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.

Key Words: 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.

INTRODUCTION

Diabetes has become one of the most rapidly growing and burdensome chronic metabolic diseases worldwide. As reported by the International Diabetes Federation, approximately 529 million individuals worldwide have diabetes, with over 90% diagnosed with type 2 diabetes mellitus (T2DM); this number is expected to rise to 1.3 billion by 2050[1]. In China, the number of individuals with diabetes has exceeded 140 million, exerting substantial medical and socioeconomic burdens[2]. In addition to cardiovascular, renal, and neurological complications, gastrointestinal motility disorders are also common among patients with diabetes, yet their clinical significance has long been underestimated[3,4]. The incidence of gastrointestinal dysfunction in individuals with diabetes is significantly higher than that in the general population, with the overall prevalence of dyspepsia being approximately 70% higher[5].

Diabetic gastroparesis (DGP) is a typical peripheral manifestation of diabetic autonomic neuropathy (DAN), characterized by delayed gastric emptying (DGE) and associated upper gastrointestinal symptoms without evidence of mechanical obstruction[6]. Common clinical manifestations include nausea, vomiting, early satiety, postprandial fullness, abdominal distension, and upper abdominal discomfort, which often occur as symptom clusters. Epidemiological data on DGP show substantial variability, with reported incidence rates ranging from 1% to 60%[7,8]. Studies based on United States electronic medical record databases indicate that the overall recorded prevalence of DGP is only 0.16%; however, DGP accounts for 57.4% of all recorded gastroparesis cases[9]. Among patients with type 1 diabetes mellitus and T2DM, the cumulative incidence of gastroparesis is approximately 4.8% and 1%, respectively, compared with approximately 0.1% in the non-diabetic population[10]. Diabetic gastrointestinal complications are characterized by a diffuse distribution and may involve multiple segments of the digestive tract, with esophageal involvement reported in more than 60% of cases, indicating that impairment of the autonomic and enteric nervous system (ENS) is systemic in nature[11,12].

Recent studies indicate that DGP and functional dyspepsia (FD) show considerable overlap in symptom phenotypes and several pathophysiological mechanisms, suggesting that they may represent distinct phenotypes within the same gastric neuromuscular disease spectrum[13]. Both FD and DGP exhibit impaired gastric regulation, increased visceral sensitivity, as well as abnormal central signal processing[14-16], and their symptoms are readily influenced by external factors, including psychosocial stress[17]. In addition, these two conditions share a common pathophysiological basis involving brain-gut axis dysfunction, characterized by low-grade inflammation and gut microbiota dysbiosis[18,19]. Although DGE is often used as an objective diagnostic indicator for DGP, the association between symptom severity and gastric motility abnormalities remains weak[20], suggesting that a motility-centered paradigm alone is insufficient to explain its complex clinical manifestations. A bibliometric cluster analysis revealed that “diabetic gastroparesis” and the “gut-brain-microbiota axis” frequently appeared within the same thematic clusters, suggesting a gradual shift in research focus from a traditional motility-disorder paradigm toward a brain-gut axis-oriented framework[21]. Therefore, reinterpreting the mechanisms of DGP through the brain-gut axis represents a promising approach to elucidate symptom heterogeneity and broaden potential therapeutic targets.

A complex neuroendocrine regulatory network linking the brain and gut, termed the brain-gut axis, maintains gastrointestinal motility and sensory homeostasis through multilayered integration of the central nervous system (CNS), autonomic nervous system (ANS), and ENS[22]. In addition, this system interacts dynamically with the immune, endocrine, and gut microbiota systems, forming a bidirectional regulatory network. Chronic hyperglycemia and associated metabolic stress disrupt the homeostatic coupling among gastric wall nerves, smooth muscle cells, and immune cells through mechanisms including oxidative stress, deposition of advanced glycation end products, and microvascular lesions, thereby leading to autonomic dysfunction and impaired gastric motility[3,23-25]. Overall, DGP should not be regarded as a single motility disorder, but rather as a syndrome characterized by multidimensional imbalance across neural, immune, and microecological systems driven by chronic hyperglycemia. Accordingly, this review systematically summarizes the pathological mechanisms and regulatory targets of DGP from the perspective of the brain-gut axis, with a particular focus on the interactions among dysglycemia, autonomic neuropathy, neuro-immune coupling, and gut microbiota, to provide insights into mechanistic interventions and precision therapeutic strategies.

PATHOPHYSIOLOGICAL MECHANISMS OF THE BRAIN-GUT AXIS IN DGP

DGP can be considered a systemic pathological condition centered on multilevel dysfunction of the brain-gut axis. Accumulating evidence indicates that long-term hyperglycemia induces oxidative stress and chronic low-grade inflammation, which progressively impair the structural and functional integrity of the CNS, ANS, and ENS, thereby disrupting the coordinated regulatory network among enteric neurons, interstitial cells, and smooth muscle. Within this framework, the CNS functions as the primary hub for information integration and regulation, the ANS serves as a critical interface linking central control with peripheral effectors, and the ENS and its effector cells directly govern the execution of gastrointestinal motility and sensory functions. In addition, gut microbiota dysbiosis and immune-inflammatory abnormalities interact with neural injury through metabolic, neural, and humoral pathways, forming a positive feedback loop that amplifies pathological signaling and accelerates the development and progression of gastrointestinal dysfunction. Overall, the pathophysiological evolution of DGP represents a continuous process driven by metabolic disturbances, dysregulated neural control, and cumulative impairment of peripheral effectors, ultimately resulting in DGE and heterogeneous clinical manifestations (Figure 1). Based on this integrative framework, the following sections systematically delineate the specific roles and interrelationships of the individual components of the brain-gut axis in the pathogenesis of DGP.

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).

CNS dysfunction

Diabetes-related metabolic stress can impair the brainstem vagal complex, including the nucleus tractus solitarius and the dorsal motor nucleus of the vagus nerve, thereby weakening the integrated control of gastrointestinal motility. Neuroimaging studies have revealed structural and functional abnormalities in the brainstem, insula, and cingulate cortex, key regions involved in brain-gut regulation. These alterations are associated with gastroparesis symptom severity, indicating that changes in CNS plasticity contribute to symptom generation in DGP[26-30]. Animal studies further demonstrated that downregulation of neuregulin-1 in the dorsal motor nucleus of the vagus nerve leads to impaired cholinergic anti-inflammatory reflexes and reduced gastric motility, whereas neuregulin-1 overexpression activates α7nAChR signaling, restores gastric emptying, and attenuates local inflammation[31]. Collectively, these findings highlight the critical role of CNS plasticity in the pathogenesis of DGP. Clinical studies have shown that patients with diabetes are more prone to early satiety and nausea, whereas patients with idiopathic gastroparesis more frequently report abdominal pain[32,33]. Furthermore, the non-linear association between symptom severity and DGE suggests that disordered central sensory processing and signal integration may substantially contribute to symptom development in DGP[34-37]. Structural and functional abnormalities of the CNS not only disrupt vagal output but also alter central perception and regulation of gastric signals, thereby playing a pivotal role in brain-gut axis dysfunction in DGP.

ANS dysfunction

Within the brain-gut axis regulatory network, the ANS serves as a critical interface linking the CNS and ENS. DAN represents a key pathological component of brain-gut axis imbalance, leading to disrupted coupling between central and peripheral signaling and constituting an important mechanistic basis of DGP. The vagus nerve is the primary neural mediator of gastric receptive relaxation, antral propulsion, and pyloric relaxation[38], with its activity jointly regulated by glycemic and hormonal signals. Acute hyperglycemia delays gastric emptying, whereas hypoglycemia accelerates gastric emptying via vagal reflexes[39,40]. Gastrointestinal hormones, including gastrin, secretin, and insulin, modulate gastric motility via both central and peripheral pathways. Insulin enhances gastric contractility via vagal nuclei, whereas gastrin primarily facilitates small intestinal peristalsis[41,42]. DAN affects both afferent and efferent pathways, resulting in impaired antral propulsion, limited pyloric relaxation, and visceral sensory dysfunction, which manifest clinically as early satiety, bloating, and epigastric abdominal discomfort[35,43,44]. These alterations are more pronounced in female patients and in individuals with longer disease duration and higher hemoglobin A1c levels[45].

The pathological manifestations of DAN include loss of sympathetic and vagal ganglion cells, reduction of interstitial cells of Cajal (ICC), and inflammatory infiltration of the enteric nerve plexus[13,20]. Prolonged hyperglycemia induces oxidative stress and microvascular ischemia through activation of the polyol and protein kinase C pathway, and accumulation of advanced glycation end products, thereby promoting neurodegeneration and ICC damage[46-48]. In addition, downregulation of neuronal nitric oxide synthase (nNOS) restricts smooth muscle relaxation, leading to pyloric spasm and DGE[49]. This peripheral neurodegeneration is frequently accompanied by systemic autonomic dysfunction. Studies have shown that DGE frequently coexists with cardiac denervation, retinopathy, and nephropathy[50-53]. Clinical and epidemiological investigations further support these observations: (1) Patients with gastroparesis often exhibit cardiovascular vagal nerve impairment[54]; (2) Approximately 60% of patients demonstrate DGE on gastric scintigraphy; and (3) Improved glycemic control is positively correlated with symptom relief[55]. Moreover, a study by AlOlaiwi et al[56] reported prevalence rates of 15.3% for cardiovascular autonomic neuropathy and 6.3% for gastroparesis symptoms, respectively, suggesting that DGP represents a peripheral phenotype of diabetic neural axis injury. Autonomic function tests further demonstrate attenuated cardiac vagal reflexes, reduced pancreatic polypeptide responses, and decreased heart rate variability in affected patients[57-61]. Overall, autonomic neuropathy – through impaired central integration and diminished vagal pathway function – disrupts the bidirectional coordination of brain-gut signaling, constituting a core pathological link in diabetic brain-gut axis imbalance and representing a key mechanistic basis for the development and progression of DGP[62-66].

Hormonal and neurotransmitter regulation

Brain-gut axis dysfunction in DGP extends beyond structural neurodegeneration and involves dysregulation of multiple neurotransmitters and gastrointestinal hormones. Reduced excitatory mediators[67-70], including acetylcholine, substance P, and ghrelin, together with aberrant expression of inhibitory mediators such as nitric oxide (NO), cholecystokinin (CCK), vasoactive intestinal peptide, and monoamine neurotransmitters (serotonin, dopamine, and norepinephrine), disrupt the balance between gastric contraction and relaxation[71-73]. These neurotransmitters and hormones are subject to multilevel regulation by the CNS, ANS, and ENS and are further modulated by metabolic, psychological stress-related, and inflammatory factors[74-76]. Disruption of these regulatory processes impairs the integration and transmission of brain-gut signaling, thereby contributing to DGE and visceral sensory dysfunction.

Motilin is a key gastrointestinal hormone involved in the regulation of gastrointestinal motility. It primarily acts on the gastric body and antrum, thereby inducing antral contraction and pyloric relaxation and promoting gastric emptying during the interdigestive period[77]. In the fasting state, plasma motilin levels increase synchronously with phase III activity of the migratory motor complex, thereby triggering gastric peristalsis via cholinergic pathways[78]. In contrast, postprandial motilin levels decline, accompanied by relaxation of the gastric fundus to accommodate increased gastric volume. Exogenous motilin enhances proximal gastric tone and accelerates gastric emptying[79], and stimulates insulin secretion via neurohumoral mechanisms, suggesting a regulatory role in the gut-pancreas axis[80]. Motilin receptors are widely expressed in gastric smooth muscle cells and enteric nerve plexuses, rendering them important targets for the modulation of gastric motility. Accordingly, motilin receptor agonists, including erythromycin derivatives, have been shown to accelerate gastric emptying in patients with DGP, particularly in those with vagal nerve dysfunction[81,82].

Ghrelin is primarily produced by endocrine cells in the gastric fundus and body and belongs to the G protein-coupled receptor ligand family, exhibiting structural homology to kinins[83,84]. Ghrelin exerts dual effects on the central and peripheral nervous systems via activation of the growth hormone secretagogue receptor 1α, thereby promoting appetite, enhancing gastric contractions, and accelerating gastric emptying[85-87]. In healthy individuals, ghrelin levels exhibit phase-dependent oscillations in synchrony with migratory motor complex activity, thereby enhancing gastric motility during the interdigestive period[88]. In early-stage diabetes mellitus, circulating ghrelin levels are elevated and are associated with increased gastrointestinal motility and appetite, whereas ghrelin levels decline in advanced stages, potentially reflecting reduced gastric motility and DGE[89]. Clinical and experimental studies further suggest that exogenous ghrelin or its analogues may promote gastric emptying and relieve symptoms in DGP patients, highlighting its potential therapeutic value[90].

The 5-hydroxytryptamine (5-HT) is a key neurotransmitter in the brain-gut axis, with approximately 95% synthesized by enterochromaffin (EC) cells. Food intake and mechanical distension stimulate EC cells to secrete 5-HT, thereby activating 5-HT receptors on intrinsic and extrinsic neurons of the ENS and regulating intestinal peristalsis, secretion, and blood flow[91,92]. Among 5-HT receptor subtypes, 5-HT type 4 receptor (5-HT₄) represent key therapeutic targets for gastric motility regulation, and their agonists have been shown to improve various functional gastrointestinal motility disorders, including constipation-predominant irritable bowel syndrome, FD, and DGP[93].

In addition to excitatory neurotransmitters, inhibitory hormones also play critical roles in gastric motility regulation. Somatostatin (SST) is mainly produced by D cells in the pyloric region and oxyntic mucosa of the stomach. Through paracrine signaling, SST inhibits gastrin secretion from G cells, histamine release from EC-like cells, and gastric acid secretion by parietal cells, thereby maintaining homeostasis between gastric acid secretion and motility[94,95]. SST and its receptors are widely distributed in the brain and gastrointestinal tract and regulate gastrointestinal motility as well as digestion and absorption through coordinated central-peripheral pathways[96]. In addition, CCK exerts inhibitory effects on gastric motility by activating intramuscular non-adrenergic and non-cholinergic inhibitory neurons. CCK1 receptor antagonists have been demonstrated to promote gastric emptying and exhibit potential therapeutic value in gastroparesis and gastroesophageal reflux disease[97].

ENS regulation

As a key hub in the peripheral effector layer of the brain-gut axis, the ENS regulates gastrointestinal motility and secretion through bidirectional signal integration with the CNS[98,99]. The ENS consists primarily of the submucosal and myenteric plexuses. The submucosal plexus mainly regulates glandular secretion and mucosal activity, whereas the myenteric plexus is responsible for generating and coordinating peristaltic rhythms[100]. Both plexuses communicate with the CNS via sympathetic and parasympathetic pathways, forming an integrated neural network for gastrointestinal motility control. ICCs serve as pacemakers in the gastrointestinal tract by generating spontaneous slow-wave electrical activity and coordinating smooth muscle contraction, thereby providing the rhythmic basis for gastric motility[101]. Under physiological conditions, excitatory (cholinergic, substance P-positive) and inhibitory (nitrergic, purinergic) neurons function in concert to maintain the balance between gastric contraction and relaxation[43,102]. Dysfunction of either neuronal subtype disrupts gastric rhythmicity and results in DGE[41].

In diabetic patients, both ENS neurons and ICCs exhibit structural degeneration. Histological studies have demonstrated decreased nerve fiber density in the gastric wall of patients with DGP, accompanied by a reduction in nNOS-positive neurons, findings that are consistent with ICC loss and impaired gastric motility[103-105]. Pasricha et al[106] observed marked reductions in nerve fibers and myenteric neurons in full-thickness gastric wall biopsies, accompanied by smooth muscle fibrosis and ICC loss. Iwasaki et al[107] reported a marked reduction in ICCs within the antral circular muscle layer of patients with T2DM, accompanied by decreased nNOS and substance P expression, resulting in disordered gastric smooth muscle rhythmicity. Animal studies further support these observations, showing that in non-obese diabetic and streptozotocin-induced models, ICC reduction and DGE occur in parallel[41,102,108]. Mechanistically, downregulation of insulin/insulin-like growth factor 1 (IGF-1) signaling reduces stem cell factor secretion by smooth muscle cells, thereby impairing ICC maintenance and survival[109-111]. Furthermore, selective loss of nitrergic inhibitory neurons induces pyloric spasm and impaired gastric regulation, whereas insulin supplementation restores nNOS expression and improves gastric emptying[102,112]. Notably, Gangula et al[113] reported that tetrahydrobiopterin levels are significantly decreased in the gastric tissue of female diabetic rats, thereby impairing nNOS dimerization and NO bioavailability; tetrahydrobiopterin supplementation restored NO signaling and improved pyloric relaxation and gastric emptying.

Dysfunction of the ENS and ICCs directly leads to abnormal gastrointestinal motility. Decreased antral contractility and pyloric spasm are considered the principal motor abnormalities underlying DGE[53,112,114]. Alterations in neurotransmitter and neuropeptide signaling further exacerbate this process. Experimental studies have shown that levels of substance P and neuropeptide Y are significantly reduced in DGP animal models, whereas the neuropeptide Y receptor Y1 is not correspondingly upregulated, suggesting that neuropeptide depletion contributes to disease progression[115]. Furthermore, some patients continue to exhibit significant symptoms even in the presence of normal gastric emptying, indicating that ENS degeneration may promote symptom persistence by impairing sensory integration and central signal processing[116]. In summary, structural degeneration and signal imbalance within the ENS-ICC-smooth muscle network constitute a core mechanism of peripheral effector dysfunction in DGP and represent a key downstream manifestation of brain-gut axis dysfunction in diabetes.

Gut microbiota dysbiosis

The gut microbiota, consisting of approximately one thousand bacterial species and trillions of microorganisms, plays a pivotal role in nutrient absorption, energy metabolism, and immune homeostasis[117]. In diabetes, the composition and function of the gut microbiota are markedly altered, marked by a reduction in beneficial taxa such as Lactobacillus and Bifidobacterium, along with an expansion of potentially pathogenic bacteria, including Gram-negative bacteria and members of the Enterobacteriaceae family[118,119]. This dysbiosis compromises intestinal barrier integrity, increases mucosal permeability and endotoxin translocation, and thereby promotes systemic inflammation, oxidative stress, and gastrointestinal motility disorders[120]. Diabetic neuropathy further exacerbates microbial dysbiosis, with DGE and small intestinal bacterial overgrowth forming a positive feedback loop between motility impairment and microbiota imbalance[121,122]. Epidemiological studies have reported that small intestinal bacterial overgrowth occurs in approximately 29% of diabetic patients, significantly higher than that in non-diabetic controls, and that approximately 45% of patients exhibit gastrointestinal complications on endoscopic evaluation[123,124]. Microbiome profiling has revealed a reduced Firmicutes/Bacteroidetes ratio and a reduction of butyrate-producing taxa, including Lachnospiraceae and Roseburia, in patients with T2DM, accompanied by enrichment of opportunistic species such as Bacteroides vulgatus, Clostridium nucleatum, and Escherichia coli[125-127]. These alterations are closely associated with insulin resistance, dysregulated glucose metabolism, and persistent low-grade inflammation[128].

Microbial metabolites are key mediators of brain-gut axis signaling, and alterations in their profiles directly influence neuroendocrine-immune interactions. Short-chain fatty acids enhance secretion of incretins, including glucagon-like peptide-1 (GLP-1) and peptide YY, via G protein-coupled receptors 41 and 43 activation[129,130]. Under dysbiotic conditions, butyrate production is reduced, leading to impaired ENS signaling and reduced vagal nerve sensitivity, thereby exacerbating neuropathic dysfunction[131]. Notably, butyrate enhances neuronal energy metabolism via the adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor γ coactivator-1α signaling pathway, thereby exerting neuroprotective effects[132,133]. Conversely, lipopolysaccharide derived from Gram-negative bacteria induces inflammatory responses and neuronal apoptosis via the toll-like receptor 4/nuclear factor-kappa B (NF-κB) pathway[134,135], whereas depletion of Akkermansia muciniphila compromises intestinal barrier integrity, further aggravating endotoxemia and neuroinflammation[136]. Collectively, these metabolic and inflammatory pathways constitute a metabolic-immune-neural coupling mechanism that drives peripheral pathophysiological processes in DGP.

The brain-gut axis mediates bidirectional communication between the gastrointestinal tract and the CNS, predominantly via the vagus nerve[137-139]. Diabetes-induced vagal degeneration, axonal demyelination, and reduced plasticity of the nucleus tractus solitarius impair vagal efferent signaling, resulting in DGE, postprandial fullness, and visceral sensory abnormalities[140,141]. Attenuated vagal function further reduces GLP-1 secretion, thereby weakening glycemic control and gastric motility regulation and forming a vicious cycle of metabolic imbalance and gastroparesis[142-144]. In addition, the gut microbiota can act on EC cells through microbiota-derived short-chain fatty acids, thereby promoting intestinal 5-HT production and modulating gastrointestinal neuroregulation and motility[145]. Grasset et al[122] further demonstrated that specific gut microbiota dysbiosis inhibits GLP-1-induced NO synthesis in enteric neurons, thereby inducing GLP-1 resistance and highlighting a key regulatory role of the gut microbiota in the pathogenesis of DGP through interference with ENS and endocrine signaling. In summary, gut microbiota dysbiosis constitutes a critical link in the peripheral pathophysiological processes of DGP through coordinated metabolic, immune, and neural signaling dysregulation. The key immune-microbiota-neural interactions and their associated molecular mechanisms are schematically illustrated in Figure 2.

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).

Inflammation and immune dysfunction

Brain-gut axis disruption in DGP is closely linked to inflammatory and immune dysregulation. Chronic hyperglycemia induces oxidative stress and metabolic inflammation, thereby promoting activation of immune cells within the intestinal wall and disrupting neuromuscular homeostasis. Cipriani et al[146] demonstrated that muscularis macrophages are key mediators of DGE in diabetes. In macrophage-deficient mice, ICC damage failed to develop even under hyperglycemic conditions, whereas wild-type diabetic mice exhibited marked ICC network disruption accompanied by increased oxidative stress. Under diabetic conditions, oxidative stress and inflammatory responses can induce enteric neuronal apoptosis and reduce nNOS-positive neurons[147-149]. In contrast, activation of transient receptor potential vanilloid 1 channels in vagal afferent fibers promotes NO release and improves pyloric relaxation[150]. Collectively, these findings suggest a bidirectional interplay between peripheral immune activation and neural reflexes in the regulation of gastric motility.

Animal studies have further elucidated the role of immune polarization in the development of gastroparesis. Under physiological conditions, macrophages are predominantly of the M2 phenotype expressing heme oxygenase-1 (HO-1), thereby maintaining a local antioxidant microenvironment. In contrast, diabetic mice exhibit a predominance of M1-polarized macrophages that release pro-inflammatory mediators, including tumor necrosis factor-α and interleukin-6, leading to ICC apoptosis[151-153]. In non-obese diabetic mice, failure of HO-1 upregulation leads to ICC loss and DGE, whereas hemin-induced HO-1 expression reverses these changes[154]. In contrast, in patients with diabetic gastroenteropathy, hemin treatment does not significantly improve gastric emptying, suggesting the presence of irreversible structural damage in human disease[155]. In addition, Berntorp et al[156] demonstrated that diabetic patients exhibit elevated levels of gonadotropin-releasing hormone autoantibodies, particularly immunoglobulin G isotypes, which are closely associated with autonomic neuropathy, suggesting that immune responses may interfere with neuroendocrine signaling along the brain-gut axis. Consistently, the streptozotocin-induced diabetic model further confirmed that M1/M2 imbalance and reduced HO-1 activity weaken macrophage-mediated protection, leading to ICC loss and DGE[63,146,157]. Notably, Kashyap et al[158] demonstrated that carbon monoxide, a downstream product of HO-1, mimics its protective effects by reducing oxidative stress, restoring c-Kit expression, and improving gastric emptying.

Chronic inflammation and oxidative stress further exacerbate brain-gut axis dysfunction by inducing injury to the ENS and central regulatory pathways. Hyperglycemia-induced oxidative damage reduces ICC density, promotes neuronal degeneration, and impairs smooth muscle contractility, thereby compromising intrinsic gastrointestinal motility regulation[50,159]. In addition, inflammatory mediators and oxidative molecules generated during immune activation can influence central regulatory nuclei, including the nucleus tractus solitarius and the hypothalamus, via vagal afferent signaling and humoral pathways[160]. This process establishes a positive neuro-immune feedback loop, further amplifying gastric motility disturbances and ANS dysfunction. Overall, inflammation, immune dysregulation, and oxidative stress collectively constitute key pathological drivers of brain-gut axis imbalance, driving the progression of DGP from peripheral inflammatory responses toward central signaling dysregulation.

BRAIN-GUT AXIS-TARGETED THERAPEUTIC STRATEGIES FOR DGP

Pharmacological therapy

Pharmacological therapy remains the cornerstone of intervention for DGP, and its therapeutic efficacy can be conceptualized as multilevel modulation across the central, peripheral, and effector layers of the brain-gut axis. Current clinical practice and research primarily focus on three major classes of agents, including dopamine receptor antagonists, motilin receptor agonists, and ghrelin receptor agonists. Emerging studies are further exploring multitarget strategies involving intracellular signaling pathways, gut microbiota modulation, and smooth muscle function.

Dopamine receptor antagonists exert bidirectional brain-gut regulatory effects by modulating both central and peripheral dopaminergic signaling. Network meta-analyses have demonstrated that oral dopamine antagonists significantly improve gastroparesis symptoms compared with placebo[161]. Metoclopramide exerts both peripheral prokinetic and central antiemetic effects by enhancing lower esophageal sphincter tone, promoting antral and duodenal peristalsis, and reducing nausea and vomiting via blockade of D₂ and 5-HT type 3 receptor within the medullary chemoreceptor trigger zone[162-165]. As the only Food and Drug Administration-approved pharmacological treatment for gastroparesis, its long-term use is limited by its ability to cross the blood-brain barrier, leading to extrapyramidal adverse effects[166,167]. Notably, novel nanoparticle-based delivery systems, such as bovine serum albumin-metoclopramide composite nanoparticles, offer a promising strategy for brain-gut axis-targeted drug delivery by reducing CNS toxicity while preserving therapeutic efficacy[168]. Domperidone, a peripheral D₂ receptor antagonist, exhibits a favorable safety profile owing to its limited penetration of the CNS and effectively alleviates symptoms such as early satiety, nausea, and bloating[169-172], suggesting that its therapeutic effects are primarily mediated through peripheral neural pathways regulating gastric motility.

Motilin receptor agonists mimic endogenous motilin-mediated activation of gastric antral and pyloric neuromuscular circuits, thereby promoting phase III migratory motor complex activity, accelerating gastric emptying, and restoring peripheral rhythmicity of the brain-gut axis[173,174]. As a representative prokinetic, erythromycin exhibits short-term benefits by promoting gastric motility and alleviating relevant symptoms[175]. However, long-term use of erythromycin may increase the risk of cardiac arrhythmias. Azithromycin, with a longer half-life and a more favorable safety profile, has therefore been proposed as a potential alternative[176,177].

Ghrelin receptor agonists, by activating the brain-gut-pancreas signaling axis, coordinate gastric motility and systemic energy metabolism and have emerged as a focus of recent pharmacological research targeting the brain-gut axis. Representative agents include ulimorelin (TZP-101/102) and relamorelin (RM-131), both of which have demonstrated significant acceleration of solid gastric emptying and improvement of nausea and upper gastrointestinal symptoms in preclinical and clinical studies[178-181]. Phase II clinical trials of relamorelin further showed that subcutaneous administration significantly improved gastric emptying half-time and alleviated core gastroparesis symptoms[182].

Furthermore, 5-HT₄ receptor agonists including mosapride and prucalopride, enhance acetylcholine release, thereby promoting antral propulsion and gastric emptying and representing an excitatory modulatory pathway within brain-gut axis chemical signaling. Animal studies have demonstrated that mosapride, either alone or in combination with metformin, improves gastric emptying and glycemic control in diabetic rat models[183]. Randomized controlled trials have further shown that prucalopride significantly accelerates solid gastric emptying, although symptomatic improvement appears limited[184]. In addition, the centrally acting neurokinin-1 receptor antagonist aprepitant alleviates nausea and vomiting and improves gastric regulatory function[185].

Beyond conventional prokinetic agents, targeted modulation of the gut microbiota represents an emerging dimension of brain-gut axis regulation. Studies in functional gastrointestinal disorders have demonstrated that gut microbiota dysbiosis and altered microbial metabolites disrupt brain-gut signaling and gastric motility by modulating ENS excitability, intestinal immune responses, and epithelial barrier integrity[186]. The herbal medicine Alpinia officinarum Hance extract markedly enhances gastric motility and mucosal architecture in DGP rat models, exerting multitarget brain-gut regulatory effects by upregulating the SCF/c-Kit signaling pathway and reshaping gut microbiota composition[187]. Similarly, the compound traditional Chinese medicine FoxiangSan improved gastric motility by modulation of gut microbiota structure and activation of the cAMP/PKA/5-HT₄ signaling pathway, thereby supporting the concept of synergistic interactions among the gut microbiota, intracellular signaling pathways, and the brain-gut axis[188]. In addition, Salsola collina ethyl acetate extract promoted restoration of brain-gut signaling through upregulation of c-Kit and SCF expression and correction of abnormalities in multiple brain-gut peptides[72], whereas Amomum compactum volatile oil enhanced gastric emptying via activation of IGF-1/IGF-1R signaling[189]. Curcumin and berberine have been shown to reconstruct peripheral neural function within the brain-gut axis through inhibition of oxidative stress, modulation of NF-κB signaling, enhancement of cholinergic transmission, and repair of gastric nerve plexus structure, respectively[190,191]. Furthermore, plant-derived serotonin promotes gastric smooth muscle cell proliferation and inhibits apoptosis via the β₂-adrenergic receptor/phosphatidylinositol 3-kinase/protein kinase B pathway, thereby improving the structural and functional integrity of the peripheral effector component of the brain-gut axis[192].

Overall, pharmacological therapy modulates brain-gut axis function across central-to-peripheral chemical signaling levels through regulation of a multilayered signaling network involving neurotransmitters, gastrointestinal hormones, gut microbiota, and smooth muscle-associated pathways. Future research should emphasize multitarget synergistic mechanisms and long-term safety, and explore integrated therapeutic strategies that combine pharmacological agents with neuromodulatory and metabolic interventions to achieve systemic remodeling of brain-gut axis function (Tables 1 and 2).

Table 1 Phenotype-oriented pharmacological strategies targeting the brain-gut axis in diabetic gastroparesis.

Patient phenotype	Dominant pathophysiological features	Representative agents	Therapeutic focus
Central-dominant phenotype	Central sensory integration and regulatory dysfunction, with symptom severity disproportionate to DGE	Metoclopramide; aprepitant	Predominantly central modulation to alleviate nausea and vomiting and improve brain-gut signal processing
Peripheral neuro-effector-dominant phenotype	Enteric nervous system and interstitial cells of Cajal injury with impaired antral motility and pyloric dysfunction, associated with marked DGE	Domperidone; erythromycin; azithromycin; ulimorelin (TZP-101/102); relamorelin (RM-131); mosapride; prucalopride	Enhancement of peripheral neuromuscular function to restore gastric rhythmicity and accelerate gastric emptying
Inflammation-microbiota-associated phenotype	Low-grade inflammation, oxidative stress, and gut microbiota dysbiosis	Alpinia officinarum extract; FoxiangSan; Salsola collina ethyl acetate extract; amomum compactum volatile oil; curcumin; berberine; plant-derived serotonin	Modulation of inflammatory responses and gut microbiota to improve overall brain-gut axis homeostasis

DGE: Delayed gastric emptying.

Table 2 Comparison of neuromodulatory approaches targeting the brain-gut axis in diabetic gastroparesis.

Neuromodulation modality	Target population/stage	Main therapeutic effects	Proposed mechanisms
GES	Refractory DGP, particularly patients with severe nausea and vomiting	Marked reduction in vomiting frequency and overall symptom improvement; variable effects on gastric emptying	Activation of vagal afferent pathways, modulation of gastric electrical rhythms, promotion of ENS synaptic regeneration, and improvement of ICC function
GES combined with pyloroplasty	DGP with prominent pyloric dysfunction	Greater improvement in symptoms and gastric emptying compared with single intervention	Synergistic effects of neuromodulation and mechanical outflow relief, enhancing remodeling of peripheral effector components of the brain-gut axis
VNS/transcutaneous VNS	DGP with autonomic dysfunction or central regulatory abnormalities	Symptom improvement and partial acceleration of gastric emptying, with inconsistent results across randomized controlled trials	Enhancement of vagal efferent activity, modulation of central-peripheral brain-gut signaling, and activation of cholinergic anti-inflammatory reflexes
Intrapyloric botulinum toxin injection	DGP associated with pyloric spasm	Short-term improvement in gastric emptying and symptoms; limited long-term efficacy	Local inhibition of acetylcholine release and smooth muscle excitability, with limited capacity for sustained brain-gut axis remodeling
Low-energy shockwave	Experimental stage (preclinical DGP models)	Improvement of gastric contractile function and increased density of enteric neuromuscular plexuses	Promotion of axonal regeneration and enhancement of gastrointestinal neuromuscular structural integrity
EA/transcutaneous EA	Mild to moderate DGP or adjunctive therapy	Improvement of nausea, restoration of gastric slow-wave rhythm, and acceleration of gastric emptying	Regulation of autonomic balance via the nucleus tractus solitarius-vagal pathway, restoration of excitatory-inhibitory neurotransmitter balance in the ENS, and promotion of ICC protection and regeneration
Low-intensity pulsed ultrasound	Experimental stage (preclinical DGP models)	Acceleration of gastric emptying and improvement of ICC network integrity	Inhibition of the tumor necrosis factor-α/Ikappa B kinase beta/nuclear factor-kappa B inflammatory pathway and restoration of ENS-ICC coupling

DGP: Diabetic gastroparesis; EA: Electroacupuncture; ENS: Enteric nervous system; GES: Gastric electrical stimulation; ICC: Interstitial cells of Cajal; VNS: Vagus nerve stimulation.

Neuromodulation therapy

Neuromodulation therapy has emerged as a major focus in DGP research in recent years. By modulating neural signaling within the brain-gut axis, neuromodulatory interventions have the potential to improve gastric motility disturbances and ANS dysfunction.

Gastric electrical stimulation (GES) is currently the most widely applied neuromodulation technique. A multicenter prospective randomized crossover study by McCallum et al[193] demonstrated that, in patients with drug-refractory DGP, Enterra stimulation resulted in a 57% reduction in weekly vomiting frequency and a 67.8% improvement in overall symptoms at one year, accompanied by improvements in gastric emptying and quality of life. Additional studies have further confirmed that GES alleviates symptoms primarily through activation of vagal afferent fibers[194,195]. Animal studies have demonstrated that GES promotes enteric synaptic regeneration, upregulates synaptophysin, PGP9.5, 5-HT₂B, nNOS, choline acetyltransferase, and glial cell line-derived neurotrophic factor, and thereby improves ICC function[196,197]. Vagus nerve stimulation (VNS) and its non-invasive modality (tVNS) represent key neuromodulatory approaches within the central-peripheral axis of the brain-gut system. Early studies suggested that tVNS could improve symptoms and accelerate gastric emptying[198]; however, results from subsequent multicenter randomized controlled trials have been inconsistent[199]. These findings indicate that peripheral vagal stimulation alone may be insufficient, and its therapeutic efficacy may be influenced by vagal nerve degeneration and central neural plasticity.

Pyloric dysfunction is regarded as a critical peripheral pathological component in DGP. Botulinum toxin transiently improves gastric emptying and associated symptoms by inhibiting acetylcholine release and excitatory neuromuscular transmission at nerve terminals[200]. However, randomized controlled trials have failed to demonstrate sustained efficacy, indicating that isolated local neural inhibition is insufficient to remodel brain-gut axis function[201]. Recent studies have demonstrated that GES combined with pyloroplasty significantly improves both symptoms and gastric emptying compared with pyloroplasty alone[202]. These findings suggest that neuro-mechanical dual-target interventions focusing on the pyloric component may represent a promising strategy for reconstruction of peripheral brain-gut axis function.

Physical energy-based neuromodulation techniques have also demonstrated therapeutic potential in DGP. Wu et al[203] demonstrated that low-energy shockwave therapy promotes axonal regeneration, increases the density of gastrointestinal myenteric fibers, and enhances gastric contractility. In addition, low-intensity pulsed ultrasound applied to the ST36 acupoint has been shown to improve gastric emptying in diabetic rat models, primarily through inhibition of the tumor necrosis factor-α/Ikappa B kinase beta/NF-κB inflammatory pathway and restoration of the ICC network[204]. Electroacupuncture (EA), as a non-invasive neuromodulatory approach, represents an important intervention targeting peripheral components of the brain-gut axis. Sarosiek et al[205] demonstrated, using combined EEG-EGG monitoring, that transcutaneous EA significantly reduces nausea scores and restores gastric slow-wave rhythm in patients with DGP, while modulating activity distribution in the prefrontal cortex, suggesting symptom improvement via a brain-prefrontal cortex-gastric electrical coupling mechanism. Animal studies have demonstrated that EA restores excitatory-inhibitory neurotransmitter balance within the ENS via the nucleus tractus solitarius-vagus nerve axis, upregulates nNOS and choline acetyltransferase expression in the gastric antrum, and increases ICC (c-Kit+) expression following ST36 stimulation, thereby improving gastric emptying[206-208]. Moreover, EA promotes ICC protection and regeneration by modulating autophagic flux and activating the SDF-1/CXCR4 and mSCF/c-Kit-ETV1 signaling pathways, thereby restoring ENS-ICC network integrity and enhancing gastric motility[209,210].

In summary, neuromodulation therapy improves gastric motility and symptom burden by modulating multiple hierarchical layers of the brain-gut axis, including the vagus nerve-ENS-ICC network. GES has established clinical efficacy, whereas non-invasive approaches such as tVNS, transcutaneous EA, EA, and low-energy shockwave offer emerging avenues for personalized neuromodulation. Future research should emphasize patient phenotypic stratification and stimulation parameter optimization to develop precision neuromodulation strategies that integrate central, peripheral, and gastric wall neural circuits.

Nutritional and metabolic support

Nutritional and metabolic disturbances are considered important contributors to brain-gut axis dysfunction in DGP. Ahmed et al[211] reported that 54.5% of DGP patients were found to have vitamin B12 deficiency, a prevalence significantly higher than that observed in the general diabetic population. Serum vitamin B12 levels are positively correlated with gastric emptying rates, and deficiency may result in peripheral myelin sheath damage and impaired vagal nerve conduction, suggesting that neurotrophic supplementation may help attenuate brain-gut axis degeneration. Patients with DGP frequently experience hypoglycemia and marked glycemic variability due to DGE, resulting in asynchronous insulin action and nutrient absorption[212]. Using continuous glucose monitoring, Betônico et al[213] demonstrated that semi-liquid, low-fat diets significantly reduce postprandial glycemic excursions and improve gastroparesis-related symptoms. Overall, vitamin supplementation, dietary texture optimization, and appropriate adjustment of insulin timing represent fundamental components of comprehensive DGP management by stabilizing metabolic homeostasis, enhancing gastric emptying, and improving neuroreflex coordination, thereby achieving bidirectional regulation of the brain-gut axis.

PERSPECTIVE

Future research should prioritize elucidating molecular mechanisms within the multilayered brain-gut axis and establishing biomarker systems that integrate neuroimaging, neurotransmitter profiling, and gut microbiota signatures to enable phenotypic stratification and precision intervention. Parallel efforts should focus on developing multitarget therapeutic strategies that combine neuromodulation, microbiota remodeling, and signaling pathway regulation. In addition, greater attention should be given to the potential roles of traditional Chinese medicine and natural bioactive compounds in brain-gut axis reconstruction and symptom control.

CONCLUSION

In summary, DGP is not merely a disorder of DGE, but rather a brain-gut axis-related syndrome arising from integrated dysfunction across central regulatory mechanisms, the autonomic and ENSs, the ICC network, pyloric function, immune inflammation, and gut microbiota under chronic hyperglycemia and metabolic stress. Diagnosis and therapeutic evaluation should therefore be based on standardized, multidimensional assessment frameworks, with four-hour solid-meal gastric emptying scintigraphy remaining a key objective measure[214]. Importantly, from a brain-gut axis perspective, clinical evaluation of DGP may benefit from integrating neural functional assessment, imaging of regulatory circuits, and gut microbiota-related indicators, rather than relying solely on gastric emptying measurements. Current management emphasizes comprehensive and individualized strategies, while available pharmacological options remain limited by long-term safety concerns[215]. Overall, DGP research is shifting from a motility-centered paradigm toward an integrated brain-gut axis model, in which multidisciplinary collaboration and mechanism-driven approaches are increasingly important for improving patient prognosis and quality of life.