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

Figure 1 Brain-gut axis dysfunction and core cascade in diabetic gastroparesis. Chronic hyperglycemia-driven oxidative stress/inflammation disrupts central nervous system-autonomic nervous system-enteric nervous system regulation and the enteric nervous system-interstitial cells of Cajal-smooth muscle network, leading to pyloric/antral dysmotility and delayed gastric emptying. Bidirectional feedback among immune activation, neural injury, and gut dysbiosis contributes to symptom heterogeneity with a limited symptom-emptying correlation. ANS: Autonomic nervous system; DMV: Dorsal motor nucleus of the vagus; ENS: Enteric nervous system; ICC: Interstitial cells of Cajal; IL-6: Interleukin-6; LPS: Lipopolysaccharides; NO: Nitric oxide; nNOS: Neuronal nitric oxide synthase; NTS: Nucleus tractus solitarius; ROS: Reactive oxygen species; SCFAs: Short chain fatty acids; TNF-α: Tumor necrosis factor-α; 5-HT: 5-hydroxytryptamine. Created in BioRender (Supplementary material).

Figure 2 Microbiota-immune-neural links underlying delayed gastric emptying in diabetic gastroparesis. Dysbiosis-related barrier impairment and microbial mediators (lipopolysaccharides, short chain fatty acids) drive immune-neural imbalance (e.g., toll-like receptor 4/nuclear factor-kappa B, G protein-coupled receptors 41 and 43/glucagon-like peptide-1/peptide YY, macrophage M1/M2-heme oxygenase-1/carbon monoxide), converging on enteric nervous system-interstitial cells of Cajal coupling and impaired nitrergic relaxation to promote delayed gastric emptying. Delayed gastric emptying may facilitate small intestinal bacterial overgrowth, further reinforcing dysbiosis and inflammation. CO: Carbon monoxide; ENS: Enteric nervous system; HO-1: Heme oxygenase-1; ICC: Interstitial cells of Cajal; IL-6: Interleukin-6; GLP-1: Glucagon-like peptide-1; GPR41/43: G protein-coupled receptors 41 and 43; LPS: Lipopolysaccharides; NF-κB: Nuclear factor-kappa B; nNOS: Neuronal nitric oxide synthase; PYY: Peptide YY; ROS: Reactive oxygen species; SCFAs: Short chain fatty acids; SIBO: Small intestinal bacterial overgrowth; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α. Created in BioRender (Supplementary material).