Modulation of the microbiota-enteric nervous system axis by environmental factors: from adaptive plasticity to maladaptive neuroenteric remodeling.

The enteric nervous system (ENS) is increasingly recognized as a highly plastic integrative network positioned at the interface between the intestinal microbiota, epithelial barrier, immune system, and gut-brain axis. Beyond its established role in regulating gastrointestinal motility, secretion, and blood flow, the ENS continuously senses and integrates microbial, metabolic, immune, and environmental signals to maintain intestinal homeostasis and coordinate adaptive physiological responses. Recent advances have revealed that microbiota-derived metabolites, including short-chain fatty acids, bile acid derivatives, tryptophan metabolites, and neuroactive compounds, can influence enteric neuronal activity and neuroepithelial communication through multiple direct and indirect pathways. These include signaling involving enteric neurons and glia as well as epithelial, enteroendocrine, immune, metabolic, and barrier-dependent mechanisms. Environmental factors including diet, antibiotic exposure, pollutants, and neuroactive substances can further modulate these interactions by altering microbial composition and metabolism, epithelial integrity, immune signaling, and neuronal responsiveness. In this review, we critically examine the evidence supporting these different routes of microbiota-ENS communication and propose a conceptual framework distinguishing acute modulation and adaptive ENS plasticity from maladaptive neuroenteric remodeling. Whereas adaptive plasticity maintains or restores gastrointestinal homeostasis, sustained or insufficiently reversible functional, neurochemical, cellular, and structural alterations may contribute to persistent neuroenteric dysfunction. We discuss how exposure intensity and duration, developmental timing, reversibility, and host susceptibility may influence this transition and consider its relevance to gastrointestinal, inflammatory, and neurodegenerative disorders. Finally, we critically assess current therapeutic approaches and highlight the limited direct clinical evidence for restoration of ENS function. A deeper mechanistic understanding of microbiota-ENS communication and the transition from adaptive to maladaptive responses may provide new opportunities for precision-targeted therapeutic strategies in gastrointestinal and gut-brain disorders.