One of the most transformative developments in neurogastroenterology is the realization that many functions normally attributed to enteric neurons involve interactions with enteric glial cells: a large population of peripheral neuroglia associated with enteric neurons throughout the gastrointestinal tract. The notion that glial cells function solely as passive support cells has been refuted by compelling evidence that demonstrates that enteric glia are important homeostatic cells of the intestine. Active signalling mechanisms between enteric glia and neurons modulate gastrointestinal reflexes and, in certain circumstances, function to drive neuroinflammatory processes that lead to long-term dysfunction. Bidirectional communication between enteric glia and immune cells contributes to gastrointestinal immune homeostasis, and crosstalk between enteric glia and cancer stem cells regulates tumorigenesis. These neuromodulatory and immunomodulatory roles place enteric glia in a unique position to regulate diverse gastrointestinal disease processes. In this Review, we discuss current concepts regarding enteric glial development, heterogeneity and functional roles in gastrointestinal pathophysiology and pathophysiology, with a focus on interactions with neurons and immune cells. We also present a working model to differentiate glial states based on normal function and disease-induced dysfunctions.
Enteric glia are a heterogeneous population of peripheral neuroglia that regulate homeostasis in the enteric nervous system.
Bidirectional communication between enteric glia and neurons modulates intestinal reflexes.
Enteric glia are central players in neuroinflammation and contribute to neuroplasticity through interactions with neurons and immune cells.
Enteric glia regulate disease processes involved in tumorigenesis and extragastrointestinal diseases.
Therapies targeting glial mechanisms, such as gliotransmitter release or signalling pathways that promote gliosis, could substantially advance the treatment of common gastrointestinal diseases.
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Furness, J. B. The enteric nervous system: normal functions and enteric neuropbbathies. Neurogastroenterol. Motil. 20, 32–38 (2008).
Furness, J. B. The Enteric Nervous System (John Wiley & Sons, 2008).
Fung, C. & Vanden Berghe, P. Functional circuits and signal processing in the enteric nervous system. Cell Mol. Life Sci. 77, 4505–4522 (2020).
Lasrado, R. et al. Lineage-dependent spatial and functional organization of the mammalian enteric nervous system. Science 356, 722–726 (2017). This paper describes how the developing enteric nervous system is organized into overlapping clonally related units that exhibit synchronous activity in response to network stimulation.
Jarret, A. et al. Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity. Cell 180, 50–63.e12 (2020).
Klose, C. S. N. et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017).
Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 17, 755 (2017).
Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).
Boesmans, W. et al. Structurally defined signaling in neuro-glia units in the enteric nervous system. Glia 67, 1167–1178 (2019).
McClain, J. L., Fried, D. E. & Gulbransen, B. D. Agonist-evoked Ca2+ signaling in enteric glia drives neural programs that regulate intestinal motility in mice. Cell. Mol. Gastroenterol. Hepatol. 1, 631–645 (2015). This study uses a chemogenetic mouse model to activate Ca2+ signalling in enteric glia; the results showed that glial activity enhances and/or activates myenteric motor neurocircuits.
Grubišić, V. & Gulbransen, B. D. Enteric glial activity regulates secretomotor function in the mouse colon but does not acutely affect gut permeability. J. Physiol. 595, 3409–3424 (2017).
Delvalle, N. M. et al. Communication between enteric neurons, glia, and nociceptors underlies the effects of tachykinins on neuroinflammation. Cell. Mol. Gastroenterol. Hepatol. 6, 321–344 (2018). This study shows that extrinsic sensory neurons promote neuroinflammation through effects on enteric glia and also provides a database of transcriptional changes in reactive enteric glia during experimental colitis.
Brown, I. A. M., McClain, J. L., Watson, R. E., Patel, B. A. & Gulbransen, B. D. Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. Cell. Mol. Gastroenterol. Hepatol. 2, 77–91 (2016).
Delvalle, N. M., Fried, D. E., Rivera-Lopez, G., Gaudette, L. & Gulbransen, B. D. Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G473–G483 (2018).
Vergnolle, N. & Cirillo, C. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology 33, 269–280 (2018).
Fung, C. et al. VPAC receptor subtypes tune purinergic neuron-to-glia communication in the murine submucosal plexus. Front. Cell. Neurosci. 11, 118 (2017).
Nasser, Y. et al. Role of enteric glia in intestinal physiology: effects of the gliotoxin fluorocitrate on motor and secretory function. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G912–G927 (2006).
Gulbransen, B. D., Bains, J. S. & Sharkey, K. A. Enteric glia are targets of the sympathetic innervation of the myenteric plexus in the guinea pig distal colon. J. Neurosci. 30, 6801–6809 (2010).
Costantini, T. W. et al. Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G1308–G1318 (2010).
Valès, S. et al. Tumor cells hijack enteric glia to activate colon cancer stem cells and stimulate tumorigenesis. EBioMedicine 49, 172–188 (2019).
Sundaresan, S. et al. Gastrin induces nuclear export and proteasome degradation of menin in enteric glial cells. Gastroenterology 153, 1555–1567.e15 (2017).
Selgrad, M. et al. JC virus infects the enteric glia of patients with chronic idiopathic intestinal pseudo-obstruction. Gut 58, 25–32 (2009).
Hanani, M. & Reichenbach, A. Morphology of horseradish peroxidase (HRP)-injected glial cells in the myenteric plexus of the guinea-pig. Cell Tissue Res. 278, 153–160 (1994).
Boesmans, W., Lasrado, R., Vanden Berghe, P. & Pachnis, V. Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia 63, 229–241 (2015). This study uses immunohistochemistry and Ca2+ imaging to provide evidence of heterogeneity among enteric glia in the myenteric plexus of the mouse colon.
Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018). This study demonstrates functional and phenotypic heterogeneity across distinct enteric glia subtypes.
Drokhlyansky, E. et al. The human and mouse enteric nervous system at single-cell resolution. Cell 182, 1606–1622.e23 (2020).
Bon-Frauches, A. C. & Boesmans, W. The enteric nervous system: the hub in a star network. Nat. Rev. Gastroenterol. Hepatol. 17, 717–718 (2020).
Dulac, C. & Le Douarin, N. M. Phenotypic plasticity of Schwann cells and enteric glial cells in response to the microenvironment. Proc. Natl Acad. Sci. USA 88, 6358–6362 (1991).
Soret, R. et al. Glial cell derived neurotrophic factor induces enteric neurogenesis and improves colon structure and function in mouse models of Hirschsprung disease. Gastroenterology 159, 1824–1838 (2020). Data in this study suggest that Schwann cells associated with extrinsic nerves are capable of forming new enteric neurons and glia under certain circumstances.
Espinosa-Medina, I. et al. Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest. Proc. Natl Acad. Sci. USA 114, 11980–11985 (2017).
Uesaka, T., Nagashimada, M. & Enomoto, H. Neuronal differentiation in Schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system. J. Neurosci. 35, 9879–9888 (2015).
El-Nachef, W. N. & Bronner, M. E. De novo enteric neurogenesis in post-embryonic zebrafish from Schwann cell precursors rather than resident cell types. Development 147, dev186619 (2020).
Rao, M. et al. Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system. Glia 63, 2040–2057 (2015). This study provides the first transcriptional analysis of enteric glia and compares transcriptional profiles to other populations of glia.
Kabouridis, P. S. et al. Microbiota controls the homeostasis of glial cells in the gut lamina propria. Neuron 85, 289–295 (2015). Results from this study show that enteric glia at the level of the lamina propria are continuously renewed by cells that originate in the submucosal and myenteric plexuses.
Bohórquez, D. V. et al. An enteroendocrine cell – enteric glia connection revealed by 3D electron microscopy. PLoS ONE 9, e89881 (2014).
Neunlist, M. et al. Enteric glia inhibit intestinal epithelial cell proliferation partly through a TGF-beta1-dependent pathway. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G231–G241 (2007).
Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).
Liu, Y. A. et al. 3-D imaging, illustration, and quantitation of enteric glial network in transparent human colon mucosa. Neurogastroenterol. Motil. 25, e324–e338 (2013).
Kaelberer, M. M. et al. A gut-brain neural circuit for nutrient sensory transduction. Science 361, eaat5236 (2018).
Lin, W. et al. Interferon-gamma induced medulloblastoma in the developing cerebellum. J. Neurosci. 24, 10074–10083 (2004).
Jessen, K. R., Thorpe, R. & Mirsky, R. Molecular identity, distribution and heterogeneity of glial fibrillary acidic protein: an immunoblotting and immunohistochemical study of Schwann cells, satellite cells, enteric glia and astrocytes. J. Neurocytol. 13, 187–200 (1984).
Park, Y. M., Chun, H., Shin, J. I. & Lee, C. J. Astrocyte specificity and coverage of hGFAP-CreERT2 [Tg(GFAP-Cre/ERT2)13Kdmc] mouse line in various brain regions. Exp. Neurobiol. 27, 508–525 (2018).
Zhang, Z. et al. The appropriate marker for astrocytes: comparing the distribution and expression of three astrocytic markers in different mouse cerebral regions. BioMed. Res. Int. 2019, 9605265 (2019).
Jessen, K. R. & Mirsky, R. Glial fibrillary acidic polypeptides in peripheral glia. Molecular weight, heterogeneity and distribution. J. Neuroimmunol. 8, 377–393 (1985).
Rao, M. et al. Enteric glia regulate gastrointestinal motility but are not required for maintenance of the epithelium in mice. Gastroenterology 153, 1068–1081.e7 (2017). This study highlights complications with glial ablation models that draw the necessity of glial support into question.
Van Landeghem, L. et al. Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G976–G987 (2011).
Savidge, T. C. et al. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132, 1344–1358 (2007).
Grubišić, V. et al. Enteric glia modulate macrophage phenotype and visceral sensitivity following inflammation. Cell Rep. 32, 108100 (2007).
Li, Z. et al. Regional complexity in enteric neuron wiring reflects diversity of motility patterns in the mouse large intestine. eLife 8, 899 (2019).
Avetisyan, M., Schill, E. M. & Heuckeroth, R. O. Building a second brain in the bowel. J. Clin. Invest. 125, 899–907 (2015).
Nishiyama, C. et al. Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system. Nat. Neurosci. 15, 1211–1218 (2012).
Young, H. M., Bergner, A. J. & Müller, T. Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine. J. Comp. Neurol. 456, 1–11 (2003).
Hao, M. M., Capoccia, E., Cirillo, C., Boesmans, W. & Vanden Berghe, P. Arundic acid prevents developmental upregulation of S100B expression and inhibits enteric glial development. Front. Cell. Neurosci. 11, 42 (2017).
Burns, A. J. & Le Douarin, N. M. Enteric nervous system development: analysis of the selective developmental potentialities of vagal and sacral neural crest cells using quail-chick chimeras. Anat. Rec. 262, 16–28 (2001).
Kabouridis, P. S. & Pachnis, V. Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system. J. Clin. Invest. 125, 956–964 (2015).
Hao, M. M. et al. Enteric nervous system assembly: functional integration within the developing gut. Dev. Biol. 417, 168–181 (2016).
Joseph, N. M. et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011).
Laranjeira, C. et al. Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury. J. Clin. Invest. 121, 3412–3424 (2011). Joseph et al. and Laranjeira et al. provide complementary evidence that suggests enteric glia are able to form neurons and glia in culture, but only seem to give rise to neurons in vivo in response to intestinal injury.
Verkhratsky, A., Ho, M. S., Zorec, R. & Parpura, V. The concept of neuroglia. Adv. Exp. Med. Biol. 1175, 1–13 (2019).
McClain, J. L. et al. Ca2+ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice. Gastroenterology 146, 497–507.e1 (2014). This study shows that connexin 43 hemichannels are an important molecular mediator of glia intercellular communication and that perturbing this mechanism impairs intestinal motility in mice.
MacEachern, S. J., Patel, B. A., McKay, D. M. & Sharkey, K. A. Nitric oxide regulation of colonic epithelial ion transport: a novel role for enteric glia in the myenteric plexus. J. Physiol. 589, 3333–3348 (2011).
Esposito, G. et al. Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation. Gut 63, 1300–1312 (2014).
Grubišić, V. & Parpura, V. Two modes of enteric gliotransmission differentially affect gut physiology. Glia 65, 699–711 (2017).
Broadhead, M. J., Bayguinov, P. O., Okamoto, T., Heredia, D. J. & Smith, T. K. Ca2+ transients in myenteric glial cells during the colonic migrating motor complex in the isolated murine large intestine. J. Physiol. 590, 335–350 (2012). This study provides important evidence showing that glial activity is recruited during physiological patterns of neural activity that generate the colonic migrating motor complex.
Grubišić, V. & Gulbransen, B. D. Enteric glia: the most alimentary of all glia. J. Physiol. 595, 557–570 (2016).
Gabella, G. Fine structure of the myenteric plexus in the guinea-pig ileum. J. Anat. 111, 69–97 (1972).
Kimball, B. C. & Mulholland, M. W. Enteric glia exhibit P2U receptors that increase cytosolic calcium by a phospholipase C-dependent mechanism. J. Neurochem. 66, 604–612 (1996). This study provides early evidence that neurotransmitters evoke activity in enteric glia and defined the intracellular signal transduction mechanisms involved.
Gomes, P. et al. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice. Neurogastroenterol. Motil. 21, 870–e62 (2009).
Boesmans, W., Hao, M. M. & Vanden Berghe, P. Optical tools to investigate cellular activity in the intestinal wall. J. Neurogastroenterol. Motil. 21, 337–351 (2015).
Gulbransen, B. D. & Sharkey, K. A. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology 136, 1349–1358 (2009). This study shows that enteric glia sense neurotransmitters released by enteric neurons and display activity encoded by intracellular Ca2+ responses.
Boesmans, W. et al. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol. Motil. 25, e151–e160 (2013).
Garrido, R., Segura, B., Zhang, W. & Mulholland, M. Presence of functionally active protease-activated receptors 1 and 2 in myenteric glia. J. Neurochem. 83, 556–564 (2002).
Fried, D. E., Watson, R. E., Robson, S. C. & Gulbransen, B. D. Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G570–G580 (2017).
Smith, T. K. & Koh, S. D. A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G1–G14 (2017).
Antonioli, L. et al. Colonic dysmotility associated with high-fat diet-induced obesity: role of enteric glia. FASEB J. 34, 5512–5524 (2020).
Bush, T. G. et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93, 189–201 (1998).
Cornet, A. et al. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn’s disease? Proc. Natl Acad. Sci. USA 98, 13306–13311 (2001).
Aikawa, H. & Suzuki, K. Enteric gliopathy in niacin-deficiency induced by CNS glio-toxin. Brain Res. 334, 354–356 (1985).
McClain, J. L. & Gulbransen, B. D. The acute inhibition of enteric glial metabolism with fluoroacetate alters calcium signaling, hemichannel function, and the expression of key proteins. J. Neurophysiol. 117, 365–375 (2017).
Ro, S., Hwang, S. J., Muto, M., Jewett, W. K. & Spencer, N. J. Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G710–G718 (2006).
Savtchouk, I. & Volterra, A. Gliotransmission: beyond black-and-white. J. Neurosci. 38, 14–25 (2018).
Fiacco, T. A. & McCarthy, K. D. Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J. Neurosci. 38, 3–13 (2018).
Martín, R., Bajo-Grañeras, R., Moratalla, R., Perea, G. & Araque, A. Glial cell signaling. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 349, 730–734 (2015).
Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549.e9 (2017).
Yu, X. et al. Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior. Neuron 99, 1170–1187.e9 (2018).
Auteri, M., Zizzo, M. G. & Serio, R. GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. Pharmacol. Res. 93, 11–21 (2015).
Grider, J. R. & Makhlouf, G. M. Enteric GABA: mode of action and role in the regulation of the peristaltic reflex. Am. J. Physiol. 262, G690–G694 (1992).
King, B. F. Purinergic signalling in the enteric nervous system (An overview of current perspectives). Auton. Neurosci. 191, 141–147 (2015).
Murakami, M., Ohta, T., Otsuguro, K.-I. & Ito, S. Involvement of prostaglandin E2 derived from enteric glial cells in the action of bradykinin in cultured rat myenteric neurons. Neuroscience 145, 642–653 (2007).
Cabarrocas, J., Savidge, T. C. & Liblau, R. S. Role of enteric glial cells in inflammatory bowel disease. Glia 41, 81–93 (2003).
Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018).
Aoki, E., Semba, R. & Kashiwamata, S. Evidence for the presence of L-arginine in the glial components of the peripheral nervous system. Brain Res. 559, 159–162 (1991).
Jessen, K. R. & Mirsky, R. Astrocyte-like glia in the peripheral nervous system: an immunohistochemical study of enteric glia. J. Neurosci. 3, 2206–2218 (1983).
Ruhl, A., Hoppe, S., Frey, I., Daniel, H. & Schemann, M. Functional expression of the peptide transporter PEPT2 in the mammalian enteric nervous system. J. Comp. Neurol. 490, 1–11 (2005).
Fletcher, E. L., Clark, M. J. & Furness, J. B. Neuronal and glial localization of GABA transporter immunoreactivity in the myenteric plexus. Cell Tissue Res. 308, 339–346 (2002).
Lavoie, E. G. et al. Ectonucleotidases in the digestive system: focus on NTPDase3 localization. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G608–G620 (2011).
Grubišić, V. et al. NTPDase1 and -2 are expressed by distinct cellular compartments in the mouse colon and differentially impact colonic physiology and function after DSS colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 317, G314–G332 (2019).
Braun, N. et al. Association of the ecto-ATPase NTPDase2 with glial cells of the peripheral nervous system. Glia 45, 124–132 (2004).
Brown, I. A. M. & Gulbransen, B. D. The antioxidant glutathione protects against enteric neuron death in situ, but its depletion is protective during colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 314, G39–G52 (2018).
Abdo, H. H. et al. Enteric glial cells protect neurons from oxidative stress in part via reduced glutathione. FASEB J. 24, 1082–1094 (2010).
von Boyen, G. B. T. et al. Nerve growth factor secretion in cultured enteric glia cells is modulated by proinflammatory cytokines. J. Neuroendocrinol. 18, 820–825 (2006).
Belkind-Gerson, J. et al. Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells. Sci. Rep. 7, 2525 (2017).
Le Berre-Scoul, C. et al. A novel enteric neuron-glia coculture system reveals the role of glia in neuronal development. J. Physiol. 595, 583–598 (2017).
Neunlist, M. et al. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 90–100 (2013).
Soret, R. et al. Characterization of human, mouse, and rat cultures of enteric glial cells and their effect on intestinal epithelial cells. Neurogastroenterol. Motil. 25, e755–e764 (2013).
Bach-Ngohou, K. et al. Enteric glia modulate epithelial cell proliferation and differentiation through 15-deoxy-12,14-prostaglandin J2. J. Physiol. 588, 2533–2544 (2010).
Matheis, F. et al. Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss. Cell 180, 64–78.e16 (2020).
Nagahama, M., Semba, R., Tsuzuki, M. & Aoki, E. L-arginine immunoreactive enteric glial cells in the enteric nervous system of rat ileum. Biol. Signals Recept. 10, 336–340 (2001).
Bannerman, P. G., Mirsky, R. & Jessen, K. R. Analysis of enteric neurons, glia and their interactions using explant cultures of the myenteric plexus. Dev. Neurosci. 9, 201–227 (1987).
Broussard, D. L., Bannerman, P. G., Tang, C. M., Hardy, M. & Pleasure, D. Electrophysiologic and molecular properties of cultured enteric glia. J. Neurosci. Res. 34, 24–31 (1993).
Hanani, M. et al. Patch-clamp study of neurons and glial cells in isolated myenteric ganglia. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G644–G651 (2000). This study characterizes the electrophysiological properties of enteric glia.
Long, X. et al. Butyrate promotes visceral hypersensitivity in an IBS-like model via enteric glial cell-derived nerve growth factor. Neurogastroenterol. Motil. 30, e13227 (2018).
Rosenbaum, C. et al. Activation of myenteric glia during acute inflammation in vitro and in vivo. PLoS ONE 11, e0151335 (2016). This study highlights genomic changes that reflect a reactive phenotype of myenteric glia in vivo driven by exposure to lipopolysaccharide.
Murakami, M., Ohta, T. & Ito, S. Lipopolysaccharides enhance the action of bradykinin in enteric neurons via secretion of interleukin-1beta from enteric glial cells. J. Neurosci. Res. 87, 2095–2104 (2009).
Gougeon, P.-Y. et al. The pro-inflammatory cytokines IL-1β and TNFα are neurotrophic for enteric neurons. J. Neurosci. 33, 3339–3351 (2013).
Cirillo, C. et al. S100B protein in the gut: the evidence for enteroglial-sustained intestinal inflammation. World J. Gastroenterol. 17, 1261–1266 (2011).
Magnusson, F. C. et al. Direct presentation of antigen by lymph node stromal cells protects against CD8 T-cell-mediated intestinal autoimmunity. Gastroenterology 134, 1028–1037 (2008).
Aikawa, H. & Suzuki, K. Lesions in the skin, intestine, and central nervous system induced by an antimetabolite of niacin. Am. J. Pathol. 122, 335–342 (1986).
D’Errico, F. et al. Estrogen receptor β controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage. Proc. Natl Acad. Sci. USA 115, 5798–5803 (2018).
Zoumboulakis, D., Cirella, K. R., Gougeon, P. Y., Lourenssen, S. R. & Blennerhassett, M. G. MMP-9 processing of intestinal smooth muscle-derived GDNF is required for neurotrophic action on enteric neurons. Neuroscience 443, 8–18 (2020).
Betageri, K. R. et al. Enteric glial networks visualized using SOX10 fluorescent reporter in optically-cleared full thickness intestinal tissues. FASEB J. 34 (Suppl. 1), 1–1 (2020).
Pochard, C. et al. Defects in 15-HETE production and control of epithelial permeability by human enteric glial cells from patients with Crohn’s disease. Gastroenterology 150, 168–180 (2016).
Bauman, B. D. et al. Enteric glial-mediated enhancement of intestinal barrier integrity is compromised by morphine. J. Surg. Res. 219, 214–221 (2017).
Lomasney, K. W. et al. Selective influence of host microbiota on cAMP-mediated ion transport in mouse colon. Neurogastroenterol. Motil. 26, 887–890 (2014).
Cavin, J. B., Cuddihey, H., MacNaughton, W. K. & Sharkey, K. A. Acute regulation of intestinal ion transport and permeability in response to luminal nutrients: the role of the enteric nervous system. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G254–G264 (2020).
De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415.e13 (2018).
Obata, Y. et al. Neuronal programming by microbiota regulates intestinal physiology. Nature 578, 284–289 (2020).
Drossman, D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology 150, 1262–1279.e2 (2016).
Phillips, R. J., Kieffer, E. J. & Powley, T. L. Loss of glia and neurons in the myenteric plexus of the aged Fischer 344 rat. Anat. Embryol. 209, 19–30 (2004).
Camilleri, M., Cowen, T. & Koch, T. R. Enteric neurodegeneration in ageing. Neurogastroenterol. Motil. 20, 418–429 (2008).
Saffrey, M. J. Aging of the mammalian gastrointestinal tract: a complex organ system. Age 36, 9603 (2014).
Seguella, L., Sarnelli, G. & Esposito, G. Leaky gut, dysbiosis, and enteric glia activation: the trilogy behind the intestinal origin of Parkinson’s disease. Neural Regen. Res. 15, 1037–1038 (2020).
Liñán-Rico, A. et al. Molecular signaling and dysfunction of the human reactive enteric glial cell phenotype: implications for GI infection, IBD, POI, neurological, motility, and GI disorders. Inflamm. Bowel Dis. 22, 1812–1834 (2016). This study provides a comprehensive analysis of human reactive enteric glia.
Baydas, G., Nedzvetskii, V. S., Tuzcu, M., Yasar, A. & Kirichenko, S. V. Increase of glial fibrillary acidic protein and S-100B in hippocampus and cortex of diabetic rats: effects of vitamin E. Eur. J. Pharmacol. 462, 67–71 (2003).
De Filippis, D. et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS ONE 6, e28159 (2011).
Nogueira, L. T. et al. The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis. J. Neuroinflammation 14, 79 (2017).
Sofroniew, M. V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).
Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).
Krauter, E. M. et al. Changes in colonic motility and the electrophysiological properties of myenteric neurons persist following recovery from trinitrobenzene sulfonic acid colitis in the guinea pig. Neurogastroenterol. Motil. 19, 990–1000 (2007).
Hoffman, J. M., McKnight, N. D., Sharkey, K. A. & Mawe, G. M. The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon. Neurogastroenterol. Motil. 23, 673–e279 (2011).
Roberts, J. A., Durnin, L., Sharkey, K. A., Mutafova-Yambolieva, V. N. & Mawe, G. M. Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. J. Physiol. 591, 3725–3737 (2013).
Spencer, N. J. & Hu, H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat. Rev. Gastroenterol. Hepatol. 17, 338–351 (2020).
Lomax, A. E., Fernández, E. & Sharkey, K. A. Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol. Motil. 17, 4–15 (2005).
Lomax, A. E., O’Hara, J. R., Hyland, N. P., Mawe, G. M. & Sharkey, K. A. Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G482–G491 (2007).
Linden, D. R., Sharkey, K. A. & Mawe, G. M. Enhanced excitability of myenteric AH neurones in the inflamed guinea-pig distal colon. J. Physiol. 547, 589–601 (2003).
Strong, D. S. et al. Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colon. J. Physiol. 588, 847–859 (2010).
Gulbransen, B. D. et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat. Med. 18, 600–604 (2012).
Turco, F. et al. Enteroglial-derived S100B protein integrates bacteria-induced Toll-like receptor signalling in human enteric glial cells. Gut 63, 105–115 (2014). The results of this study show that pathogens and probiotics have differential effects on enteric glia.
Murakami, M., Ohta, T. & Ito, S. Interleukin-1β enhances the action of bradykinin in rat myenteric neurons through up-regulation of glial B1 receptor expression. Neuroscience 151, 222–231 (2008).
Buckley, M. M., O’Halloran, K. D., Rae, M. G., Dinan, T. G. & O’Malley, D. Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome. J. Physiol. 592, 5235–5250 (2014).
Kermarrec, L., Durand, T., Neunlist, M., Naveilhan, P. & Neveu, I. Enteric glial cells have specific immunosuppressive properties. J. Neuroimmunol. 295-296, 79–83 (2016).
Stoffels, B. et al. Postoperative ileus involves interleukin-1 receptor signaling in enteric glia. Gastroenterology 146, 176–187.e1 (2014). This study shows that pro-inflammatory mediators such as IL-1β disrupt intestinal motility through effects on enteric glia. This is one example of the detrimental effects of reactive enteric glia.
Wang, P. et al. BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit. Sci. Rep. 6, 20320 (2016).
Wangzhou, A. et al. A pharmacological interactome platform for discovery of pain mechanisms and targets. bioRxiv https://doi.org/10.1101/2020.04.14.041715 (2020).
Cirillo, C. et al. Increased mucosal nitric oxide production in ulcerative colitis is mediated in part by the enteroglial-derived S100B protein. Neurogastroenterol. Motil. 21, 1209–e112 (2009).
Chow, A. K. & Gulbransen, B. D. Potential roles of enteric glia in bridging neuroimmune communication in the gut. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G145–G152 (2017).
Langness, S., Kojima, M., Coimbra, R., Eliceiri, B. P. & Costantini, T. W. Enteric glia cells are critical to limiting the intestinal inflammatory response after injury. Am. J. Physiol. Gastrointest. Liver Physiol. 312, G274–G282 (2017). Data in this study show that enteric glia modulate local immune responses and gut barrier integrity after injury by transmitting vagal anti-inflammatory signals to resident immune cells.
Seguella, L. et al. Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue. J. Cell. Mol. Med. 24, 3053–3063 (2020).
Duchalais, E. et al. Colorectal cancer cells adhere to and migrate along the neurons of the enteric nervous system. Cell. Mol. Gastroenterol. Hepatol. 5, 31–49 (2018).
Clairembault, T. et al. Enteric GFAP expression and phosphorylation in Parkinson’s disease. J. Neurochem. 130, 805–815 (2014).
Stenkamp-Strahm, C., Patterson, S., Boren, J., Gericke, M. & Balemba, O. High-fat diet and age-dependent effects on enteric glial cell populations of mouse small intestine. Auton. Neurosci. 177, 199–210 (2013).
Seelig, D. M., Mason, G. L., Telling, G. C. & Hoover, E. A. Chronic wasting disease prion trafficking via the autonomic nervous system. Am. J. Pathol. 179, 1319–1328 (2011).
Corbillé, A. -G. et al. What a gastrointestinal biopsy can tell us about Parkinson’s disease? Neurogastroenterol. Motil. 28, 966–974 (2016).
Devos, D. et al. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48 (2013).
Perez-Pardo, P. et al. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68, 829–843 (2019).
Chen, Q. Q. et al. Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson’s disease. Transl. Neurodegener. 7, 13 (2018).
Dutta, S. K. et al. Parkinson’s disease: the emerging role of gut dysbiosis, antibiotics, probiotics, and fecal microbiota transplantation. J. Neurogastroenterol. Motil. 25, 363–376 (2019).
Albanese, V. et al. Evidence for prion protein expression in enteroglial cells of the myenteric plexus of mouse intestine. Auton. Neurosci. 140, 17–23 (2008).
Ma, E. L. et al. Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice. Brain Behav. Immun. 66, 56–69 (2017).
Esposito, G. et al. HIV-1 Tat-induced diarrhea evokes an enteric glia-dependent neuroinflammatory response in the central nervous system. Sci. Rep. 7, 7735 (2017).
Camilleri, M. et al. Pharmacological, pharmacokinetic, and pharmacogenomic aspects of functional gastrointestinal disorders. Gastroenterology 150, 1319–1331.e20 (2016).
Sarnelli, G. et al. HIV-1 Tat-induced diarrhea is improved by the PPARalpha agonist, palmitoylethanolamide, by suppressing the activation of enteric glia. J. Neuroinflammation 15, 94 (2018).
Costa, D. V. S. et al. 5-Fluorouracil induces enteric neuron death and glial activation during intestinal mucositis via a S100B-RAGE-NFκB-dependent pathway. Sci. Rep. 9, 665 (2019).
Angelo, M. F. et al. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia. PLoS ONE 9, e107901 (2014).
Lue, L. F. et al. Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp. Neurol. 171, 29–45 (2001).
Moraes, C. A. et al. Activated microglia-induced deficits in excitatory synapses through IL-1β: implications for cognitive impairment in sepsis. Mol. Neurobiol. 52, 653–663 (2015).
Tack, J. et al. The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS. Gut 66, 1403–1413 (2017).
Good, M. E. et al. Pannexin 1 channels as an unexpected new target of the anti-hypertensive drug Spironolactone. Circ. Res. 122, 606–615 (2018).
Fried, D. E. & Gulbransen, B. D. In situ Ca2+ imaging of the enteric nervous system. J. Vis. Exp. 95, 52506 (2015).
Van Landeghem, L. et al. Regulation of intestinal epithelial cells transcriptome by enteric glial cells: impact on intestinal epithelial barrier functions. BMC Genomics 10, 507 (2009).
Coquenlorge, S. et al. The arachidonic acid metabolite 11β-prostaglandinF2α controls intestinal epithelial healing: deficiency in patients with Crohn’s disease. Sci. Rep. 6, 25203 (2016).
Eser, A. et al. Safety and efficacy of an oral inhibitor of the purinergic receptor P2X7 in adult patients with moderately to severely active Crohn’s disease: a randomized placebo-controlled, double-blind, phase IIa study. Inflamm. Bowel Dis. 21, 2247–2253 (2015).
Burnstock, G., Jacobson, K. A. & Christofi, F. L. Purinergic drug targets for gastrointestinal disorders. Curr. Opin. Pharmacol. 37, 131–141 (2017).
Esposito, G. et al. Enteric glial-derived S100B protein stimulates nitric oxide production in celiac disease. Gastroenterology 133, 918–925 (2007).
Asano, T. et al. Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B. CNS Neurol. Disord. Drug Targets 4, 127–142 (2005).
B.D.G. receives support from grants R01DK103723 and R01DK120862 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The content is solely the responsibility of the Authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare no competing interests.
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Seguella, L., Gulbransen, B.D. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00423-7