OBJECTIVE: Diabetes-induced gastrointestinal (GI) motility disorders are increasingly prevalent. Damage to the enteric nervous system (ENS), composed primarily of enteric neurons and glial cells, is an essential mechanism involved in these disorders. Although electroacupuncture (EA) has shown the potential to mitigate enteric neuronal loss, its mechanism is not fully understood. Additionally, the effects of EA on enteric glial cells have not been investigated. Enteric neural precursor cells (ENPCs) contribute to the structural and functional integrity of the ENS, yet whether EA enhances their differentiation into enteric neurons and glial cells remains unexplored. This study investigates whether EA promotes ENS repair through enhancing ENPC-derived neurogenesis and gliogenesis and elucidates the potential molecular mechanisms involved. METHODS: Transgenic mice were used to trace Nestin⁺/nerve growth factor receptor (Ngfr)⁺ ENPCs labeled with green fluorescent protein (GFP) in vivo. Mice were randomly divided into four groups: control, diabetes mellitus (DM), DM + sham EA, and DM + EA. The effects of EA on diabetic mice were evaluated by GI motility, ENS structure, and ENPC differentiation. Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling was detected to clarify the underlying molecular mechanisms. RESULTS: EA alleviated diabetes-induced GI motility disorders, as indicated by reduced whole gut transit time, shortened colonic bead expulsion time, and enhanced smooth muscle contractility. Furthermore, EA attenuated diabetes-induced losses of enteric neurons and glial cells, thereby restoring ENS integrity. Notably, EA reversed the diabetes-induced decrease in ENPCs and significantly increased the absolute number and the proportion of ENPC-derived enteric neurons. However, immunofluorescence analyses revealed no colocalization between EA-induced glial fibrillary acidic protein⁺ glial cells and GFP-labeled ENPCs. Mechanistically, GDNF/Ret signaling was elevated in intestinal tissues and upregulated in ENPCs in EA-treated diabetic mice. CONCLUSION EA facilitates ENS repair by promoting Nestin⁺/Ngfr⁺ ENPC differentiation into enteric neurons via upregulation of GDNF/Ret signaling, and driving enteric gliogenesis from non-Nestin⁺/Ngfr⁺ ENPCs. These findings highlight EA's role in ameliorating diabetes-induced GI dysmotility through ENPC-derived ENS restoration. Please cite this article as: Guo JL, Liu S, Ding SJ, Yang X, Du F. Electroacupuncture at ST36 improves gastrointestinal motility disorders by promoting enteric nervous system regeneration through GDNF/Ret signaling in diabetic mice. J Integr Med. 2025; 23(5):548-559.
Animals ; Electroacupuncture ; Enteric Nervous System/physiology* ; Gastrointestinal Motility/physiology* ; Glial Cell Line-Derived Neurotrophic Factor/metabolism* ; Diabetes Mellitus, Experimental/therapy* ; Signal Transduction ; Mice ; Gastrointestinal Diseases/physiopathology* ; Proto-Oncogene Proteins c-ret/metabolism* ; Mice, Transgenic ; Male ; Nerve Regeneration ; Neural Stem Cells ; Mice, Inbred C57BL ; Acupuncture Points

The role of the brain-gut microbiota axis in functional gastrointestinal diseases has been gradually recognized. According to the ROME IV diagnostic criteria, functional gastrointestinal diseases are classified as diseases caused by abnormal brain-gut interaction. This concept is of great significance to the change of diagnosis and treatment paradigm of functional gastrointestinal diseases. Chronic constipation is the most common functional gastrointestinal disease. The pathogenesis of chronic constipation is closely related to the imbalance of intestinal flora, the abnormality of enteric nervous system and neurotransmitter in brain. Therefore, in the diagnosis and treatment of chronic constipation, enough attention should be paid to the concept of integration of brain-gut microflora axis, but the clinical application of brain-gut microflora axis is still limited. This may be one of the factors for high incidence but poor treatment efficacy of chronic constipation. Based on the global research progress and our clinical experience, this article expounds the clinical significance of the brain-gut microbiota axis in chronic constipation.
Brain ; Constipation ; Enteric Nervous System ; Gastrointestinal Microbiome ; Humans

Enteric nervous system (ENS) is composed of intestinal submucosal and myenteric plexuses. ENS may independently regulate intestinal digestive and absorptive function, and it is also known as "the second brain" or gut brain. ENS has significant specificity relative to central nervous system (CNS) in properties and functional activities of neurons and neural circuits. ENS is connected with CNS through the feedback pathway (brain-gut-axis) of sympathetic and parasympathetic nerves and peripheral primary sensory afferent nerves to form the bidirectional brain-gut-axis, which may affect emotion, appetite and behavioral states of individuals. Gastrointestinal functional disorder (GIFD) induced by ENS dysfunction may not only cause abnormal gastrointestinal function but also has been implicated in cognitive and mood disorders, such as irritable bowel syndrome (IBS). GIFD would influence deeply the quality of life in patients. Nevertheless, in the worldwide, ENS has so far received much less attention as compared with CNS. The depth of research and scale of investment in ENS studies have been much lower than those in CNS studies. The situation in China is even more evident. From ENS research history, an outstanding problem is to ignore largely the unique properties of ENS and apply mechanically the hypotheses formed in CNS studies to ENS researches. In this review, the structure and function of ENS are briefly introduced, and the importance of extraordinary characteristics of ENS is illustrated by the problems encountered in our studies.
Brain ; China ; Enteric Nervous System ; Humans ; Quality of Life

Interactions among the nervous, the endocrine and the immune systems enable the gut to respond to the dietary products, pathogens and microbiota, which maintains the homeostasis of the body. However, dysbiosis may induce or aggravate the gastrointestinal (GI) and extra-GI diseases through changing the activities of enteric nervous system (ENS), enteroendocrine cells and enteric immune cells. Here we review recent advances in the understandings on how intestinal flora may impact the enteric neuro-endocrine-immune system in the gut, thereby contributing to the regulation of pathophysiological processes.
Enteric Nervous System ; Gastrointestinal Diseases ; Gastrointestinal Microbiome ; Humans ; Immune System

BACKGROUND/AIMS: Previous studies from Korea have described chronic intestinal pseudo-obstruction (CIPO) patients with transition zone (TZ) in the colon. In this study, we evaluated the pathological characteristics and their association with long-term outcomes in Korean colonic pseudo-obstruction (CPO) patients with TZ. METHODS: We enrolled 39 CPO patients who were refractory to medical treatment and underwent colectomy between November 1989 and April 2016 (median age at symptoms onset: 45 [interquartile range, 29–57] years, males 46.2%). The TZ was defined as a colonic segment connecting a proximally dilated and distally non-dilated segment. Detailed pathologic analysis was performed. RESULTS: Among the 39 patients, 37 (94.9%) presented with TZ and 2 (5.1%) showed no definitive TZ. Median ganglion cell density in the TZ adjusted for the colonic circumference was significantly decreased compared to that in proximal dilated and distal non-dilated segments in TZ (+) patients (9.2 vs 254.3 and 150.5, P < 0.001). Among the TZ (+) patients, 6 showed additional pathologic findings including eosinophilic ganglionitis (n = 2), ulcers with combined cytomegalovirus infection (n = 2), diffuse ischemic changes (n = 1), and heterotropic myenteric plexus (n = 1). During follow-up (median, 61 months), 32 (82.1%) TZ (+) patients recovered without symptom recurrence after surgery. The presence of pathological features other than hypoganglionosis was an independent predictor of symptom recurrence after surgery (P = 0.046). CONCLUSIONS: Hypoganglionosis can be identified in the TZ of most Korean CPO patients. Detection of other pathological features in addition to TZ-associated hypoganglionosis was associated with poor post-operative outcomes.
Cell Count ; Colectomy ; Colon ; Colonic Pseudo-Obstruction ; Cytomegalovirus Infections ; Eosinophils ; Follow-Up Studies ; Ganglion Cysts ; Humans ; Intestinal Pseudo-Obstruction ; Korea ; Male ; Myenteric Plexus ; Pathology ; Recurrence ; Ulcer

Achalasia is a motility disorder of the esophagus that is characterized by loss of ganglionic neurons within the myenteric plexus of the lower esophageal sphincter (LES) resulting in failure of the LES to relax. Clinically this disorder presents with simultaneous dysphagia to solids and liquids, and if left untreated, leads to esophageal dilation, which can give rise to many adverse consequences. Extrinsic compression of respiratory structures is one such consequence, and rarely, cases of tracheal compression secondary to achalasia have been reported. However, cases of extrinsic bronchial compression are yet rarer. Here, we present a case series comprised of two patients with achalasia who presented with extrinsic bronchial compression by a dilated esophagus secondary to achalasia.
Airway Obstruction ; Cardia ; Deglutition Disorders ; Esophageal Achalasia ; Esophageal Motility Disorders ; Esophageal Sphincter, Lower ; Esophagus ; Ganglion Cysts ; Humans ; Myenteric Plexus ; Neurons

KBG syndrome is an autosomal dominant syndrome presenting with macrodontia, distinctive facial features, skeletal anomalies, and neurological problems caused by mutations in the ankyrin repeat domain 11 (ANKRD11) gene. The diagnosis of KBG is difficult in very young infants as the characteristic macrodontia and typical facial features are not obvious. The youngest patient diagnosed to date was almost one year of age. We here describe a 2-month-old Korean boy with distinctive craniofacial features but without any evidence of macrodontia due to his very early age. He also had a congenital megacolon without ganglion cells in the rectum. A de novo deletion of exons 5–9 of the ANKRD11 gene was identified in this patient by exome sequencing and real-time genomic polymerase chain reaction. As ANKRD11 is involved in the development of myenteric plexus, a bowel movement disorder including a congenital megacolon is not surprising in a patient with KBG syndrome and has possibly been overlooked in past cases.
Ankyrin Repeat ; Diagnosis ; Exome ; Exons ; Ganglion Cysts ; Hirschsprung Disease ; Humans ; Infant ; Male ; Movement Disorders ; Myenteric Plexus ; Polymerase Chain Reaction ; Rectum

Parkinson's disease (PD) is a common neurodegenerative disorder arising from an interplay between genetic and environmental risk factors. Studies have suggested that the pathological hallmarks of intraneuronal α-synuclein aggregations may start from the olfactory bulb and the enteric nervous system of the gut and later propagate to the brain via the olfactory tract and the vagus nerve. This hypothesis correlates well with clinical symptoms, such as constipation, that may develop up to 20 years before the onset of PD motor symptoms. Recent interest in the gut–brain axis has led to vigorous research into the gastrointestinal pathology and gut microbiota changes in patients with PD. In this review, we provide current clinical and pathological evidence of gut involvement in PD by summarizing the changes in gut microbiota composition and gut inflammation associated with its pathogenesis.
Brain ; Constipation ; Enteric Nervous System ; Gastrointestinal Microbiome ; Humans ; Inflammation ; Microbiota ; Neurodegenerative Diseases ; Olfactory Bulb ; Parkinson Disease ; Pathology ; Risk Factors ; Vagus Nerve

The role of the microbiome in health and human disease has emerged at the forefront of medicine in the 21st century. Over the last 2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play a significant role in the neuronal damage associated with Parkinson's disease (PD). Presence of pro-inflammatory cytokines and T cell infiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes has been reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in the post-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested that the α-synuclein misfolding might begin in the gut and spread “prion like” via the vagus nerve into lower brainstem and ultimately to the midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation, dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to the clinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the role of genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gut microbiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designed studies using customized probiotics and fecal microbiota transplantation.
Animals ; Anti-Bacterial Agents ; Biopsy ; Brain ; Brain Stem ; Cytokines ; Deglutition Disorders ; Dysbiosis ; Enteric Nervous System ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Humans ; In Vitro Techniques ; Inflammation ; Mesencephalon ; Mice ; Microbiota ; Neuroglia ; Neurons ; Parkinson Disease ; Probiotics ; Vagus Nerve

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, long-acting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility.
Acetylcholine ; Child ; Cholinesterase Inhibitors ; Diagnosis ; Enteric Nervous System ; Female ; Gastrointestinal Motility ; Humans ; Intestinal Obstruction ; Intestinal Pseudo-Obstruction ; Parenteral Nutrition ; Pyridostigmine Bromide