Diabetic gastrointestinal autonomic neuropathy: Integrating neuronal degeneration and gut microbial dysbiosis

Figure 2 Molecular pathways underlying the pathophysiology of diabetic enteric autonomic neuropathy. Persistent hyperglycemia activates multiple pathogenic signaling pathways leading to autonomic neuronal damage. Increased glucose influx activates the polyol pathway, causing intracellular accumulation of sorbitol and fructose, disrupting osmotic balance. Advanced glycation end (AGE)-products accumulate and interact with their receptors, activating downstream signaling pathways such as protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt, leading to the activation of nuclear factor kappa B (NF-κB). Additionally, Toll-like receptors (TLRs), particularly TLR4, are activated by lipopolysaccharide (LPS), derived from gut microbiota dysbiosis, further promoting NF-κB activation. NF-κB translocates into the nucleus, triggering DNA damage and promoting transcription of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin 8 [IL-8], IL-1β). Increased oxidative stress, mediated by NADPH oxidase and impaired mitochondrial function, exacerbates axonal transport dysfunction. Concurrently, gut microbial dysbiosis reduces beneficial bacteria and short-chain fatty acid (SCFA) production, decreasing activation of AMP-activated protein kinase (AMPK) and proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus impairing neuronal energy metabolism. Reduced activation of SCFA receptors (G-protein-coupled receptor 41 [GPR41]/GPR43) also diminishes release of gut-derived neuroendocrine factors (glucagon-like peptide 1 [GLP-1], peptide YY [PYY]), impairing gut-brain signaling, appetite regulation, glucose homeostasis, and gastric motility. RAGE: Receptor for advanced glycation end-product; ROS: Reactive oxygen species.