肠神经系统的结构功能及双向调控机制的研究进展

doi:10.16098/j.issn.0529-1356.2026.06.018

PDF(1071 KB)

解剖学报 ›› 2026, Vol. 57 ›› Issue (5) : 656-662. DOI: 10.16098/j.issn.0529-1356.2026.06.018

综述

肠神经系统的结构功能及双向调控机制的研究进展

陶新磊¹ 王子旭¹ 王大清² 杜晨光² 曹贵方² 陈耀星¹ 曹静^1*

作者信息 +

Research progress on the structure, function and bidirectional regulation mechanism of the enteric nervous system

TAO Xin-lei ¹, WANG Zi-xu ¹, WANG Da-qing ², DU Chen-guang ², CAO Gui-fang ², CHEN Yao-xing ¹, CAO Jing^1*

Author information +

文章历史 +

摘要

肠神经系统（ENS）被称为“第二大脑”，是自主神经系统的重要组成部分，它独立调节胃肠道功能，同时也通过肠-脑轴与中枢神经系统（CNS）沟通。ENS起源于神经嵴细胞，主要来源于迷走神经嵴和荐神经嵴，形成由神经元和肠胶质细胞（EGCs）组成的神经节网络，包括肌间神经丛和黏膜下神经丛。ENS神经元可分为感觉神经元、中间神经元和运动神经元，它们利用各种神经递质，如乙酰胆碱（Ach）、5-羟色胺（5-HT）、一氧化氮（NO）和血管活性肠肽（VIP）等来管理胃肠道运动、分泌、血流和免疫反应。尽管ENS具有重要的作用，但由于其解剖结构的复杂性和分子标记的不确定性，目前对其的认识仍然落后于CNS。本综述梳理了ENS的起源和发展，描述了ENS神经元的功能和不同神经递质在肠道生理中的作用。此外，还总结了ENS与肠黏膜免疫屏障、免疫细胞和微生物群之间的双向调节关系，凸显出其在维持肠道稳态中的关键作用。

Abstract

Commonly known as “the second brain”, the enteric nervous system (ENS) is a vital part of the autonomic nervous system that independently regulates gastrointestinal functions while also communicating with the central nervous system (CNS) through the gut-brain axis. The ENS originates from neural crest cells, primarily from vagal and sacral neural crests, and forms a ganglionic network composed of neurons and enteric glial cells (EGCs), including myenteric plexus and submucosal plexuses. ENS neurons can be categorized as sensory, interneurons, or motor neurons, and they utilize various neurotransmitters such as acetylcholine (Ach), 5-hydroxytryptamine (5-HT), nitric oxide (NO), and vasoactive intestinal peptide (VIP) to manage gastrointestinal (GI) motility, secretion, blood flow, and immune responses. Despite its important role, the ENS still lags the CNS due to its complex anatomy and unclear molecular markers. This review summarized the origin and development of the ENS, and clarified the functions of ENS neurons and the roles of various neurotransmitters in intestinal physiology. Additionally, we also summarized the bidirectional regulatory relationship between ENS and the intestinal mucosal immune barrier, immune cells, and microbiota, highlighting its crucial role in maintaining intestinal homeostasis.

导出引用

陶新磊王子旭王大清杜晨光曹贵方陈耀星曹静. 肠神经系统的结构功能及双向调控机制的研究进展[J]. 解剖学报. 2026, 57(5): 656-662 https://doi.org/10.16098/j.issn.0529-1356.2026.06.018

TAO Xin-lei , WANG Zi-xu , WANG Da-qing , DU Chen-guang , CAO Gui-fang , CHEN Yao-xing , CAO Jing. Research progress on the structure, function and bidirectional regulation mechanism of the enteric nervous system[J]. Acta Anatomica Sinica. 2026, 57(5): 656-662 https://doi.org/10.16098/j.issn.0529-1356.2026.06.018

中图分类号： R358.16

参考文献

［1］Lake JI, Heuckeroth RO. Enteric nervous system development: migration, differentiation, and disease［J］. Am J Physiol Gastrointest Liver Physiol, 2013, 305(1):G1-24.

［2］Furness JB. Types of neurons in the enteric nervous system［J］. J Auton Nerv Syst, 2000,81(1-3):87-96.

［3］Suarez AN, Hsu TM, Liu CM, et al. Gut vagal sensory signaling regulates hippocampus function through multi-order pathways［J］. Nat Commun, 2018, 9(1):2181.

［4］Ambartsumyan L, Smith C, Kapur RP. Diagnosis of hirschsprung disease［J］. Pediatr Dev Pathol, 2020, 23(1):8-22.

［5］Foong JP, Tough IR, Cox HM, et al. Properties of cholinergic and non-cholinergic submucosal neurons along the mouse colon［J］. J Physiol, 2014, 592(4):777-793.

［6］Jacobson A, Yang D, Vella M, et al. The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes［J］. Mucosal Immunol, 2021, 14(3):555-565.

［7］Yntema CL, Hammond WS. The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo［J］. J Comp Neurol, 1954, 101(2):515-541.

［8］Le Douarin NM, Teillet TM. Experimental analysis of the migration and differentiation of neuroblasts of the autonomic nervous system and of neurectodermal mesenchymal derivatives, using a biological cell marking technique［J］. Dev Biol, 1974, 41(1):162-184.

［9］Krzyszton-Russjan J. Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington’s disease［J］. Postepy Hig Med Dosw (Online), 2016, 70(0):1331-1342.

［10］Nagy N, Goldstein AM. Enteric nervous system development: a crest cell’s journey from neural tube to colon［J］. Semin Cell Dev Biol, 2017, 66:94-106.

［11］Li CH, Kersten N, Ozkan N, et al. Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons［J］. Nat Commun, 2024, 15(1):10829.

［12］Bodi N, Szalai Z, Bagyanszki M. Nitrergic enteric neurons in health and disease-focus on animal models［J］. Int J Mol Sci, 2019, 20(8):2003.

［13］Majd H, Samuel RM, Cesiulis A, et al. Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice［J］. Nature, 2025, 645(8079):158-167.

［14］Nagy N, Burns AJ, Goldstein AM. Immunophenotypic characterization of enteric neural crest cells in the developing avian colorectum［J］. Dev Dyn, 2012, 241(5):842-851.

［15］Morarach K, Mikhailova A, Knoflach V, et al. Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing［J］. Nat Neurosci, 2021, 24(1):34-46.

［16］Lundgren O, Jodal M, Jansson M, et al. Intestinal epithelial stem/progenitor cells are controlled by mucosal afferent nerves［J］. PLoS One, 2011, 6(2):e16295.

［17］Wolfson RL, Abdelaziz A, Rankin G, et al. DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon［J］. Cell, 2023, 186(16):3368-3385. e18.

［18］Schneider KM, Blank N, Alvarez Y, et al. The enteric nervous system relays psychological stress to intestinal inflammation［J］. Cell, 2023, 186(13):2823-2838. e20.

［19］Munoz M, Covenas R, Esteban F, et al. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs［J］. J Biosci, 2015, 40(2):441-463.

［20］Smith TK, Spencer NJ, Hennig GW, et al. Recent advances in enteric neurobiology: mechanosensitive interneurons［J］. Neurogastroenterol Motil, 2007, 19(11):869-878.

［21］Linden DR. Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis［J］. Neurosci Lett, 2013, 545:91-95.

［22］Stachowski NJ, Dougherty KJ. Spinal inhibitory interneurons: gatekeepers of sensorimotor pathways［J］. Int J Mol Sci, 2021, 22(5):2667.

［23］Sanders KM, Koh SD, Ro S, et al. Regulation of gastrointestinal motility-insights from smooth muscle biology［J］. Nat Rev Gastroenterol Hepatol, 2012, 9(11):633-645.

［24］Dicks LMT. Gut bacteria and neurotransmitters［J］. Microorganisms, 2022, 10(9):1838.

［25］Uwada J, Nakazawa H, Muramatsu I, et al. Role of muscarinic acetylcholine receptors in intestinal epithelial homeostasis: insights for the treatment of inflammatory bowel disease［J］. Int J Mol Sci, 2023, 24(7):6508.

［26］Garg BK, Loring RH. GTS-21 has cell-specific anti-inflammatory effects independent of alpha7 nicotinic acetylcholine receptors［J］. PLoS One, 2019, 14(4):e0214942.

［27］Bertrand PP, Bertrand RL. Serotonin release and uptake in the gastrointestinal tract［J］. Auton Neurosci, 2010, 153(1-2):47-57.

［28］Swami T, Weber HC. Updates on the biology of serotonin and tryptophan hydroxylase［J］. Curr Opin Endocrinol Diabetes Obes, 2018, 25(1):12-21.

［29］Li Z, Chalazonitis A, Huang YY, et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons［J］. J Neurosci, 2011, 31(24):8998-9009.

［30］Cao X, Zhao H, Liang Z, et al. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway［J］. Open Med (Wars), 2023, 18(1):20230869.

［31］Russwurm M, Russwurm C, Koesling D, et al. NO/cGMP: the past, the present, and the future［J］. Methods Mol Biol, 2013, 1020:1-16.

［32］Sheng X, Yang Y, Liu J, et al. Down-regulation of miR-18b-5p protects against splenic hemorrhagic shock by directly targeting HIF-1alpha/iNOS pathway［J］. Immunobiology, 2022, 227(2):152188.

［33］Mu K, Yu S, Kitts DD. The role of nitric oxide in regulating intestinal redox status and intestinal epithelial cell functionality［J］. Int J Mol Sci, 2019, 20(7):1755.

［34］Katsube T, Tsuji H, Onoda M. Nitric oxide attenuates hydrogen peroxide-induced barrier disruption and protein tyrosine phosphorylation in monolayers of intestinal epithelial cell［J］. Biochim Biophys Acta, 2007, 1773(6):794-803.

［35］Agibalova T, Hempel A, Maurer HC, et al. Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury［J］. Stem Cell Res Ther, 2024, 15(1):348.

［36］Pascal M, Kazakov A, Chevalier G, et al. The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding［J］. Mucosal Immunol, 2022, 15(4):629-2641.

［37］Ravisankar P, Wong DSH, Zeng MY. Microbiota regulation of gut-brain neuroimmune crosstalk in early life［J］. Int Immunol, 2026, 38(5):282-295.

［38］Nicoletti C. Age-associated changes of the intestinal epithelial barrier: local and systemic implications［J］. Expert Rev Gastroenterol Hepatol, 2015, 9(12):1467-1469.

［39］Kulkarni S, Saha M, Slosberg J, et al. Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease［J］. Elife, 2023,12:RP88051.

［40］Zhang J, Shi AB. The Prelude to Aging: The deterioration of the intestinal barrier and decline in immune function［J］. J Med Mol Biol, 2026, 23(1):90-96.（in Chinese）

张静, 史岸冰.衰老的序曲—肠道屏障崩塌与免疫失调［J］.医学分子生物学杂志, 2026, 23(1):90-96.

［41］Chand N, Muhammad S, Khan RU, et al. Ameliorative effect of synthetic gamma-aminobutyric acid (GABA) on performance traits, antioxidant status and immune response in broiler exposed to cyclic heat stress［J］. Environ Sci Pollut Res Int, 2016, 23(23):23930-23935.

［42］Huh JR, Veiga-Fernandes H. Neuroimmune circuits in inter-organ communication［J］. Nat Rev Immunol, 2020, 20(4):217-228.

［43］Maruyama M, Yoshikata M, Sakaguchi M, et al. Establishment of a novel in vitro co-culture system of enteric neurons and Caco-2 cells for evaluating the effect of enteric nervous system on transepithelial transport of drugs［J］. Int J Pharm, 2023, 633:122617.

［44］Zhang H, Li D, Liu L, et al. Cellular composition and differentiation signaling in chicken small intestinal epithelium［J］. Animals (Basel), 2019, 9(11):870.

［45］Caputi V. Functional role of the enteric nervous system in poultry intestinal health and production［J］. Poult Sci, 2026, 105(4):106563.

［46］Rolig AS, Mittge EK, Ganz J, et al. The enteric nervous system promotes intestinal health by constraining microbiota composition［J］. PLoS Biol, 2017, 15(2):e2000689.

［47］Kabouridis PS, Lasrado R, McCallum S, et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria［J］. Neuron, 2015, 85(2):289-295.

［48］Park JH, Kotani T, Konno T, et al. Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids［J］. PLoS One, 2016, 11(5):e0156334.

［49］Chong HX, Yusoff NAA, Hor YY, et al. Lactobacillus plantarum DR7 alleviates stress and anxiety in adults: a randomised, double-blind, placebo-controlled study［J］. Benef Microbes, 2019, 10(4):355-373.