Dysfunction of the brain-gut axis in diabetic gastroparesis: Underlying mechanisms and therapeutic strategies

Abstract

Diabetic gastroparesis (DGP) is a common but long-underestimated gastrointestinal complication of diabetes, characterized by complex and heterogeneous clinical manifestations, and shows only a limited correlation between symptom severity and delayed gastric emptying. Traditional pathological paradigms centered on gastric motility disturbances are insufficient to fully account for its multidimensional phenotypes and variable therapeutic responses. In recent years, advances in neuroscience, immunology, and gut microbiota research have increasingly supported the concept that DGP represents a systemic disorder primarily mediated by brain-gut axis dysfunction. Its pathogenesis involves the coordinated disruption of multilevel regulatory networks, encompassing the central nervous system, autonomic nervous system, the enteric nervous system-interstitial cells of Cajal network, pyloric function, inflammatory and immune responses, and the gut microbiota. Under conditions of chronic hyperglycemia and metabolic stress, neurodegenerative alterations, immune-neural coupling imbalance, and gut microbiota dysbiosis interact to impair gastrointestinal sensorimotor integration. This review systematically summarizes the key pathological mechanisms and cross-system regulatory features of DGP in an integrated brain-gut axis framework. Furthermore, based on recent advances, it discusses pharmacological, neuromodulatory, and metabolic intervention strategies that target the brain-gut axis. Future research should prioritize brain-gut axis-based phenotypic stratification, biomarker system development, and multitarget precision interventions to facilitate the transition of DGP management from a single-function motility-centered approach to mechanism-guided personalized therapy.

Keywords: Diabetic gastroparesis; Brain-gut axis; Autonomic neuropathy; Inflammation; Gut microbiota

Core Tip: Diabetic gastroparesis (DGP) has traditionally been regarded as a motility disorder characterized by delayed gastric emptying. Emerging evidence indicates that DGP is a systemic disorder driven by dysfunction of the brain-gut axis, involving the central nervous system, autonomic and enteric neural networks, immune-inflammatory responses, and gut microbiota dysbiosis. This review integrates these multilevel mechanisms into a unified brain-gut axis framework and highlights therapeutic strategies targeting neural regulation, inflammation, and microbiota, providing a conceptual basis for mechanism-guided and personalized management of DGP.