{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:33:58Z","timestamp":1791322438383,"version":"4.3.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Enteric glial cells (EGCs) are increasingly recognized as key regulators of the gut-brain axis, extending far beyond their traditional role as structural support cells within the enteric nervous system. Growing evidence demonstrates that EGCs integrate neuronal, immune, epithelial, and microbial signals to maintain intestinal homeostasis and coordinate adaptive responses to physiological and pathological stimuli. This review summarizes current knowledge on enteric glial heterogeneity, stress responsiveness, hormonal regulation, and their emerging capacity for regenerative plasticity. While inflammatory and oxidative stress responses of EGCs are increasingly well characterized, their regulation by endocrine signaling remains poorly understood despite accumulating evidence for sex-dependent differences and hormone receptor expression. Furthermore, recent studies suggest that EGCs retain facultative progenitor properties and may contribute to tissue repair and neuronal regeneration under specific conditions. By integrating these largely independent research areas, we propose a conceptual framework in which enteric glia function as central signal integrators linking stress, hormonal signaling, and regenerative responses within the gut-brain axis. A better understanding of these mechanisms may identify enteric glia as promising therapeutic targets for gastrointestinal and neurodegenerative diseases.<\/jats:p>","DOI":"10.3389\/fnins.2026.1922802","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:34:50Z","timestamp":1786426490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Enteric glial cells as regulators of the gut-brain axis: hormonal signaling, stress responses and progenitor potential"],"prefix":"10.3389","volume":"20","author":[{"given":"Sarah","family":"Stahlke","sequence":"first","affiliation":[{"name":"Department of Cytology, Faculty of Medicine, Ruhr-University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Lappe","sequence":"additional","affiliation":[{"name":"Medical Imaging Center (MIC), Electron Microscopy Medical Analysis \u2013 Core Facility (EMMACF), Faculty of Medicine, Ruhr-University Bochum","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Matschke","sequence":"additional","affiliation":[{"name":"Department of Cytology, Faculty of Medicine, Ruhr-University Bochum","place":["Bochum, Germany"]},{"name":"International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum","place":["44801 Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Theiss","sequence":"additional","affiliation":[{"name":"Department of Cytology, Faculty of Medicine, Ruhr-University Bochum","place":["Bochum, Germany"]},{"name":"Medical Imaging Center (MIC), Electron Microscopy Medical Analysis \u2013 Core Facility (EMMACF), Faculty of Medicine, Ruhr-University Bochum","place":["Bochum, Germany"]},{"name":"International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum","place":["44801 Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1096\/fj.09-139519","article-title":"Enteric glial cells protect neurons from oxidative stress in part via reduced glutathione.","volume":"24","author":"Abdo","year":"2010","journal-title":"FASEB J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.3390\/cells11071214","article-title":"Estrogens play a critical role in stress-related gastrointestinal dysfunction in a spontaneous model of disorders of gut-brain interaction","volume":"11","author":"Accarie","year":"2022","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.1093\/nutrit\/nuac030","article-title":"Relaxing the \u201cSecond Brain\u201d: Nutrients and bioactive compounds as a therapeutic and preventive strategy to alleviate oxidative stress in the enteric nervous system.","volume":"80","author":"Almeida","year":"2022","journal-title":"Nutr. Rev."},{"key":"B4","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.stem.2021.10.004","article-title":"Enteric glial cell heterogeneity regulates intestinal stem cell niches","volume":"29","author":"Baghdadi","year":"2022","journal-title":"Cell Stem Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.1038\/s41598-017-02890-y","article-title":"Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells.","volume":"7","author":"Belkind-Gerson","year":"2017","journal-title":"Sci. Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3390\/antiox15010083","article-title":"Obesity-Related oxidative stress and antioxidant properties of natural compounds in the enteric nervous system: A literature overview.","volume":"15","author":"Bellitto","year":"2026","journal-title":"Antioxidants"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-443-19104-6.00001-2","article-title":"Neuroglia and the microbiota-gut-brain axis","volume-title":"Neuroglia in the Healthy Nervous System, Part I","author":"Blair","year":"2025"},{"key":"B8","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/glia.22746","article-title":"Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system.","volume":"63","author":"Boesmans","year":"2014","journal-title":"Glia"},{"key":"B9","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/glia.22746","article-title":"Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system","volume":"63","author":"Boesmans","year":"2015","journal-title":"Glia"},{"key":"B10","doi-asserted-by":"publisher","first-page":"775102","DOI":"10.3389\/fcell.2021.775102","article-title":"Development, diversity, and neurogenic capacity of enteric glia.","volume":"9","author":"Boesmans","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"6387","DOI":"10.1242\/dev.00857","article-title":"Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and postnatal gut cultures.","volume":"130","author":"Bondurand","year":"2003","journal-title":"Development"},{"key":"B12","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41598-018-36878-z","article-title":"5-Fluorouracil induces enteric neuron death and glial activation during intestinal mucositis via a S100B-RAGE-NF\u03baB-Dependent pathway.","volume":"9","author":"Costa","year":"2019","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1177\/10738584231163460","article-title":"Enteric glia and brain astroglia: Complex communication in health and disease along the gut-brain axis.","volume":"30","author":"D\u2019Antongiovanni","year":"2023","journal-title":"Neuroscientist"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5798","DOI":"10.1073\/pnas.1720267115","article-title":"Estrogen receptor \u03b2 controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage.","volume":"115","author":"D\u2019Errico","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3386","DOI":"10.1172\/jci59573","article-title":"Behind an enteric neuron there may lie a glial cell.","volume":"121","author":"Gershon","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.31.596805","article-title":"Early life adversity promotes gastrointestinal dysfunction through a sex-dependent phenotypic switch in enteric glia.","author":"Gonzales","year":"2024","journal-title":"bioRxiv"},{"key":"B17","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1113\/jp271021","article-title":"Enteric glia: The most alimentary of all glia.","volume":"595","author":"Grubi\u0161i\u0107","year":"2016","journal-title":"J. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/nrgastro.2012.138","article-title":"Novel functional roles for enteric glia in the gastrointestinal tract.","volume":"9","author":"Gulbransen","year":"2012","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.3969\/j.issn.1673-5374.2012.028.001","article-title":"Enteric glia mediate neuronal outgrowth through release of neurotrophic factors.","volume":"7","author":"Hansebout","year":"2012","journal-title":"Neural Regenerat. Res."},{"key":"B20","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1053\/gast.1996.v110.pm8608885","article-title":"Neurotrophins and their receptors in the human enteric nervous system","volume":"110","author":"Hoehner","year":"1996","journal-title":"Gastroenterology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1007\/s00384-009-0785-0","article-title":"Estrogen and its role in gastrointestinal health and disease","volume":"24","author":"Hogan","year":"2009","journal-title":"Int. J. Colorectal. Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/nature18644","article-title":"Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence.","volume":"535","author":"Ibiza","year":"2016","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e12782","DOI":"10.1111\/jne.12782","article-title":"Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson\u2019s disease.","volume":"32","author":"Jarras","year":"2019","journal-title":"J. Neuroendocrinol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2324234","DOI":"10.1080\/13510002.2024.2324234","article-title":"Hyperglycemic stress induces oxidative damage of enteric glial cells by triggering redoxosomes\/p66SHC activation.","volume":"29","author":"Jiang","year":"2024","journal-title":"Redox Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"863","DOI":"10.3390\/ijms27020863","article-title":"Progesterone receptor expression in the human enteric nervous system.","volume":"27","author":"Kallabis","year":"2026","journal-title":"Intern. J. Mol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"5904","DOI":"10.1038\/s41467-023-41492-3","article-title":"A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia.","volume":"14","author":"Laddach","year":"2023","journal-title":"Nat. Commun."},{"key":"B27","doi-asserted-by":"publisher","first-page":"3412","DOI":"10.1172\/jci58200","article-title":"Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury.","volume":"121","author":"Laranjeira","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B28","doi-asserted-by":"publisher","first-page":"12475","DOI":"10.3390\/ijms241512475","article-title":"Harnessing the power of enteric glial cells\u2019 plasticity and multipotency for advancing regenerative medicine.","volume":"24","author":"Lef\u00e8vre","year":"2023","journal-title":"Intern. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"137395","DOI":"10.1016\/j.neulet.2023.137395","article-title":"Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain.","volume":"812","author":"Linan-Rico","year":"2023","journal-title":"Neurosci. Lett."},{"key":"B30","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ygcen.2018.11.016","article-title":"Localization of estrogen receptor ER\u03b1, ER\u03b2 and GPR30 on myenteric neurons of the gastrointestinal tract and their role in motility.","volume":"272","author":"Liu","year":"2019","journal-title":"General Comparat. Endocrinol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e24899","DOI":"10.1016\/j.heliyon.2024.e24899","article-title":"Enteric glial cells contribute to chronic stress-induced alterations in the intestinal microbiota and barrier in rats.","volume":"10","author":"Lu","year":"2024","journal-title":"Heliyon"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e56086","DOI":"10.7554\/elife.56086","article-title":"Enteric glia as a source of neural progenitors in adult zebrafish.","volume":"9","author":"McCallum","year":"2020","journal-title":"eLife"},{"key":"B33","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.jcmgh.2018.11.005","article-title":"Enteric glia: A new player in abdominal pain.","volume":"7","author":"Morales-Soto","year":"2019","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1016\/j.neuron.2025.11.030","article-title":"Tachykinin signaling defines distinct populations of glia in the enteric nervous system","volume":"114","author":"Muppirala","year":"2026","journal-title":"Neuron"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1053\/j.gastro.2014.09.040","article-title":"Enteric glial cells: Recent developments and future directions.","volume":"147","author":"Neunlist","year":"2014","journal-title":"Gastroenterology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.neulet.2013.12.071","article-title":"The dual role of astrocyte activation and reactive gliosis.","volume":"565","author":"Pekny","year":"2014","journal-title":"Neurosci. Lett."},{"key":"B37","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.neuron.2014.12.066","article-title":"Bugs, guts, and glia: How microbiota influence enteric gliogenesis and migration.","volume":"85","author":"Rao","year":"2015","journal-title":"Neuron"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e150789","DOI":"10.1172\/jci150789","article-title":"Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice.","volume":"132","author":"Rastelli","year":"2022","journal-title":"J. Clin. Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1186\/s12905-024-03480-7","article-title":"Implication of the enteric glia in the IBS-like colonic inflammation associated with endometriosis.","volume":"24","author":"Rivera-Arce","year":"2024","journal-title":"BMC Women\u2019s Health"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e0151335","DOI":"10.1371\/journal.pone.0151335","article-title":"Activation of myenteric glia during acute inflammation In Vitro and In Vivo. (Y. Tache, Hrsg.).","volume":"11","author":"Rosenbaum","year":"2016","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/s41575-021-00423-7","article-title":"Enteric glial biology, intercellular signalling and roles in gastrointestinal disease.","volume":"18","author":"Seguella","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"8694","DOI":"10.1523\/jneurosci.2379-20.2022","article-title":"Functional intraregional and interregional heterogeneity between myenteric glial cells of the colon and duodenum in mice.","volume":"42","author":"Seguella","year":"2022","journal-title":"J. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1172\/jci76303","article-title":"Emerging roles for enteric glia in gastrointestinal disorders.","volume":"125","author":"Sharkey","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.3390\/cells12081206","article-title":"Progesterone: A neuroprotective steroid of the intestine.","volume":"12","author":"Stegemann","year":"2023","journal-title":"Cells"},{"key":"B45","doi-asserted-by":"publisher","first-page":"BR117","DOI":"10.12659\/msm.882612","article-title":"Apoptosis in enteric glia:Part of the puzzle in Crohn\u2019s disease?","volume":"18","author":"Steinkamp","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1281710","DOI":"10.3389\/fnins.2023.1281710","article-title":"Enteric glia as a player of gut-brain interactions during Parkinson\u2019s disease.","volume":"17","author":"Thomasi","year":"2023","journal-title":"Front. Neurosci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.brainres.2018.02.001","article-title":"Enteric glia: Diversity or plasticity?","volume":"1693","author":"Val\u00e8s","year":"2018","journal-title":"Brain Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1111\/j.1365-2826.2006.01478.x","article-title":"Nerve growth factor secretion in cultured enteric glia cells is modulated by proinflammatory cytokines.","volume":"18","author":"von Boyen","year":"2006","journal-title":"J. Neuroendocrinol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1136\/gut.2003.012625","article-title":"Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia.","volume":"53","author":"von Boyen","year":"2004","journal-title":"Gut"},{"key":"B50","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1055\/s-2006-926968","article-title":"Die enterische Glia und neurotrophe Faktoren.","volume":"44","author":"von Boyen","year":"2006","journal-title":"Zeitschrift Gastroenterol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1922802\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:34:53Z","timestamp":1786426493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1922802\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":50,"alternative-id":["10.3389\/fnins.2026.1922802"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2026.1922802","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"1922802"}}