Diet, microbiota, and lipidomics: How fatty acids shape the endocannabinoidome and host metabolism

The endocannabinoidome (eCBome) is a complex lipid signaling network that integrates metabolic, immune, and neurobehavioral processes in response to environmental cues. Dietary lipids and gut microbiota have emerged as major modulators of its activity and signaling tone. Intake of specific fatty acids, including the monounsaturated oleic acid, the omega-6 polyunsaturated linoleic acid, and omega-3 polyunsaturated fatty acids, influences the eCBome not only by serving as structural precursors of bioactive lipid mediators, but also by altering the relative abundance of these mediators through changes in substrate availability, enzymatic competition, and receptor-mediated feedback loops. Concurrently, gut microbiota shape host eCBome signaling by regulating lipid metabolism, inflammatory tone, and intestinal barrier integrity, while eCBome mediators reciprocally modulate microbial composition and function. Dysregulation of this complex diet-microbiota-eCBome interplay has been implicated in the pathogenesis of metabolic disorders, chronic inflammation, and neuropsychiatric conditions. In this review, we critically examine the molecular mechanisms underlying the interactions between dietary lipid composition, gut microbial ecology, and eCBome signaling. We discuss the implications for human health and highlight emerging diet-based therapeutic strategies targeting this axis.