The gut microbiota-enteric nervous system axis: from bidirectional programming to precision therapeutics in digestive diseases

The bidirectional communication between the gut microbiota (GM) and the enteric nervous system (ENS) is fundamental for gastrointestinal homeostasis. This review dissects the intricate GM–ENS dialogue, emphasizing its transition from a developmental programmer in early life to a sustained regulator of neural plasticity in adulthood. We synthesize the core signaling mechanisms—microbial metabolites, neuroactive substances, and immune mediators—that orchestrate ENS activity. We further propose a multi−timescale model (rapid neuropod/bioelectric, intermediate metabolite, slow immune) with differential relevance to irritable bowel syndrome (IBS) (fast distortions) versus inflammatory bowel disease(IBD)(slow amplification). Critically, we delineate how this axis adopts distinct pathophysiological roles across major digestive disorders: acting as a “signal distorter” in IBS, an “inflammation amplifier” in IBD, and a “tumor accomplice” in colorectal cancer (CRC). By integrating these mechanistic insights with emerging therapeutic paradigms (e.g., precision biomarkers, synthetic microbial consortia, postbiotics), we position the GM–ENS axis as a central hub for understanding disease pathogenesis and a promising framework for developing next-generation precision medicine strategies.