010palmitoyl\u2010glycine and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010oleoyl\u2010L\u2010serine. Concomitantly, Mn enrichment promoted segment\u2010specific changes in the relative abundance of several taxa in intestinal microbiota following the HFHS diet. Microbial families such as\n                    <jats:italic>Peptostreptococcaceae<\/jats:italic>\n                    ,\n                    <jats:italic>Muribaculaceae<\/jats:italic>\n                    , and\n                    <jats:italic>Erysipelotrichaceae<\/jats:italic>\n                    responded differentially to dietary variations in Mn. This study hints at potential interactions between Mn levels and diet composition with the eCBome and intestinal bacteria during dietary Mn variations within HFHS\u2010induced dysmetabolic processes in a sex\u2010dependent manner. These results will eventually contribute to identifying members of the gut microbiome and mediators of the eCBome useful for improving metabolic health.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500934r","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T09:36:28Z","timestamp":1750930588000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dietary Manganese Modulates Microbiota and Intestinal\n                    <i>N<\/i>\n                    \u2010Acylethanolamines in a Sex\u2010Specific Manner in Mice With Diet\u2010Induced Obesity"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2758-6964","authenticated-orcid":false,"given":"Fredy Alexander Guevara","family":"Agudelo","sequence":"first","affiliation":[{"name":"Centre Nutrition, sant\u00e9 et soci\u00e9t\u00e9 (NUTRISS), and Institute of Nutrition and Functional Foods (INAF) 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