Microbiome‐Derived Metabolites as Molecular Mediators of Gut‐Organ Communication: Mechanisms and Therapeutic Opportunities

The gut microbiome is a metabolically active component of human physiology that converts dietary substrates and host‐derived molecules into a diverse repertoire of bioactive metabolites. These microbiome‐derived metabolites provide a functional interface between intestinal microbial activity and host signaling, allowing gut‐derived information to reach distant organs through vascular, lymphatic, immune and neural pathways. This review presents a metabolite‐centered framework for understanding gut‐organ communication. Rather than treating the gut‐liver, gut‐brain, gut‐lung, gut‐kidney, gut‐cardiovascular, gut‐skin, gut‐oral and gut‐immune axes as independent entities, we examine them as interconnected outputs of a common host‐microbe metabolic network. We discuss short‐chain fatty acids, bile acid derivatives, tryptophan metabolites, trimethylamine N‐oxide, microbial ethanol and other amino acid‐derived products, with an emphasis on their receptors, downstream signaling pathways and physiological context. Particular attention is given to G‐protein‐coupled receptors, FXR/TGR5 (GPBAR1), AhR, TLR4 and metabolite‐sensitive epigenetic mechanisms. We further examine how altered metabolic outputs contribute to inflammatory bowel disease, metabolic dysfunction‐associated steatotic liver disease, cardiovascular disease, chronic kidney disease, neurodegenerative and neurodevelopmental disorders, rheumatoid arthritis and inflammatory skin disease. Multi‐omics, germ‐free and gnotobiotic models, organoids and gut‐on‐chip systems are considered as complementary approaches for establishing mechanisms and causality. Finally, we critically evaluate diet, prebiotics, probiotics, postbiotics, pharmacological pathway modulation and engineered microbes, distinguishing promising preclinical concepts from clinically validated interventions. A functional‐metabolome perspective complements taxonomic profiling and may provide a more direct mechanistic bridge between microbial ecology, host physiology and therapeutic development.