Host-microbial co-metabolites: from biogenesis to immunomodulation and implications for health and disease.

Host-microbial co-metabolites are small bioactive molecules generated through obligatory sequential or complementary enzymatic transformations by both gut microbiota and host tissues, including secondary bile acids, trimethylamine N-oxide (TMAO), indoxyl sulfate, p-cresyl sulfate, phenylacetylglutamine, and hippurate. The dysregulation of this co-metabolic axis, often through gut microbial dysbiosis, contributes to chronic low-grade inflammation and has been implicated in inflammatory bowel disease, metabolic disorders, cardiovascular disease, kidney disease, neurological disorders, and cancer. This review synthesizes the definition, biogenesis, immunomodulatory mechanisms, disease relevance, and translational biomarker potential of strict host-microbial co-metabolites.