Gastrointestinal motility disorders: from pathogenesis to therapeutic strategies

Abstract

Gastrointestinal motility disorders (GIMDs) are characterized by impaired gastrointestinal motility. The prevention and treatment of GIMDs remain challenging, because of their prevalence and complexity. The pathogenesis of GIMDs involves multiple factors, such as dysregulation of the enteric nervous system, smooth muscle dysfunction, neurotransmitter imbalance, chronic inflammation, and gut microbiota dysbiosis, which synergistically contribute to GIMD development and progression. Currently, modern medicine remains the primary approach for treating GIMDs, with prokinetic agents such as mosapride and domperidone. However, traditional Chinese medicine (TCM) has attracted attention as a complementary and alternative therapy that can considerably alleviate GIMDs. Accordingly, this review is aimed at comprehensively summarizing the pathogenesis and current management of GIMDs, on the basis of articles in the PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. Future GIMD research should focus on the discovery of new therapeutic targets and the deep synergies between TCM and modern medicine, to achieve a transition from evidence-based medicine to precision medicine, which may aid in the development of more effective interventions and optimization of GIMD management.

Keywords

Gastrointestinal motility disorders / Pathogenesis / Therapeutic Strategies

References

[1] Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L: American College of Gastroenterology: Clinical Guideline: Management of Gastroparesis. The American Journal of Gastroenterology 2013, 108: 18-37.

[2] Iida H, Ohkubo H, Inamori M, Nakajima A, Sato H: Epidemiology and Clinical Experience of Chronic Intestinal Pseudo-obstruction in Japan: A Nationwide Epidemiologic Survey. Journal of Epidemiology 2013, 23: 288-294.

[3] Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC: Functional Bowel Disorders. Gastroenterology 2006, 130: 1480-1491.

[4] Lehmann S, Ferrie S, Carey S: Nutrition Management in Patients with Chronic Gastrointestinal Motility Disorders: A Systematic Literature Review. Nutrition in Clinical Practice 2020, 35: 219-230.

[5] Singh R, Zogg H, Ghoshal UC, Ro S: Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Frontiers in Pharmacology 2022, 13: 808195.

[6] Ohlsson B, Sjöberg K, Alm R, Fredrikson GN: Patients with Irritable Bowel Syndrome and Dysmotility Express Antibodies Against Gonadotropin-releasing Hormone in Serum. Neurogastroenterology and Motility 2011, 23: 1000-1006.

[7] Huang J, Lu M, Zheng Y, Ma J, Ma X, Wang Y, et al.: Quality of Evidence Supporting the Role of Acupuncture for the Treatment of Irritable Bowel Syndrome. Pain Research & Management 2021, 2021: 2752246.

[8] Kemppinen A, Howell C, Allgar V, Dodd M, Gregson J, Knowles C, et al.: Randomised, Double-blind, Placebo Controlled Multi-centre Study to Assess the Efficacy, Tolerability and Safety of Enterosgel^® in the Treatment of Irritable Bowel Syndrome with Diarrhoea (IBS-D) in Adults . Trials 2020, 21: 122.

[9] Farthing M, Roberts SE, Samuel DG, Williams JG, Thorne K, Morrison-Rees S, et al.: Survey of Digestive Health Across Europe: Final Report. Part 1: The Burden of Gastrointestinal Diseases and the Organisation and Delivery of Gastroenterology Services Across Europe. United European Gastroenterology Journal 2014, 2: 539-543.

[10] Curran MP, Robinson DM: Mosapride in Gastrointestinal Disorders. Drugs 2008, 68: 981-991.

[11] Takahashi T, Kurosawa S, Wiley JW, Owyang C: Mechanism for the Gastrokinetic Action of Domperidone. In Vitro Studies in Guinea Pigs. Gastroenterology 1991, 101: 703-710.

[12] Ou LB, Moriello C, Douros A, Filion KB: Domperidone and the Risks of Sudden Cardiac Death and Ventricular Arrhythmia: A Systematic Review and Meta-analysis of Observational Studies. British Journal of Clinical Pharmacology 2021, 87: 3649-3658.

[13] Parlak I, Atilla R, Cicek M, Parlak M, Erdur B, Guryay M, et al.: Rate of Metoclopramide Infusion Affects the Severity and Incidence of Akathisia. Emergency Medicine Journal 2005, 22: 621-624.

[14] Reddymasu SC, Soykan I, McCallum RW: Domperidone: Review of Pharmacology and Clinical Applications in Gastroenterology. The American Journal of Gastroenterology 2007, 102: 2036-2045.

[15] Salvioli B: Trimebutine: A State-of-the-Art Review. Minerva Gastroenterologica e Dietologica 2019, 65: 229-238.

[16] Sanger GJ, Furness JB: Ghrelin and Motilin Receptors as Drug Targets for Gastrointestinal Disorders. Nature Reviews Gastroenterology & Hepatology 2016, 13: 38-48.

[17] Tait C, Sayuk GS: The Brain-Gut-Microbiotal Axis: A Framework for Understanding Functional GI Illness and Their Therapeutic Interventions. European Journal of Internal Medicine 2021, 84: 1-9.

[18] Sanger GJ, Lee K: Hormones of the Gut-brain Axis as Targets for the Treatment of Upper Gastrointestinal Disorders. Nature Reviews Drug Discovery 2008, 7: 241-254.

[19] Xue R, Gu H, Qiu Y, Guo Y, Korteweg C, Huang J, et al.: Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Ganglia of Human Gastrointestinal Tract. Scientific Reports 2016, 6: 30926.

[20] Henningsen P, Zimmermann T, Sattel H: Medically Unexplained Physical Symptoms, Anxiety, and Depression: A Meta-analytic Review. Psychosomatic Medicine 2003, 65: 528-533.

[21] Makino S, Hashimoto K, Gold PW: Multiple Feedback Mechanisms Activating Corticotropin-releasing Hormone System in the Brain During Stress. Pharmacology Biochemistry and Behavior 2002, 73: 147-158.

[22] Dudek KA, Dion-Albert L, Kaufmann FN, Tuck E, Lebel M, Menard C: Neurobiology of Resilience in Depression: Immune and Vascular Insights from Human and Animal Studies. The European Journal of Neuroscience 2021, 53: 183-221.

[23] Clark A, Mach N: Exercise-induced Stress Behavior, Gut-microbiota-brain Axis and Diet: A Systematic Review for Athletes. Journal of the International Society of Sports Nutrition 2016, 13: 43.

[24] Clyburn C, Browning KN: Glutamatergic Plasticity within Neurocircuits of the Dorsal Vagal Complex and the Regulation of Gastric Functions. American Journal of Physiology-Gastrointestinal and Liver Physiology 2021, 320: G880-G887.

[25] Ming X, Gao S, Sun J, Zhang N, Guo R, Feng X, et al.: Regulation of the MCHergic Neural Circuit to Dorsal Raphe Nucleus on Emotion-related Behaviors and Intestinal Dysfunction in Mice Model of Irritable Bowel Syndrome with Diarrhea. Neuroendocrinology 2024, 114: 605-622.

[26] Drossman DA, Tack J, Ford AC, Szigethy E, Törnblom H, Van Oudenhove L: Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-brain Interaction): A Rome Foundation Working Team Report. Gastroenterology 2018, 154: 1140-1171.

[27] Wehrwein EA, Orer HS, Barman SM: Overview of the Anatomy, Physiology, and Pharmacology of the Autonomic Nervous System. Comprehensive Physiology 2016, 6: 1239-1278.

[28] Fukuda H, Tsuchida D, Koda K, Miyazaki M, Pappas TN, Takahashi T: Inhibition of Sympathetic Pathways Restores Postoperative Ileus in the Upper and Lower Gastrointestinal Tract. Journal of Gastroenterology and Hepatology 2007, 22: 1293-1299.

[29] Traeger L, Bedrikovetski S, Fitzsimmons T, Nguyen TM, Moore JW, Lewis M, et al.: Pyridostigmine to Reduce the Duration of Postoperative Ileus after Colorectal Surgery (PyRICo-RCT): Randomized Clinical Trial. The British Journal of Surgery 2024, 111: znae121.

[30] Guerci B, Bourgeois C, Bresler L, Scherrer ML, Böhme P: Gastric Electrical Stimulation for the Treatment of Diabetic Gastroparesis. Diabetes & Metabolism 2012, 38: 393-402.

[31] Sugimoto K, Yasujima M, Yagihashi S: Role of Advanced Glycation End Products in Diabetic Neuropathy. Current Pharmaceutical Design 2008, 14: 953-961.

[32] Yao D, Brownlee M: Hyperglycemia-induced Reactive Oxygen Species Increase Expression of the Receptor for Advanced Glycation End Products (RAGE) and RAGE Ligands. Diabetes 2010, 59: 249-255.

[33] Gutowska K, Czajkowski K, Kuryłowicz A: Receptor for the Advanced Glycation End Products (RAGE) Pathway in Adipose Tissue Metabolism. International Journal of Molecular Sciences 2023, 24: 10982.

[34] Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, et al.: AGEs/RAGE Complex Upregulates BACE1 via NF-κB Pathway Activation. Neurobiology of Aging 2012, 33: 196.e13-e27.

[35] Chang XW, Qin Y, Jin Z, Xi TF, Yang X, Lu ZH, et al.: Interleukin-6 (IL-6) Mediated the Increased Contraction of Distal Colon in Streptozotocin-induced Diabetes in Rats via IL-6 Receptor Pathway. International Journal of Clinical and Experimental Pathology 2015, 8: 4514-4524.

[36] Lehrskov LL, Christensen RH: The Role of Interleukin-6 in Glucose Homeostasis and Lipid Metabolism. Seminars in Immunopathology 2019, 41: 491-499.

[37] Furness JB, Costa M: Types of Nerves in the Enteric Nervous System. Neuroscience 1980, 5: 1-20.

[38] Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W: The Enteric Nervous System in Gastrointestinal Disease Etiology. Cellular and Molecular Life Sciences 2021, 78: 4713-4733.

[39] Yarandi SS, Srinivasan S: Diabetic Gastrointestinal Motility Disorders and the Role of Enteric Nervous System: Current Status and Future Directions. Neurogastroenterology and Motility 2014, 26: 611-624.

[40] Bassotti G, Villanacci V, Antonelli E, Morelli A, Salerni B: Enteric Glial Cells: New Players in Gastrointestinal Motility? Laboratory Investigation 2007, 87: 628-632.

[41] Friedmacher F, Rolle U: Interstitial Cells of Cajal: Clinical Relevance in Pediatric Gastrointestinal Motility Disorders. Pediatric Surgery International 2023, 39: 188.

[42] Chanpong A, Borrelli O, Thapar N: The Potential Role of Microorganisms on Enteric Nervous System Development and Disease. Biomolecules 2023, 13: 447.

[43] Yip JLK, Balasuriya GK, Spencer SJ, Hill-Yardin EL: Examining Enteric Nervous System Function in Rat and Mouse: An Interspecies Comparison of Colonic Motility. American Journal of Physiology-Gastrointestinal and Liver Physiology 2022, 323: G477-G487.

[44] Suman S: Enteric Nervous System Alterations in Inflammatory Bowel Disease: Perspectives and Implications. Gastrointestinal Disorders (Basel, Switzerland) 2024, 6: 368-379.

[45] Ahmadzai MM, McClain JL, Dharshika C, Seguella L, Giancola F, De Giorgio R, et al.: LPAR1 Regulates Enteric Nervous System Function Through Glial Signaling and Contributes to Chronic Intestinal Pseudo-obstruction. The Journal of Clinical Investigation 2022, 132: e149464.

[46] Kaji N, Hori M: Interstitial Cells of Cajal in Gastrointestinal Inflammatory Diseases. Journal of Smooth Muscle Research 2023, 59: 1-13.

[47] Choi EL, Taheri N, Tan E, Matsumoto K, Hayashi Y: The Crucial Role of the Interstitial Cells of Cajal in Neurointestinal Diseases. Biomolecules 2023, 13: 1358.

[48] Sanders KM, Santana LF, Baker SA: Interstitial Cells of Cajal - Pacemakers of the Gastrointestinal Tract. The Journal of Physiology 2023. DOI: 10.1113/JP284745.

[49] Won KJ, Sanders KM, Ward SM: Interstitial Cells of Cajal Mediate Mechanosensitive Responses in the Stomach. Proceedings of the National Academy of Sciences of the United States of America 2005, 102: 14913-14918.

[50] Chikkamenahalli LL, Pasricha PJ, Farrugia G, Grover M: Gastric Biopsies in Gastroparesis: Insights into Gastric Neuromuscular Disorders to Aid Treatment. Gastroenterology Clinics of North America 2020, 49: 557-570.

[51] Mikkelsen HB: Interstitial Cells of Cajal, Macrophages and Mast Cells in the Gut Musculature: Morphology, Distribution, Spatial and Possible Functional Interactions. Journal of Cellular and Molecular Medicine 2010, 14: 818-832.

[52] Bettolli M, De Carli C, Jolin-Dahel K, Bailey K, Khan HF, Sweeney B, et al.: Colonic Dysmotility in Postsurgical Patients with Hirschsprung’s Disease. Potential Significance of Abnormalities in the Interstitial Cells of Cajal and the Enteric Nervous System. Journal of Pediatric Surgery 2008, 43: 1433-1438.

[53] Iino S, Horiguchi K, Horiguchi S: c-Kit-Stem Cell Factor Signal-independent Development of Interstitial Cells of Cajal in Murine Small Intestine. Cell and Tissue Research 2020, 379: 121-129.

[54] Iino S, Horiguchi S, Horiguchi K: Interstitial Cells of Cajal in the Gastrointestinal Musculature of Wjic c-kit Mutant Mice . Journal of Smooth Muscle Research 2011, 47: 111-121.

[55] Reber L, Da Silva CA, Frossard N: Stem Cell Factor and its Receptor c-Kit as Targets for Inflammatory Diseases. European Journal of Pharmacology 2006, 533: 327-340.

[56] Gonzalez Z, McCallum R: Small Bowel Dysmotility, Pseudoobstruction, and Functional Correlation with Histopathology: Lessons Learned. Current Gastroenterology Reports 2020, 22: 14.

[57] Li F, Zhang L, Li C, Ni B, Wu Y, Huang Y, et al.: Adenovirus-mediated Stem Cell Leukemia Gene Transfer Induces Rescue of Interstitial Cells of Cajal in ICC-loss Mice. International Journal of Colorectal Disease 2010, 25: 557-566.

[58] Zheng H, Liu YJ, Chen ZC, Fan GQ: miR-222 Regulates Cell Growth, Apoptosis, and Autophagy of Interstitial Cells of Cajal Isolated from Slow Transit Constipation Rats by Targeting c-kit. Indian Journal of Gastroenterology 2021, 40: 198-208.

[59] Shimojima N, Nakaki T, Morikawa Y, Hoshino K, Kitajima M: Imatinib Blocks Spontaneous Mechanical Activities in the Adult Mouse Small Intestine: Possible Inhibition of c-Kit Signaling. Pharmacology 2005, 74: 95-99.

[60] Tong W, Jia H, Zhang L, Li C, Ridolfi TJ, Liu B: Exogenous Stem Cell Factor Improves Interstitial Cells of Cajal Restoration after Blockade of c-kit Signaling Pathway. Scandinavian Journal of Gastroenterology 2010, 45: 844-851.

[61] Foxx-Orenstein AE, Grider JR: Regulation of Colonic Propulsion by Enteric Excitatory and Inhibitory Neurotransmitters. The American Journal of Physiology 1996, 271: G433-G437.

[62] Singh K, Randhwa G, Salloum FN, Grider JR, Murthy KS: Decreased Smooth Muscle Function, Peristaltic Activity, and Gastrointestinal Transit in Dystrophic (mdx) Mice. Neurogastroenterology and Motility 2021, 33: e13968.

[63] Ge X, Ding C, Zhao W, Xu L, Tian H, Gong J, et al.: Antibiotics-induced Depletion of Mice Microbiota Induces Changes in Host Serotonin Biosynthesis and Intestinal Motility. Journal of Translational Medicine 2017, 15: 13.

[64] Koh SD, Campbell JD, Carl A, Sanders KM: Nitric Oxide Activates Multiple Potassium Channels in Canine Colonic Smooth Muscle. The Journal of Physiology 1995, 489: 735-743.

[65] Groneberg D, König P, Koesling D, Friebe A: Nitric Oxide-sensitive Guanylyl Cyclase is Dispensable for Nitrergic Signaling and Gut Motility in Mouse Intestinal Smooth Muscle. Gastroenterology 2011, 140: 1608-1617.

[66] Ghalayini IF: Nitric Oxide-cyclic GMP Pathway with Some Emphasis on Cavernosal Contractility. International Journal of Impotence Research 2004, 16: 459-469.

[67] Kreiss C, Toegel S, Bauer AJ: α₂-Adrenergic Regulation of NO Production Alters Postoperative Intestinal Smooth Muscle Dysfunction in Rodents . American Journal of Physiology-Gastrointestinal and Liver Physiology 2004, 287: G658-G666.

[68] Darwiche W, Delanaud S, Dupont S, Ghamlouch H, Ramadan W, Joumaa W, et al.: Impact of Prenatal and Postnatal Exposure to the Pesticide Chlorpyrifos on the Contraction of Rat Ileal Muscle Strips: Involvement of an Inducible Nitric Oxide Synthase-dependent Pathway. Neurogastroenterology and Motility 2017, 29: e12918.

[69] Hosaka K, Rayner SE, von der Weid PY, Zhao J, Imtiaz MS, van Helden DF: Calcitonin Gene-related Peptide Activates Different Signaling Pathways in Mesenteric Lymphatics of Guinea Pigs. American Journal of Physiology Heart and Circulatory Physiology 2006, 290: H813-H822.

[70] Lu G, Mazet B, Sarr MG, Szurszewski JH: Effect of Nitric Oxide on Calcium-activated Potassium Channels in Colonic Smooth Muscle of Rabbits. American Journal of Physiology 1998, 274: G848-G856.

[71] Bisnett B, Wanjara S, Hoselton S, Schuh J, Dorsam G: Vasoactive Intestinal Peptide (VIP) Upregulates Synaptotagmin XIII Through a VIP1/PKA-dependent Signaling Mechanism in Mouse Splenocytes (611.4). The FASEB Journal 2014, 28: 611.4.

[72] Gros M, Gros B, Mesonero JE, Latorre E: Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management. Journal of Clinical Medicine 2021, 10: 3429.

[73] Shi XZ, Sarna SK: Homeostatic and Therapeutic Roles of VIP in Smooth Muscle Function: Myo-neuroimmune Interactions. American Journal of Physiology-Gastrointestinal and Liver Physiology 2009, 297: G716-G725.

[74] Guo J, Li L, Chen F, Fu M, Cheng C, Wang M, et al.: Forces Bless You: Mechanosensitive Piezo Channels in Gastrointestinal Physiology and Pathology. Biomolecules 2024, 14: 804.

[75] Xie Z, Rose L, Feng J, Zhao Y, Lu Y, Kane H, et al.: Enteric Neuronal Piezo1 Maintains Mechanical and Immunological Homeostasis by Sensing Force. Cell 2025, 188: 2417-2432.

[76] Beyder A, Farrugia G: Ion Channelopathies in Functional GI Disorders. American Journal of Physiology-Gastrointestinal and Liver Physiology 2016, 311: G581-G586.

[77] Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, et al.: Ano1, a Ca²⁺-activated Cl⁻ Channel, Coordinates Contractility in Mouse Intestine by Ca²⁺ Transient Coordination Between Interstitial Cells of Cajal . The Journal of Physiology 2014, 592: 4051-4068.

[78] Sanders KM, Zhu MH, Britton F, Koh SD, Ward SM: Anoctamins and Gastrointestinal Smooth Muscle Excitability. Experimental Physiology 2012, 97: 200-206.

[79] Lees-Green R, Gibbons SJ, Farrugia G, Sneyd J, Cheng LK: Computational Modeling of Anoctamin 1 Calcium-activated Chloride Channels as Pacemaker Channels in Interstitial Cells of Cajal. American Journal of Physiology-Gastrointestinal and Liver Physiology 2014, 306: G711-G727.

[80] Hwang SJ, Blair PJA, Britton FC, O’Driscoll KE, Hennig G, Bayguinov YR, et al.: Expression of Anoctamin 1/TMEM16A by Interstitial Cells of Cajal is Fundamental for Slow Wave Activity in Gastrointestinal Muscles. The Journal of Physiology 2009, 587: 4887-4904.

[81] Yang H, Hou C, Xiao W, Qiu Y: The Role of Mechanosensitive Ion Channels in the Gastrointestinal Tract. Frontiers in Physiology 2022, 13: 904203.

[82] Zeng Z, Chen E, Xue J: Emerging Roles of Mechanically Activated Ion Channels in Autoimmune Disease. Autoimmunity Reviews 2025, 24: 103813.

[83] Luo J, Qian A, Oetjen LK, Yu W, Yang P, Feng J, et al.: TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells. Immunity 2018, 49: 107-119.e4.

[84] Jakob D, Klesen A, Allegrini B, Darkow E, Aria D, Emig R, et al.: Piezo1 and BK_Ca Channels in Human Atrial Fibroblasts: Interplay and Remodelling in Atrial Fibrillation . Journal of Molecular and Cellular Cardiology 2021, 158: 49-62.

[85] Rajasekhar P, Carbone SE, Johnston ST, Nowell CJ, Wiklendt L, Crampin EJ, et al.: TRPV4 is Expressed by Enteric Glia and Muscularis Macrophages of the Colon but does not Play a Prominent Role in Colonic Motility. bioRxiv 2024, 574831. doi: 10.1101/2024.01.09.574831.

[86] Glogowska E, Arhatte M, Chatelain FC, Lesage F, Xu A, Grashoff C, et al.: Piezo1 and Piezo2 Foster Mechanical Gating of K_2P Channels . Cell Reports 2021, 37: 110070.

[87] Gibson-Corley KN, Meyerholz DK, Engelhardt JF: Pancreatic Pathophysiology in Cystic Fibrosis. The Journal of Pathology 2016, 238: 311-320.

[88] Olivier AK, Gibson-Corley KN, Meyerholz DK: Animal Models of Gastrointestinal and Liver Diseases. Animal Models of Cystic Fibrosis: Gastrointestinal, Pancreatic, and Hepatobiliary Disease and Pathophysiology. American Journal of Physiology-Gastrointestinal and Liver Physiology 2015, 308: G459-G471.

[89] Trouvé P, Férec C, Génin E: The Interplay Between the Unfolded Protein Response, Inflammation and Infection in Cystic Fibrosis. Cells 2021, 10: 2980.

[90] Kerbiriou M, Le Drévo MA, Férec C, Trouvé P: Coupling Cystic Fibrosis to Endoplasmic Reticulum Stress: Differential Role of Grp78 and ATF6. Biochimica et Biophysica Acta 2007, 1772: 1236-1249.

[91] Bresso F, Askling J, Astegiano M, Demarchi B, Sapone N, Rizzetto M, et al.: Potential Role for the Common Cystic Fibrosis ΔF508 Mutation in Crohn’s Disease. Inflammatory Bowel Diseases 2007, 13: 531-536.

[92] Carattino F, Mutchler S, Dalghi MG, Apodaca G, Satlin L, Kleyman TR, et al.: Piezo1 Regulates Expression of BK and TRPV4 Channels in Mouse Cortical Collecting Duct (CCD). Physiology 2023, 38: 5732759.

[93] Miranda MR, Vestuto V, Moltedo O, Manfra M, Campiglia P, Pepe G: The Ion Channels Involved in Oxidative Stress-Related Gastrointestinal Diseases. Oxygen 2023, 3: 336-365.

[94] Endesh N, Chuntharpursat-Bon E, Revill C, Yuldasheva NY, Futers TS, Parsonage G, et al.: Independent Endothelial Functions of PIEZO1 and TRPV4 in Hepatic Portal Vein and Predominance of PIEZO1 in Mechanical and Osmotic Stress. Liver International 2023, 43: 2026-2038.

[95] Maqoud F, Tricarico D, Mallamaci R, Orlando A, Russo F: The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets. International Journal of Molecular Sciences 2023, 24: 11074.

[96] Izzy M, Lee M, Johns-Keating K, Kargoli F, Beckoff S, Chun K, et al.: Glycosylated Hemoglobin Level may Predict the Severity of Gastroparesis in Diabetic Patients. Diabetes Research and Clinical Practice 2018, 135: 45-49.

[97] Uppaluri S, Jain MA, Ali H, Shingala J, Amin D, Ajwani T, et al.: Pathogenesis and Management of Diabetic Gastroparesis: An Updated Clinically Oriented Review. Diabetes & Metabolic Syndrome 2024, 18: 102994.

[98] Kashyap P, Farrugia G: Oxidative Stress: Key Player in Gastrointestinal Complications of Diabetes. Neurogastroenterology and Motility 2011, 23: 111-114.

[99] Petri M, Singh I, Baker C, Underkofler C, Rasouli N: Diabetic Gastroparesis: An Overview of Pathogenesis, Clinical Presentation and Novel Therapies, with a Focus on Ghrelin Receptor Agonists. Journal of Diabetes and Its Complications 2021, 35: 107733.

[100] Bos S, Laukens D: Metabolic Modulation During Intestinal Fibrosis. Journal of Digestive Diseases 2020, 21: 319-325.

[101] Fan W, Bradford TM, Török NJ: Metabolic Dysfunction-Associated Liver Disease and Diabetes: Matrix Remodeling, Fibrosis, and Therapeutic Implications. Annals of the New York Academy of Sciences 2024, 1538: 21-33.

[102] Miguel V, Busnadiego O, Fierro-Fernández M, Lamas S: Protective Role for miR-9-5p in the Fibrogenic Transformation of Human Dermal Fibroblasts. Fibrogenesis & Tissue Repair 2016, 9: 7.

[103] Zhang J, Yang M, Tang X, Li S, Zhang J, Lu L, et al.: Intestinal Delivery of ROS-scavenging Carbonized Polymer Dots for Full-course Treatment of Acute and Chronic Radiation Enteritis. Applied Materials Today 2022, 28: 101544.

[104] D’Arpino MC, Fuchs AG, Sánchez SS, Honoré SM: Extracellular Matrix Remodeling and TGF-β1/Smad Signaling in Diabetic Colon Mucosa. Cell Biology International 2018, 42: 443-456.

[105] Caturano A, Cavallo M, Nilo D, Vaudo G, Russo V, Galiero R, et al.: Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions. Gastrointestinal Disorders 2024, 6: 214-229.

[106] Feng R, Hu W, Li Y, Yao X, Li J, Li X, et al.: Mechanotransduction in Subchondral Bone Microenvironment and Targeted Interventions for Osteoarthritis. Mechanobiology in Medicine 2024, 2: 100043.

[107] Gallo A, Pellegrino S, Pero E, Agnitelli MC, Parlangeli C, Landi F, et al.: Main Disorders of Gastrointestinal Tract in Older People: An Overview. Gastrointestinal Disorders 2024, 6: 313-336.

[108] Liu Q, Luo Y, Ke X: Interaction Between the Gut Microbiota and Intestinal Motility. Evidence-Based Complementary and Alternative Medicine 2022, 2022: 3240573.

[109] Chen A, Teng C, Wei J, Wu X, Zhang H, Chen P, et al.: Gut Microbial Dysbiosis Exacerbates Long-term Cognitive Impairments by Promoting Intestinal Dysfunction and Neuroinflammation Following Neonatal Hypoxia-ischemia. Gut Microbes 2025, 17: 2471015.

[110] Lu J, Ma SS, Zhang WY, Duan JP: Changes in Peripheral Blood Inflammatory Factors (TNF-α and IL-6) and Intestinal Flora in AIDS and HIV-positive Individuals. Journal of Zhejiang University-Science B 2019, 20: 793-802.

[111] Verma R, Shiva K, Singh R, Sherawat K, Simran, Bhardwaj P: Inflammatory Bowel Disease and Gut Microbiota Dysbiosis: Current understanding and Future Direction. Journal of Biomedical and Pharmaceutical Research 2024, 13: 1-16.

[112] Ma WW, Huang ZQ, Liu K, Li DZ, Mo TL, Liu Q: The Role of Intestinal Microbiota and Metabolites in Intestinal Inflammation. Microbiological Research 2024, 288: 127838.

[113] Logroño IEN, Coronel AAN, Vera ADB, Santillán RSD: Dysbiosis and Intestinal Permeability: Causes and Effects of Altering Normal Intestinal Flora. ESPOCH Congresses: The Ecuadorian Journal of S.T.E.A.M 2021, 1: 1524-1537.

[114] Xu J, Ma X, Bai C, Jiang X, Huang L, Gao F, et al.: Intestinal Flora: A Potential Mechanism by Which Yinlai Decoction Treats Lipopolysaccharide-induced Pneumonia . Evidence-Based Complementary and Alternative Medicine 2022, 2022: 3034714.

[115] Zhan L, Liu H, Zheng J, Meng J, Fu D, Pang L, et al.: Electroacupuncture at Zusanli Alleviates Sepsis by Regulating the TLR4-MyD88-NF-Kappa B Pathway and Diversity of Intestinal Flora. Evidence-Based Complementary and Alternative Medicine 2022, 2022: 6706622.

[116] Lu DX, Liu F, Wu H, Liu HX, Chen BY, Yan J, et al.: Wumei Pills Attenuates 5-Fluorouracil-induced Intestinal Mucositis Through Toll-like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-κB Pathway and Microbiota Regulation. World Journal of Gastroenterology 2022, 28: 4574-4599.

[117] Melbye P, Olsson A, Hansen TH, Søndergaard HB, Bang Oturai A: Short-chain Fatty Acids and Gut Microbiota in Multiple Sclerosis. Acta Neurologica Scandinavica 2019, 139: 208-219.

[118] Ning Y, Zhu JX, Chan HC: Regulation of Ion Transport by 5-hydroxytryptamine in Rat Colon. Clinical and Experimental Pharmacology & Physiology 2004, 31: 424-428.

[119] Kaji I, Akiba Y, Said H, Narimatsu K, Kaunitz JD: Luminal 5-HT Stimulates Colonic Bicarbonate Secretion in Rats. British Journal of Pharmacology 2015, 172: 4655-4670.

[120] Majumdar A, Siva Venkatesh IP, Basu A: Short-chain Fatty Acids in the Microbiota-Gut-Brain Axis: Role in Neurodegenerative Disorders and Viral Infections. ACS Chemical Neuroscience 2023, 14: 1045-1062.

[121] Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I: Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation. Nutrients 2015, 7: 2839-2849.

[122] Li X, Ren Y, Huang G, Zhang R, Zhang Y, Zhu W, et al.: Succinate Communicates Pro-inflammatory Signals to the Host and Regulates Bile Acid Enterohepatic Metabolism in a Pig Model. Food & Function 2022, 13: 11070-11082.

[123] Jardou M, Brossier C, Marquet P, Picard N, Druilhe A, Lawson R: Solid Organ Transplantation and Gut Microbiota: A Review of the Potential Immunomodulatory Properties of Short-chain Fatty Acids in Graft Maintenance. Frontiers in Cellular and Infection Microbiology 2024, 14: 1342354.

[124] Daily JW, Kang S, Park S: Protection Against Alzheimer’s Disease by Luteolin: Role of Brain Glucose Regulation, Anti-inflammatory Activity, and the Gut Microbiota-Liver-Brain Axis. Biofactors 2021, 47: 218-231.

[125] Li Z, Ruan M, Chen J, Fang Y: Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neuroscience Bulletin 2021, 37: 863-880.

[126] Oh JH, Kwon JG, Jung HK, Tae CH, Song KH, Kang SJ, et al.: Clinical Practice Guidelines for Functional Dyspepsia in Korea. Journal of Neurogastroenterology and Motility 2020, 26: 29-50.

[127] Rettura F, Bronzini F, Campigotto M, Lambiase C, Pancetti A, Berti G, et al.: Refractory Gastroesophageal Reflux Disease: A Management Update. Frontiers in Medicine (Lausanne) 2021, 8: 765061.

[128] Góngora-Benítez M, Tulla-Puche J, Albericio F: Constella™(EU)-Linzess™(USA): The Last Milestone in the Long Journey of the Peptide Linaclotide and Its Implications for the Future of Peptide Drugs. Future Medicinal Chemistry 2013, 5: 291-300.

[129] Lea R, Whorwell PJ: Serotonergic Agents in the Treatment of Functional Gastrointestinal Disorders. Current Treatment Options in Gastroenterology 2002, 5: 293-300.

[130] Okamura K, Sasaki N, Yamada M, Yamada H, Inokuma H: Effects of Mosapride Citrate, Metoclopramide Hydrochloride, Lidocaine Hydrochloride, and Cisapride Citrate on Equine Gastric Emptying, Small Intestinal and Caecal Motility. Research in Veterinary Science 2009, 86: 302-308.

[131] Hillman L, Yadlapati R, Thuluvath AJ, Berendsen MA, Pandolfino JE: A Review of Medical Therapy for Proton Pump Inhibitor Nonresponsive Gastroesophageal Reflux Disease. Diseases of the Esophagus 2017, 30: 1-15.

[132] Zheng LF, Song J, Fan RF, Chen CL, Ren QZ, Zhang XL, et al.: The Role of the Vagal Pathway and Gastric Dopamine in the Gastroparesis of Rats after a 6-Hydroxydopamine Microinjection in the Substantia Nigra. Acta Physiologica (Oxford, England) 2014, 211: 434-446.

[133] Lu X, Liu Q, Deng Y, Wu J, Mu X, Yang X, et al.: Research Progress on the Roles of Dopamine and Dopamine Receptors in Digestive System Diseases. Journal of Cellular and Molecular Medicine 2024, 28: e18154.

[134] Mosli MH, Aljudaibi B, Al-Madi M: Saudi Gastroenterology Association Position Statement on Safety Issues Associated with the Use of Domperidone. Saudi Journal of Gastroenterology: Official Journal of the Saudi Gastroenterology Association 2014, 20: 267-269.

[135] Van Nueten JM, Ennis C, Helsen L, Laduron PM, Janssen PA: Inhibition of Dopamine Receptors in the Stomach: An Explanation of the Gastrokinetic Properties of Domperidone. Life Sciences 1978, 23: 453-457.

[136] Zamani NF, Sjahid AS, Tuan Kamauzaman TH, Lee YY, Islam MA: Efficacy and Safety of Domperidone in Combination with Proton Pump Inhibitors in Gastroesophageal Reflux Disease: A Systematic Review and Meta-analysis of Randomised Controlled Trials. Journal of Clinical Medicine 2022, 11: 5268.

[137] Corsetti M, Tack J: Linaclotide: A New Drug for the Treatment of Chronic Constipation and Irritable Bowel Syndrome with Constipation. United European Gastroenterology Journal 2013, 1: 7-20.

[138] Yiannakou Y, Agrawal A, Allen PB, Arebi N, Brown SR, Eugenicos MP, et al.: UK Clinical Experience up to 52 Weeks with Linaclotide for Irritable Bowel Syndrome with Constipation. Therapeutic Advances in Gastroenterology 2018, 11: 1-14. DOI: 10.1177/1756284818798791.

[139] Parker CH, Yuan Y, Liu LWC: Linaclotide: A New Option for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation in Adults. Clinical Medicine Insights. Gastroenterology 2013, 6: 21-32.

[140] Bryant AP, Busby RW, Bartolini WP, Cordero EA, Hannig G, Kessler MM, et al.: Linaclotide is a Potent and Selective Guanylate Cyclase C Agonist that Elicits Pharmacological Effects Locally in the Gastrointestinal Tract. Life Sciences 2010, 86: 760-765.

[141] Di Lorenzo C, Khlevner J, Rodriguez-Araujo G, Xie W, Huh SY, Ando M, et al.: Efficacy and Safety of Linaclotide in Treating Functional Constipation in Paediatric Patients: A Randomised, Double-blind, Placebo-controlled, Multicentre, Phase 3 Trial. The Lancet Gastroenterology & Hepatology 2024, 9: 238-250.

[142] Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, et al.: A 12-week, Randomized, Controlled Trial with a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome with Constipation. The American Journal of Gastroenterology 2012, 107: 1714-1724.

[143] Johnston JM, Shiff SJ, Quigley EMM: A Review of the Clinical Efficacy of Linaclotide in Irritable Bowel Syndrome with Constipation. Current Medical Research and Opinion 2013, 29: 149-160.

[144] Kim YK, Shin C: The Microbiota-Gut-Brain Axis in Neuropsychiatric Disorders: Pathophysiological Mechanisms and Novel Treatments. Current Neuropharmacology 2018, 16: 559-573.

[145] Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, et al.: Neuroprotective Effects of Fecal Microbiota Transplantation on MPTP-induced Parkinson’s Disease Mice: Gut Microbiota, Glial Reaction and TLR4/TNF-α Signaling Pathway. Brain, Behavior, and Immunity 2018, 70: 48-60.

[146] Rocha CS, Alexander KL, Herrera C, Weber MG, Grishina I, Hirao LA, et al.: Microbial Remodeling of Gut Tryptophan Metabolism and Indole-3-lactate Production Regulate Epithelial Barrier Repair and Viral Suppression in Human and Simian Immunodeficiency Virus Infections. Mucosal Immunology 2025, 18: 583-595.

[147] Yin J, Chen JD: Noninvasive Electrical Neuromodulation for Gastrointestinal Motility Disorders. Expert Review of Gastroenterology & Hepatology 2023, 17: 1221-1232.

[148] Payne SC, Furness JB, Stebbing MJ: Bioelectric Neuromodulation for Gastrointestinal Disorders: Effectiveness and Mechanisms. Nature Reviews. Gastroenterology & Hepatology 2019, 16: 89-105.

[149] Veldman F, Hawinkels K, Keszthelyi D: Efficacy of Vagus Nerve Stimulation in Gastrointestinal Disorders: A Systematic Review. Gastroenterology Report 2025, 13: goaf009.

[150] Yavi M, Henter ID, Park LT, Zarate C: Key Considerations in the Pharmacological Management of Treatment-resistant Depression. Expert Opinion on Pharmacotherapy 2021, 22: 2405-2415.

[151] Arca KN, Cai J, Wang F, Kassim G, Hasler WL, Batheja MJ: Migraine and Gastroparesis. Current Neurology and Neuroscience Reports 2022, 22: 813-821.

[152] Ling S, Xu JW: Model Organisms and Traditional Chinese Medicine Syndrome Models. Evidence-Based Complementary and Alternative Medicine 2013, 2013: 761987.

[153] Tian XT, Zhan JP, Qiao C, Ge JL, Li DH: Rising of Natural Therapies: Potential and Challenges of Traditional Chinese Medicine in the Management of Gastrointestinal Diseases. World Journal of Gastroenterology 2025, 31: 103145.

[154] Liu C: Clinical Observation of Banxia Xiexin Decoction in the Treatment of Functional Dyspepsia with Cold-heat Complex Pattern. Guangming Journal of Chinese Medicine 2020, 35: 482-484.

[155] Zhao J: Based on Evidence-based Medicine Method and Animal Experiment, Preliminary Discussion on the Promoting Gastrointestinal Motility and Related Mechanisms of BanxiaXiexin Decoction . China: Shanghai University of Traditional Chinese Medicine; 2021.

[156] Gu R, Zou D, Tao R, Lu K, Ren L, Sun Z: The Efficacy and Safety of Banxia Xiexin Decoction in Treating Functional Dyspepsia: A Meta-analysis. Chinese Journal of Medicinal Guide 2023, 25: 482-490 (in Chinese).

[157] Zhang D, Lu R, Wang M, Ji J, Zhang S, Wang S, et al.: Effects of Banxia Xiexin Decoction on Apoptosis of Interstitial Cells of Cajal via Regulation of MiR-451-5p: An In Vivo and In Vitro Study. Journal of Ethnopharmacology 2023, 314: 116606.

[158] Jiang N, Yu Y, Chen FQ, Yuan LL, Wang QM: Effects of Banxia Xiexin Decoction on the Small Intestinal Motility and Its Mechanisms in Diabetic Rats. Lishizhen Medicine and Materia Medica Research 2013, 24: 2631-2634.

[159] Zhang FH, Sun XJ, Qiu GL, Zhou XF, Liu TT, Huang XS: Study of Banxiaxiexin Decoction on Gastric Motility Regulation Mechanism of the Rat Diabetic Gastroparesis. Pharmacology and Clinics of Chinese Materia Medica 2014, 30: 4-6 (in Chinese).

[160] Li Z, Ding N, Yue R: Effect of Banxia Xiexin Decoction on Gastric Emptying, AGEs Content in Gastric Tissue and Expression of RAGE and nNOS Proteins in Diabetic Gastroparesis Model Mice. Journal of Traditional Chinese Medicine 2022, 63: 2375-2381.

[161] Yu WY, Wu PF, Rui J, Zhang H: Mechanism of Buzhong Yiqi Decoction in Treatment of Diabetic Gastroparesis Based on Network Pharmacology Analysis. Zhejiang Journal of Integrated Traditional Chinese and Western Medicine 2022, 32: 703-709 (in Chinese).

[162] Ju W, Guo L, Chen S, Du G, Wen X: Metabolomics Study of Buzhong Yiqi Decoction Improving Gastrointestinal Motility Disorder in Rats with Spleen Deficiency. Chinese Archives of Traditional Chinese Medicine 2020, 38: 69-73 (in Chinese).

[163] Ju WJ, Zhao ZK, Chen SL, Zhou DD, Yang WN, Wen XP, et al.: Buzhongyiqi Decoction Protects Against Loperamide-induced Constipation by Regulating the Arachidonic Acid Pathway in Rats. Frontiers in Pharmacology 2020, 11: 423.

[164] Zhang YJ, Huang X, Wang Y, Xie Y, Qiu XJ, Ren P, et al.: Ferulic Acid-induced Anti-depression and Prokinetics Similar to Chaihu-Shugan-San via Polypharmacology. Brain Research Bulletin 2011, 86: 222-228.

[165] Lv R, Wang W, Liu L, Li N, Xu W, Yao S: Effects of Chaihu Shugan Powder on Symptoms, Anxiety, Depression and Radionuclide Gastric Emptying of Functional Dyspepsia of Liver Stomach Qi Stagnation Type. China Journal of Traditional Chinese Medicine and Pharmacy 2022, 37: 1815-1818.

[166] Wang Y, Jia Y, Liu X, Yang K, Lin Y, Shao Q, et al.: Effect of Chaihu-Shugan-San on Functional Dyspepsia and Gut Microbiota: A Randomized, Double-blind, Placebo-controlled Trial. Journal of Ethnopharmacology 2024, 322: 117659.

[167] Li YH, Zhang CH, Wang SE, Qiu J, Hu SY, Xiao GL: [Effects of Chaihu Shugan San on Behavior and Plasma Levels of Corticotropin Releasing Hormone and Adrenocorticotropic Hormone of Rats with Chronic Mild Unpredicted Stress Depression]. Zhong Xi Yi Jie He Xue Bao 2009, 7: 1073-1077 (in Chinese).

[168] Xu M, Zhang QT, Zhou L, Cai YW, Liu H, Zhao QL, et al.: Ferulic Acid in Chaihu Shugan San Modulates Depression-like Behavior, Endothelial and Gastrointestinal Dysfunction in Rats via the Ghrl-Edn1/Mecp2/P-mTOR/VEGFA Pathway: A Multi-omics Study. Journal of Ethnopharmacology 2025, 346: 119624.

[169] Li D, Lv B, Wang D, Xu D, Qin S, Zhang Y, et al.: Network Pharmacology and Bioactive Equivalence Assessment Integrated Strategy Driven Q-markers Discovery for Da-Cheng-Qi Decoction to Attenuate Intestinal Obstruction. Phytomedicine 2020, 72: 153236.

[170] Yang B, Xu FY, Sun HJ, Zou Z, Shi XY, Ling CQ, et al.: Da-Cheng-Qi Decoction, A Traditional Chinese Herbal Formula, for Intestinal Obstruction: Systematic Review and Meta-analysis. African Journal of Traditional, Complementary, and Alternative Medicines 2014, 11: 101-119.

[171] Chen C, Li M, Liu X, Fan J, Zhang H, Lin S, et al.: Traditional Chinese Medicine Da-Cheng-Qi-Tang Ameliorates Impaired Gastrointestinal Motility and Intestinal Inflammatory Response in a Mouse Model of Postoperative Ileus. Evidence-Based Complementary and Alternative Medicine 2020, 2020: 9074069.

[172] Zhu L, Zhu J: Advances in the Mechanisms of Da-Cheng-Qi Decoction (DCQD) for the Prevention and Treatment of Gastrointestinal Hypomotility. Chinese Traditional Patent Medicine 2014, 36: 2591-2594.

[173] Li Y: The Meta-analysis of Simo Decoction on Patients with Functional Dyspepsia and the Study on Clinical Efficacy of Simo Decoction on Patients China: with Functional Dyspepsia with Qi Stagnancy of Both Liver and Spleen . Hunan University of Chinese Medicine; 2012.

[174] Cai GX, Bu XC: Clinical Efficacy of Simo Tang on Functional Dyspepsia with Syndrome of Incoordination Between the Liver and Spleen and Its Effect on Motilin and Substance P in Plasma. China Journal of Traditional Chinese Medicine and Pharmacy 2010, 25: 856-859 (in Chinese).

[175] Yan C, Dai C, Liu N, Qian W, Yang P, Hou X: Effects of Simo Decoction on Gastric Motility of Diabetic Rats. Neurogastroenterology and Motility 2022, 34: e14450.

[176] Luo J, Xu C, Zhao K: Effects of “Shenling Baizhu Powder” on Serum Gastrointestinal Hormones and Electrogastrogram in Children with Functional Dyspepsia of Spleen Deficiency and Qi Stagnation. Shanghai Journal of Traditional Chinese Medicine 2016, 50: 50-52 (in Chinese).

[177] Lv W, Liu C, Ye C, Sun J, Tan X, Zhang C, et al.: Structural Modulation of Gut Microbiota During Alleviation of Antibiotic-associated Diarrhea with Herbal Formula. International Journal of Biological Macromolecules 2017, 105: 1622-1629.

[178] Zhang S, Lin L, Liu W, Zou B, Cai Y, Liu D, et al.: Shen-Ling-Bai-Zhu-San Alleviates Functional Dyspepsia in Rats and Modulates the Composition of the Gut Microbiota. Nutrition Research 2019, 71: 89-99.

[179] Bian Z, Wu T, Liu L, Miao J, Wong H, Song L, et al.: Effectiveness of the Chinese Herbal Formula TongXieYaoFang for Irritable Bowel Syndrome: A Systematic Review. Journal of Alternative and Complementary Medicine 2006, 12: 401-407.

[180] Yin Y, Zhong L, Wang JW, Zhao XY, Zhao WJ, Kuang HX: Tong Xie Yao Fang Relieves Irritable Bowel Syndrome in Rats via Mechanisms Involving Regulation of 5-Hydroxytryptamine and Substance P. World Journal of Gastroenterology 2015, 21: 4536-4546.

[181] Yang C, Xiong Y, Zhang SS, An FM, Sun J, Zhang QL, et al.: Regulating Effect of TongXie-YaoFang on Colonic Epithelial Secretion via Cl⁻ and HCO₃⁻ Channel . World J Gastroenterol 2016, 22: 10584-10591.

[182] Zhang M, Zheng Y, Li X, Wu H, Liu P, Zhang K, et al.: Tong-Xie-Yao-Fang Alleviates Diarrhea-predominant Irritable Bowel Syndrome in Rats via the GCN2/PERK-eIF2α-ATF4 Signaling Pathway. Phytomedicine 2022, 107: 154350.

[183] Li J, Cui H, Cai Y, Lin J, Song X, Zhou Z, et al.: Tong-Xie-Yao-Fang Regulates 5-HT Level in Diarrhea Predominant Irritable Bowel Syndrome Through Gut Microbiota Modulation. Frontiers in Pharmacology 2018, 9: 1110.

[184] Hu J, Gao WY, Ling NS, Liu CX: Antidiarrhoeal and Intestinal Modulatory Activities of Wei-Chang-An-Wan Extract. Journal of Ethnopharmacology 2009, 125: 450-455.

[185] Qu Z, Zhang J, Gao W, Guo H, Liu C: Bidirectional Effects of Methanol Extract of Wei-Chang-An Pill on Gastrointestinal Transit and the Spasmolytic Activity on Isolated Rat Jejunum. Journal of Ethnopharmacology 2014, 155: 203-212.

[186] Chen Y, Zheng H, Zhang J, Wang L, Jin Z, Gao W: Protective Effect and Potential Mechanisms of Wei-Chang-An Pill on High-dose 5-Fluorouracil-induced Intestinal Mucositis in Mice. Journal of Ethnopharmacology 2016, 190: 200-211.

[187] Jia S, Chai L, Zhang J, Zhang M, Li L, Qi Y, et al.: Wei Chang An Pill Regulates Gastrointestinal Motility in a Bidirectional Manner. Pharmaceutical Biology 2021, 59: 1452-1463.

[188] Gao XY, Liu K, Zhu B, Litscher G: Sino-European Transcontinental Basic and Clinical High-tech Acupuncture Studies-Part 1: Auricular Acupuncture Increases Heart Rate Variability in Anesthetized Rats. Evidence-Based Complementary and Alternative Medicine 2012, 2012: 817378.

[189] Liu K, Jiang JF, Lu SF: [Effect Characteristics and Mechanism of Acupuncture in Autonomic Nerve Regulation]. Zhen Ci Yan Jiu 2021, 46: 335-341 (in Chinese).

[190] Li Y, Xu G, Hu S, Wu H, Dai Y, Zhang W, et al.: Electroacupuncture Alleviates Intestinal Inflammation and Barrier Dysfunction by Activating Dopamine in a Rat Model of Intestinal Ischaemia. Acupuncture in Medicine 2021, 39: 208-216.

[191] Zheng H, Xu J, Li J, Li X, Zhao L, Chang X, et al.: Acupuncture for Patients with Functional Dyspepsia: Study Protocol of a Randomised Controlled Trial. BMJ Open 2013, 3: e003377.

[192] Liu X, Wang Z, Yao H, Yang Y, Cao H, Toh Z, et al.: Effects of Acupuncture Treatment on Postoperative Gastrointestinal Dysfunction in Colorectal Cancer: Study Protocol for Randomized Controlled Trials. Trials 2022, 23: 100.

[193] Zhongzheng LI, Yadan Z, Weigang M, Yonglong Z, Zhifang XU, Qiang XI, et al.: Adenosine Triphosphate Mediates the Pain Tolerance Effect of Manual Acupuncture at Zusanli (ST36) in Mice. Journal of Traditional Chinese Medicine 2024, 44: 660-669.

[194] Liu YL, Li SS, Yang YR, Zhao YH, Li WX, Hao JX, et al.: Research Progress on the Molecular Mechanism of Electroacupuncture at “Zusanli” (ST36) for Regulating Gastrointestinal Dysfunction. Zhen Ci Yan Jiu 2023, 48: 1048-1054 (in Chinese).

[195] Chen B, Guo Y, Zhao X, Gao LL, Li B, Zhao TY, et al.: Efficacy Differences of Electroacupuncture with Single Acupoint or Matching Acupoints for Chemotherapy-induced Nausea and Vomiting: Study Protocol for a Randomized Controlled Trial. Trials 2017, 18: 477.

[196] Qu LZ, Zhao HC, Shen HX, Yan Y, Ma SJ, Wang KQ: [Electroacupuncture of Both Single- and Multi-acupoints Promotes Recovery of Gastrointestinal Function in Laparoscopic Cholecystectomy Patients]. Zhen Ci Yan Jiu 2020, 45: 136-140 (in Chinese).

[197] Zhang N, Huang Z, Xu F, Xu Y, Chen J, Yin J, et al.: Transcutaneous Neuromodulation at Posterior Tibial Nerve and ST36 for Chronic Constipation. Evidence-Based Complementary and Alternative Medicine 2014, 2014: 560802.

[198] You X, Wang Y, Wu J, Liu Q, Liu Y, Qian Y, et al.: Zusanli (ST36) Acupoint Injection with Neostigmine for Paralytic Postoperative Ileus following Radical Gastrectomy for Gastric Cancer: a Randomized Clinical Trial. Journal of Cancer 2018, 9: 2266-2274.

[199] Wang C, Chen X, Xie PY: Electroacupuncture at PC6 or ST36 Influences the Effect of Tacrine on the Motility of Esophagus. Evidence-Based Complementary and Alternative Medicine 2014, 2014: 263489.

[200] Wang YP, Herndon CC, Lu CL: Non-pharmacological Approach in the Management of Functional Dyspepsia. Journal of Neurogastroenterology and Motility 2020, 26: 6-15.

[201] Wang X, Lu L, Zi L, Hu H, Li H, He Y, et al.: Electroacupuncture at Acupoint ST36 (Zusanli) Improves Intestinal Motility Dysfunction Via Increasing the Proportion of Cholinergic Neurons in Rat Ileal Myenteric Ganglia after Severe Acute Pancreatitis. Evidence-Based Complementary and Alternative Medicine 2022, 2022: 7837711.

[202] Keller J, Layer P: Intestinal and Anorectal Motility and Functional Disorders. Best Practice & Research Clinical Gastroenterology 2009, 23: 407-423.

[203] Camilleri M: Abnormal Gastrointestinal Motility is a Major Factor in Explaining Symptoms and a Potential Therapeutic Target in Patients with Disorders of Gut-brain Interaction. Gut 2023, 72: 2372-2380.

[204] Li S, Song B, Jiang N, Pan C, Ren X, Dai Q, et al.: The Past and Future of Piezo: A Scientometric Review. Medicine (Baltimore) 2022, 101: e31210.

[205] Bautista GM, Du Y, Matthews MJ, Flores AM, Kushnir NR, Sweeney NK, et al.: Smooth Muscle Cell Piezo1 Depletion Results in Impaired Contractile Properties in Murine Small Bowel. Communications Biology 2025, 8: 448.

[206] Moneme C, Olutoye OO, Sobstel MF, Zhang Y, Zhou X, Kaminer JL, et al.: Activation of Mechanoreceptor Piezo1 Inhibits Enteric Neuronal Growth and Migration In Vitro . Frontiers in Molecular Neuroscience 2024, 17: 1474025.

[207] Bradesi S, Schwetz I, Ennes HS, Lamy CM, Ohning G, Fanselow M, et al.: Repeated Exposure to Water Avoidance Stress in Rats: A New Model for Sustained Visceral Hyperalgesia. American Journal of Physiology-Gastrointestinal and Liver Physiology 2005, 289: G42-G53.

[208] Majd H, Samuel RM, Cesiulis A, Ramirez JT, Kalantari A, Barber K, et al.: Engrafted Nitrergic Neurons Derived from hPSCs Improve Gut Dysmotility in Mice. Nature 2025, 645: 158-167.

[209] Song XY, Li YD, Shi YP, Jin L, Chen J: Quality Control of Traditional Chinese Medicines: A Review. Chinese Journal of Natural Medicines 2013, 11: 596-607.

[210] Liu CX, Chen SL, Xiao XH, Zhang TJ, Hou WB, Liao ML: A New Concept on Quality Marker of Chinese Materia Medica: Quality Control for Chinese Medicinal Products. Chinese Traditional and Herbal Drugs 2016, 47: 1443-1457 (in Chinese).

[211] Lu X, Jin Y, Wang Y, Chen Y, Fan X: Multimodal Integrated Strategy for the Discovery and Identification of Quality Markers in Traditional Chinese Medicine. Journal of Pharmaceutical Analysis 2022, 12: 701-710.

[212] Wang J, Li L, Shen W, Wu M, Zhou Z, Cheng H: Exploration of Integrated Traditional Chinese and Western Medicine Treatment Mode for Malignant Tumors. Journal of Nanjing University of Traditional Chinese Medicine 2024, 40: 217-222 (in Chinese).

[213] Huang B, Wang M, He H, Guo Y, Bian Y, Wang L, et al.: Gradual and Coordinated Development-Some Thoughts of Academician ZHANG Bo-li on the Integration of Chinese and Western Medicine. Chinese Journal of Integrated Traditional and Western Medicine 2020, 40: 1121-1124 (in Chinese).

[214] Han YL, Peng XM, Zhang HX, Chen S, Zhang LY: Electroacupuncture Regulates TRPV1 through PAR2/PKC Pathway to Alleviate Visceral Hypersensitivity in FD Rats. Evidence-Based Complementary and Alternative Medicine 2021, 2021: 1975228.

[215] Chojnacki C, Konrad P, Bło ska A, Chojnacki J, M drek-Socha M: Usefulness of the Hydrogen Breath Test in Patients with Functional Dyspepsia. Przeglad Gastroenterologiczny 2020, 15: 338-342.

[216] Shah A, Kang S, Talley NJ, Do A, Walker MM, Shanahan ER, et al.: The Duodenal Mucosa Associated Microbiome, Visceral Sensory Function, Immune Activation and Psychological Comorbidities in Functional Gastrointestinal Disorders with and without Self-reported Non-celiac Wheat Sensitivity. Gut Microbes 2022, 14: 2132078.