Gut guardians: the enteric neuroimmune-microbiota axis in health and disease

Abstract

The enteric nervous system (ENS), the largest and most functionally complex division of the peripheral nervous system, orchestrates nearly all core gastrointestinal physiological processes. Accumulating evidence has established that the gut microbiota acts as a central upstream regulator of ENS development, structural plasticity, and functional activity, while the enteric neuro-immune-microbiota axis (ENIMA) is closely implicated in the pathogenesis of diverse gastrointestinal disorders. In this review, we first systematically summarize the defining unique features of the ENS within the vertebrate nervous system. Next, we dissect bidirectional signaling between enteric nerves and immune compartments, highlighting the contributions of macrophages, innate lymphoid cells and T cells to intestinal homeostasis and epithelial barrier integrity. We then delineate the core molecular mechanisms by which microbial signals, including pattern recognition receptor ligands and bioactive metabolites such as short-chain fatty acids and tryptophan derivatives, are sensed and transduced by enteric neurons and glia. Building on this mechanistic foundation, we provide an in-depth analysis of ENIMA dysregulation in four paradigmatic gastrointestinal disorders: Hirschsprung’s disease, inflammatory bowel disease, infectious enteritis, and colorectal cancer. For each disease, we highlight specific neuro-immune-microbial circuitries that drive pathogenesis, discuss their clinical implications, and evaluate emerging therapeutic strategies targeting this axis. Finally, we outline key knowledge gaps in the field, introduce cutting-edge neurobiological technologies for mechanistic research, and discuss the translational potential of neuromodulation strategies for gastrointestinal disease treatment.