Microbiota and lipid mediators: from molecular crosstalk to therapeutic opportunities

The gut microbiota constitutes a metabolically active ecosystem that dynamically interacts with the host lipid metabolism and cellular signaling networks. While dietary lipids shape the microbial composition and metabolite production, the microbiota reciprocally biotransform fatty acids, thereby regulating lipid mediator bioavailability and host cellular responses. This bidirectional molecular crosstalk plays a pivotal role in maintaining metabolic homeostasis, epithelial barrier integrity, and immune regulation. Microbiota-derived lipid signals, including short-chain fatty acids, bile acids, polyunsaturated fatty acid-derived intermediates, sphingolipids, and N-acyl amides, modulate the balance between pro-inflammatory eicosanoids and specialized-pro resolving mediators. Through the engagement of G protein-coupled receptors, nuclear receptors such as Farnesoid X receptor and peroxisome proliferator activated receptors, Takeda G protein-coupled receptor 5, and the endocannabinoid system, these molecules influence gene expression, cytokine production, and cellular proliferation, thereby shaping the host physiology. Microbial enzymatic transformations, particularly bile acid biotransformation and fatty acid epoxide metabolism, further remodel the lipid mediator network and its biological effects. Disruption of this regulatory axis is associated with increased intestinal permeability, chronic low-grade inflammation, and metabolic dysfunction, contributing to the pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease, inflammatory bowel diseases, and cardiometabolic disorders. From a therapeutic perspective, multicomponent interventions integrating probiotics, prebiotics, post-biotics, dietary modulation, and physical activity may rebalance the lipid mediator profiles and attenuate inflammatory burden. In this context, the microbiota-lipid mediator interface emerges as a translationally relevant biological target for the prevention and management of chronic diseases.