Microbiome-derived Metabolites in Anti-inflammatory Therapy: from Mechanisms to Translational Potential

Chronic inflammation underlies autoimmune, metabolic, cardiovascular, and neurodegenerative disorders and remains difficult to manage because current anti-inflammatory therapies often have systemic adverse effects and variable clinical efficacy. This review synthesizes evidence on microbiome-associated metabolites relevant to inflammation, including short-chain fatty acids, microbial indole derivatives, secondary bile acids, polyamines, trimethylamine N-oxide, and selected host-microbe co-metabolites. These compounds regulate host immunity through G-protein-coupled receptors, nuclear receptors, epigenetic mechanisms, inflammasome regulation, and major inflammatory signaling pathways such as NF-kappaB, MAPK, and JAK-STAT. The translational potential of direct metabolite administration, prodrug design, microbiome engineering, dietary modulation, and targeted delivery systems is discussed alongside key limitations, including low bioavailability, context-dependent activity, interindividual microbiome variation, incomplete pharmacokinetic data, and the limited number of well-controlled human trials. Overall, microbiome-associated metabolites represent promising but still evolving therapeutic candidates; their clinical use requires stronger causal evidence, standardized formulations, safety evaluation, and disease-specific validation. Microbiome-associated metabolites, including short-chain fatty acids, microbial indole derivatives, secondary bile acids, and polyamines, contribute to epithelial homeostasis and regulate immune signaling through pathways such as NF-kappaB, MAPK, JAK-STAT, inflammasome activation, GPCR signaling, and epigenetic remodeling. Therapeutic strategies such as metabolite supplementation, prodrug design, microbiome engineering, and nano-delivery systems may enable targeted anti-inflammatory effects, but their clinical application remains dependent on stronger human evidence and standardized delivery approaches.