Research progress on enteric glial cells under intestinal motility disorder_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Na , LI Yansong , CHENG Bo , YUAN Wei ,  WANG Qiang ,  LI Shuang

Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China;

Corresponding author：

WANG Qiang, Email: dr.wangqiang@139.com; LI Shuang, Email: lish09doctor@sina.com

Keywords：

enteric glial cells; intestinal motility; enteric nervous system; intestinal motility disorder

DOI：

10.7507/1007-9424.201907102

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the current research progress on the changes of enteric glial cells (EGCs) in intestinal motility disorders and its possible molecular mechanisms in regulating intestinal motility.Method The literatures related to the EGCs and intestinal dysmotility were collected and analyzed.Results The EGCs were involved in the occurrence and development of intestinal motility disorders, and there were abnormalities in the quantity, receptor, and phenotype in the different dysmotility diseases such as the postoperative ileus, Hirschsprung disease, inflammatory bowel disease, diabetes and so on. It could sense the neuronal signals and communicate with the enteric neurons via Ca²⁺ response and connexin-43 to affect the intestinal motility.Conclusion Study of role and mechanism of EGCs in intestinal motor dysfunction is helpful to discovery new targets for treatment of these diseases.

Citation： LI Na, LI Yansong, CHENG Bo, YUAN Wei, WANG Qiang, LI Shuang. Research progress on enteric glial cells under intestinal motility disorder. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(3): 363-367. doi: 10.7507/1007-9424.201907102 Copy

1.	Grubišić V, Gulbransen BD. Enteric glia: the most alimentary of all glia. J Physiol, 2017, 595(2): 557-570.
2.	Grubišić V, Perez-Medina AL, Fried DE, 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, 2019, 317(3): G314-G332.
3.	Meir M, Burkard N, Ungewiß H, et al. Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease. J Clin Invest, 2019, 129(7): 2824-2840.
4.	McMenamin CA, Clyburn C, Browning KN. High-fat diet during the perinatal period induces loss of myenteric nitrergic neurons and increases enteric glial density, prior to the development of obesity. Neuroscience, 2018, 393: 369-380.
5.	Langness S, Kojima M, Coimbra R, et al. Enteric glia cells are critical to limiting the intestinal inflammatory response after injury. Am J Physiol Gastrointest Liver Physiol, 2017, 312(3): G274-G282.
6.	Grubišić V, Gulbransen BD. Enteric glial activity regulates secretomotor function in the mouse colon but does not acutely affect gut permeability. J Physiol, 2017, 595(11): 3409-3424.
7.	Rao M, Rastelli D, Dong L, et al. Enteric glia regulate gastrointestinal motility but are not required for maintenance of the epithelium in mice. Gastroenterology, 2017, 153(4): 1068-1081.
8.	Grubišić V, Verkhratsky A, Zorec R, et al. Enteric glia regulate gut motility in health and disease. Brain Res Bull, 2018, 136: 109-117.
9.	Rao M, Gershon MD. Enteric nervous system development: what could possibly go wrong? Nat Rev Neurosci, 2018, 19(9): 552-565.
10.	Szymanska K, Gonkowski S. Neurochemical characterization of the enteric neurons within the porcine jejunum in physiological conditions and under the influence of bisphenol A (BPA). Neurogastroenterol Motil, 2019, 31(6): e13580.
11.	Vergnolle N, Cirillo C. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology (Bethesda), 2018, 33(4): 269-280.
12.	Boesmans W, Lasrado R, Vanden Berghe P, et al. Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia, 2015, 63(2): 229-241.
13.	Luo P, Liu D, Li C, et al. Enteric glial cell activation protects enteric neurons from damage due to diabetes in part via the promotion of neurotrophic factor release. Neurogastroenterol Motil, 2018, 30(10): e13368.
14.	Jonscher R, Belkind-Gerson J. Concise review: cellular and molecular mechanisms of postnatal injury-induced enteric neurogenesis. Stem Cells, 2019, 37(9): 1136-1143.
15.	Aubé AC, Cabarrocas J, Bauer J, et al. Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption. Gut, 2006, 55(5): 630-637.
16.	Nasser Y, Fernandez E, Keenan CM, 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, 2006, 291(5): G912-G927.
17.	Tani G, Tomuschat C, O'Donnell AM, et al. Increased population of immature enteric glial cells in the resected proximal ganglionic bowel of Hirschsprung’s disease patients. J Surg Res, 2017, 218: 150-155.
18.	Qi R, Yang W, Chen J. Role of enteric glial cells in gastric motility in diabetic rats at different stages. J Huazhong Univ Sci Technolog Med Sci, 2013, 33(4): 496-500.
19.	Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil, 2014, 26(5): 611-624.
20.	Chen Y, Liu G, He F, et al. MicroRNA 375 modulates hyperglycemia-induced enteric glial cell apoptosis and diabetes-induced gastrointestinal dysfunction by targeting Pdk1 and repressing PI3K/Akt pathway. Sci Rep, 2018, 8(1): 12681.
21.	Bassotti G, Villanacci V, Maurer CA, et al. The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut, 2006, 55(1): 41-46.
22.	Fu M, Landreville S, Agapova OA, et al. Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction. J Clin Invest, 2013, 123(12): 5152-5164.
23.	Stoffels B, Hupa KJ, Snoek SA, et al. Postoperative ileus involves interleukin-1 receptor signaling in enteric glia. Gastroenterology, 2014, 146(1): 176-187.
24.	Brown IA, McClain JL, Watson RE, et al. Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. Cell Mol Gastroenterol Hepatol, 2016, 2(1): 77-91.
25.	Green CL, Ho W, Sharkey KA, et al. Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO. Am J Physiol Gastrointest Liver Physiol, 2004, 287(3): G706-G714.
26.	Gulbransen BD, Christofi FL. Are we close to targeting enteric glia in gastrointestinal diseases and motility disorders? Gastroenterology, 2018, 155(2): 245-251.
27.	Ochoa-Cortes F, Turco F, Linan-Rico A, et al. Enteric glial cells: A new frontier in neurogastroenterology and clinical target for inflammatory bowel diseases. Inflamm Bowel Dis, 2016, 22(2): 433-449.
28.	Steinkamp M, Gundel H, Schulte N, et al. GDNF protects enteric glia from apoptosis: evidence for an autocrine loop. BMC Gastroenterol, 2012, 12: 6.
29.	Turco F, Sarnelli G, Cirillo C, et al. Enteroglial-derived S100B protein integrates bacteria-induced Toll-like receptor signalling in human enteric glial cells. Gut, 2014, 63(1): 105-115.
30.	Liñán-Rico A, Turco F, Ochoa-Cortes F, 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, 2016, 22(8): 1812-1834.
31.	Clairembault T, Leclair-Visonneau L, Neunlist M, et al. Enteric glial cells: new players in Parkinson’s disease? Mov Disord, 2015, 30(4): 494-498.
32.	Clairembault T, Kamphuis W, Leclair-Visonneau L, et al. Enteric GFAP expression and phosphorylation in Parkinson's disease. J Neurochem, 2014, 130(6): 805-815.
33.	McClain JL, Fried DE, Gulbransen BD. Agonist-evoked Ca²⁺ signaling in enteric glia drives neural programs that regulate intestinal motility in mice. Cell Mol Gastroenterol Hepatol, 2015, 1(6): 631-645.
34.	Boesmans W, Cirillo C, Van den Abbeel V, et al. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol Motil, 2013, 25(2): e151-e160.
35.	Boesmans W, Martens MA, Weltens N, et al. Imaging neuron-glia interactions in the enteric nervous system. Front Cell Neurosci, 2013, 7: 183.
36.	Gomes P, Chevalier J, Boesmans W, et al. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice. Neurogastroenterol Motil, 2009, 21(8): 870-862.
37.	Gulbransen BD, Sharkey KA. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology, 2009, 136(4): 1349-1358.
38.	Fung C, Boesmans W, Cirillo C, et al. VPAC receptor subtypes tune purinergic neuron-to-glia communication in the murine submucosal plexus. Front Cell Neurosci, 2017, 11: 118.
39.	Broadhead MJ, Bayguinov PO, Okamoto T, et al. Ca²⁺ transients in myenteric glial cells during the colonic migrating motor complex in the isolated murine large intestine. J Physiol, 2012, 590(2): 335-350.
40.	Wang GD, Wang XY, Liu S, et al. β-nicotinamide adenine dinucleotide acts at prejunctional adenosine A1 receptors to suppress inhibitory musculomotor neurotransmission in guinea pig colon and human jejunum. Am J Physiol Gastrointest Liver Physiol, 2015, 308(11): G955-G963.
41.	Nasser Y, Keenan CM, Ma AC, et al. Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation. Glia, 2007, 55(8): 859-872.
42.	von Boyen GB, Steinkamp M, Adler G, et al. Glutamate receptor subunit expression in primary enteric glia cultures. J Recept Signal Transduct Res, 2006, 26(4): 329-336.
43.	Nasser Y, Ho W, Sharkey KA. Distribution of adrenergic receptors in the enteric nervous system of the guinea pig, mouse, and rat. J Comp Neurol, 2006, 495(5): 529-553.
44.	Okamoto T, Barton MJ, Hennig GW, et al. Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil, 2014, 26(4): 556-570.
45.	Delvalle NM, Fried DE, Rivera-Lopez G, et al. Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol, 2018, 315(4): G473-G483.
46.	Gulbransen BD, Bashashati M, Hirota SA, et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med, 2012, 18(4): 600-604.
47.	McClain J, Grubišić V, Fried D, et al. Ca²⁺ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice. Gastroenterology, 2014, 146(2): 497-507.
48.	Gabella G. Fine structure of the myenteric plexus in the guinea-pig ileum. J Anat, 1972, 111(Pt 1): 69-97.
49.	Boesmans W, Hao MM, Fung C, et al. Structurally defined signaling in neuro-glia units in the enteric nervous system. Glia, 2019, 67(6): 1167-1178.
50.	Grubišić V, Parpura V. Two modes of enteric gliotransmission differentially affect gut physiology. Glia, 2017, 65(5): 699-711.

1. Grubišić V, Gulbransen BD. Enteric glia: the most alimentary of all glia. J Physiol, 2017, 595(2): 557-570.
2. Grubišić V, Perez-Medina AL, Fried DE, 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, 2019, 317(3): G314-G332.
3. Meir M, Burkard N, Ungewiß H, et al. Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease. J Clin Invest, 2019, 129(7): 2824-2840.
4. McMenamin CA, Clyburn C, Browning KN. High-fat diet during the perinatal period induces loss of myenteric nitrergic neurons and increases enteric glial density, prior to the development of obesity. Neuroscience, 2018, 393: 369-380.
5. Langness S, Kojima M, Coimbra R, et al. Enteric glia cells are critical to limiting the intestinal inflammatory response after injury. Am J Physiol Gastrointest Liver Physiol, 2017, 312(3): G274-G282.
6. Grubišić V, Gulbransen BD. Enteric glial activity regulates secretomotor function in the mouse colon but does not acutely affect gut permeability. J Physiol, 2017, 595(11): 3409-3424.
7. Rao M, Rastelli D, Dong L, et al. Enteric glia regulate gastrointestinal motility but are not required for maintenance of the epithelium in mice. Gastroenterology, 2017, 153(4): 1068-1081.
8. Grubišić V, Verkhratsky A, Zorec R, et al. Enteric glia regulate gut motility in health and disease. Brain Res Bull, 2018, 136: 109-117.
9. Rao M, Gershon MD. Enteric nervous system development: what could possibly go wrong? Nat Rev Neurosci, 2018, 19(9): 552-565.
10. Szymanska K, Gonkowski S. Neurochemical characterization of the enteric neurons within the porcine jejunum in physiological conditions and under the influence of bisphenol A (BPA). Neurogastroenterol Motil, 2019, 31(6): e13580.
11. Vergnolle N, Cirillo C. Neurons and glia in the enteric nervous system and epithelial barrier function. Physiology (Bethesda), 2018, 33(4): 269-280.
12. Boesmans W, Lasrado R, Vanden Berghe P, et al. Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia, 2015, 63(2): 229-241.
13. Luo P, Liu D, Li C, et al. Enteric glial cell activation protects enteric neurons from damage due to diabetes in part via the promotion of neurotrophic factor release. Neurogastroenterol Motil, 2018, 30(10): e13368.
14. Jonscher R, Belkind-Gerson J. Concise review: cellular and molecular mechanisms of postnatal injury-induced enteric neurogenesis. Stem Cells, 2019, 37(9): 1136-1143.
15. Aubé AC, Cabarrocas J, Bauer J, et al. Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption. Gut, 2006, 55(5): 630-637.
16. Nasser Y, Fernandez E, Keenan CM, 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, 2006, 291(5): G912-G927.
17. Tani G, Tomuschat C, O'Donnell AM, et al. Increased population of immature enteric glial cells in the resected proximal ganglionic bowel of Hirschsprung’s disease patients. J Surg Res, 2017, 218: 150-155.
18. Qi R, Yang W, Chen J. Role of enteric glial cells in gastric motility in diabetic rats at different stages. J Huazhong Univ Sci Technolog Med Sci, 2013, 33(4): 496-500.
19. Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil, 2014, 26(5): 611-624.
20. Chen Y, Liu G, He F, et al. MicroRNA 375 modulates hyperglycemia-induced enteric glial cell apoptosis and diabetes-induced gastrointestinal dysfunction by targeting Pdk1 and repressing PI3K/Akt pathway. Sci Rep, 2018, 8(1): 12681.
21. Bassotti G, Villanacci V, Maurer CA, et al. The role of glial cells and apoptosis of enteric neurones in the neuropathology of intractable slow transit constipation. Gut, 2006, 55(1): 41-46.
22. Fu M, Landreville S, Agapova OA, et al. Retinoblastoma protein prevents enteric nervous system defects and intestinal pseudo-obstruction. J Clin Invest, 2013, 123(12): 5152-5164.
23. Stoffels B, Hupa KJ, Snoek SA, et al. Postoperative ileus involves interleukin-1 receptor signaling in enteric glia. Gastroenterology, 2014, 146(1): 176-187.
24. Brown IA, McClain JL, Watson RE, et al. Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. Cell Mol Gastroenterol Hepatol, 2016, 2(1): 77-91.
25. Green CL, Ho W, Sharkey KA, et al. Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO. Am J Physiol Gastrointest Liver Physiol, 2004, 287(3): G706-G714.
26. Gulbransen BD, Christofi FL. Are we close to targeting enteric glia in gastrointestinal diseases and motility disorders? Gastroenterology, 2018, 155(2): 245-251.
27. Ochoa-Cortes F, Turco F, Linan-Rico A, et al. Enteric glial cells: A new frontier in neurogastroenterology and clinical target for inflammatory bowel diseases. Inflamm Bowel Dis, 2016, 22(2): 433-449.
28. Steinkamp M, Gundel H, Schulte N, et al. GDNF protects enteric glia from apoptosis: evidence for an autocrine loop. BMC Gastroenterol, 2012, 12: 6.
29. Turco F, Sarnelli G, Cirillo C, et al. Enteroglial-derived S100B protein integrates bacteria-induced Toll-like receptor signalling in human enteric glial cells. Gut, 2014, 63(1): 105-115.
30. Liñán-Rico A, Turco F, Ochoa-Cortes F, 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, 2016, 22(8): 1812-1834.
31. Clairembault T, Leclair-Visonneau L, Neunlist M, et al. Enteric glial cells: new players in Parkinson’s disease? Mov Disord, 2015, 30(4): 494-498.
32. Clairembault T, Kamphuis W, Leclair-Visonneau L, et al. Enteric GFAP expression and phosphorylation in Parkinson's disease. J Neurochem, 2014, 130(6): 805-815.
33. McClain JL, Fried DE, Gulbransen BD. Agonist-evoked Ca²⁺ signaling in enteric glia drives neural programs that regulate intestinal motility in mice. Cell Mol Gastroenterol Hepatol, 2015, 1(6): 631-645.
34. Boesmans W, Cirillo C, Van den Abbeel V, et al. Neurotransmitters involved in fast excitatory neurotransmission directly activate enteric glial cells. Neurogastroenterol Motil, 2013, 25(2): e151-e160.
35. Boesmans W, Martens MA, Weltens N, et al. Imaging neuron-glia interactions in the enteric nervous system. Front Cell Neurosci, 2013, 7: 183.
36. Gomes P, Chevalier J, Boesmans W, et al. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice. Neurogastroenterol Motil, 2009, 21(8): 870-862.
37. Gulbransen BD, Sharkey KA. Purinergic neuron-to-glia signaling in the enteric nervous system. Gastroenterology, 2009, 136(4): 1349-1358.
38. Fung C, Boesmans W, Cirillo C, et al. VPAC receptor subtypes tune purinergic neuron-to-glia communication in the murine submucosal plexus. Front Cell Neurosci, 2017, 11: 118.
39. Broadhead MJ, Bayguinov PO, Okamoto T, et al. Ca²⁺ transients in myenteric glial cells during the colonic migrating motor complex in the isolated murine large intestine. J Physiol, 2012, 590(2): 335-350.
40. Wang GD, Wang XY, Liu S, et al. β-nicotinamide adenine dinucleotide acts at prejunctional adenosine A1 receptors to suppress inhibitory musculomotor neurotransmission in guinea pig colon and human jejunum. Am J Physiol Gastrointest Liver Physiol, 2015, 308(11): G955-G963.
41. Nasser Y, Keenan CM, Ma AC, et al. Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation. Glia, 2007, 55(8): 859-872.
42. von Boyen GB, Steinkamp M, Adler G, et al. Glutamate receptor subunit expression in primary enteric glia cultures. J Recept Signal Transduct Res, 2006, 26(4): 329-336.
43. Nasser Y, Ho W, Sharkey KA. Distribution of adrenergic receptors in the enteric nervous system of the guinea pig, mouse, and rat. J Comp Neurol, 2006, 495(5): 529-553.
44. Okamoto T, Barton MJ, Hennig GW, et al. Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil, 2014, 26(4): 556-570.
45. Delvalle NM, Fried DE, Rivera-Lopez G, et al. Cholinergic activation of enteric glia is a physiological mechanism that contributes to the regulation of gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol, 2018, 315(4): G473-G483.
46. Gulbransen BD, Bashashati M, Hirota SA, et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med, 2012, 18(4): 600-604.
47. McClain J, Grubišić V, Fried D, et al. Ca²⁺ responses in enteric glia are mediated by connexin-43 hemichannels and modulate colonic transit in mice. Gastroenterology, 2014, 146(2): 497-507.
48. Gabella G. Fine structure of the myenteric plexus in the guinea-pig ileum. J Anat, 1972, 111(Pt 1): 69-97.
49. Boesmans W, Hao MM, Fung C, et al. Structurally defined signaling in neuro-glia units in the enteric nervous system. Glia, 2019, 67(6): 1167-1178.
50. Grubišić V, Parpura V. Two modes of enteric gliotransmission differentially affect gut physiology. Glia, 2017, 65(5): 699-711.

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Research progress on enteric glial cells under intestinal motility disorder

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