Microbiome-derived signaling molecules and the brain-gut axis: emerging mechanisms and clinical implications

Recent advances in metabolomics, multi-omics integration, and neurogastroenterology have fundamentally reshaped understanding of the human gut microbiome. Rather than microbial composition alone, emerging evidence highlights microbial secretory and signaling activity as a central regulator of brain-gut communication. Understanding how microbiome-derived molecules interact with epithelial, immune, endocrine, and neural pathways is essential for advancing mechanistic insight and precision interventions in disorders of gut-brain interaction (DGBI).

Recent studies demonstrate that the gut microbiome functions as a metabolic and endocrine signaling system, producing compounds such as short-chain fatty acids, bile acids, tryptophan-derived metabolites, polyamines, and lipid mediators that act on enteroendocrine cells, immune circuits, mechanosensory pathways, and vagal afferents. These signals are integrated centrally through brainstem and cortical networks, shaping gastrointestinal motility, visceral sensitivity, stress responsiveness, and affective processing. Functional dysbiosis and altered microbial signaling - rather than consistent taxonomic changes - appear to be primary modulators of brain-gut axis dysregulation.

Emerging data calls for a reframing of gut-brain disorders as conditions of disrupted microbial signaling. Clinically, they support mechanism-based stratification and targeted dietary, microbiome-directed, and neuromodulatory therapies. The findings identify a need for functional biomarkers and targeted molecular approaches to advance precision medicine in DGBIs.