Gut microbiota-driven imbalance of the gut-brain-immune homeostatic network in constipation: Pathogenic mechanisms and evolving therapeutic prospects

Summary: Chronic constipation (CC) is increasingly recognized as a systems-level disorder that cannot be explained by impaired intestinal motility alone. Here, we integrate evidence from clinical cohorts, animal models, and mechanistic studies to examine how gut microbial dysbiosis and altered microbial metabolites perturb epithelial barrier integrity, immune homeostasis, enteric neural activity, and gut-brain signaling. We propose a “gut-brain-immune homeostatic network” in which short-chain fatty acids (SCFAs), tryptophan metabolites, bile acids, and other microbial signals may sustain self-reinforcing interactions linking dysmotility, inflammation, and neurobehavioral disturbances. We further evaluate microbiota-directed interventions, including prebiotics, probiotics, postbiotics, fecal microbiota transplantation, engineered bacteria, and multi-omics-guided personalized strategies. This framework reframes CC as a multisystem homeostatic disorder and provides a mechanistic basis for patient stratification, therapeutic target discovery, and precision interventions for constipation and related gut-brain-immune disorders.