The Metabolic Dialogue Between the Gut and Distant Organs: From Microbial Products to Host Responses

The gut microbiota, through its extensive metabolic repertoire, plays a pivotal role in regulating systemic physiological processes and contributing to the pathogenesis of extraintestinal diseases. Key microbial metabolites, including short-chain fatty acids (SCFAs), tryptophan derivatives, bile acids, and trimethylamine N-oxide (TMAO), act as molecular mediators that link the gut to distant organs. Despite substantial advances, significant knowledge gaps remain regarding the precise mechanisms by which these metabolites influence organ function and disease progression. This review aims to address these gaps by providing a comprehensive overview of the current understanding of the "gut-organ axes," with a focus on how microbial metabolites influence the brain, lungs, liver, kidneys, and heart through specific receptors and signaling pathways. It also highlights recent advances in bioinformatics and multi-omics integration that facilitate the decoding of these interactions and the identification of therapeutic targets. Furthermore, the translational potential of microbiota-based interventions is discussed, along with key challenges hindering their clinical implementation. By presenting a systems-level perspective on gut-organ metabolic crosstalk, this review proposes a framework for microbiota-targeted strategies to tackle complex diseases, highlighting crucial areas for future research.