Targeting Enteric Neurons and Plexitis for the Management of Inflammatory Bowel Disease

Rhian       Stavely; Raquel       Abalo; Kulmira       Nurgali
doi:10.2174/1389450121666200516173242
Abstract

Ulcerative colitis (UC) and Crohn’s disease (CD) are pathological conditions with an unknown aetiology that are characterised by severe inflammation of the intestinal tract and collectively referred to as inflammatory bowel disease (IBD). Current treatments are mostly ineffective due to their limited efficacy or toxicity, necessitating surgical resection of the affected bowel. The management of IBD is hindered by a lack of prognostic markers for clinical inflammatory relapse. Intestinal inflammation associates with the infiltration of immune cells (leukocytes) into, or surrounding the neuronal ganglia of the enteric nervous system (ENS) termed plexitis or ganglionitis. Histological observation of plexitis in unaffected intestinal regions is emerging as a vital predictive marker for IBD relapses. Plexitis associates with alterations to the structure, cellular composition, molecular expression and electrophysiological function of enteric neurons. Moreover, plexitis often occurs before the onset of gross clinical inflammation, which may indicate that plexitis can contribute to the progression of intestinal inflammation. In this review, the bilateral relationships between the ENS and inflammation are discussed. These include the effects and mechanisms of inflammation-induced enteric neuronal loss and plasticity. Additionally, the role of enteric neurons in preventing antigenic/pathogenic insult and immunomodulation is explored. While all current treatments target the inflammatory pathology of IBD, interventions that protect the ENS may offer an alternative avenue for therapeutic intervention.
Keywords: Enteric nervous system, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, neuro-immune, inflammation, plexitis, neuroprotection.
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Graphical Abstract

[1] 
Freeman HJ. Granuloma-positive Crohn’s disease. Can J Gastroenterol  2007; 21(9): 583-7.
[http://dx.doi.org/10.1155/2007/917649 ] [PMID:  17853953] 
[2] 
Singh UP, Singh NP, Singh B, et al. Stem cells as potential therapeutic targets for inflammatory bowel disease. Front Biosci (Schol Ed)  2010; 2: 993-1008.
[http://dx.doi.org/10.2741/s115 ] [PMID:  20515838] 
[3] 
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet  2012; 380(9853): 1590-605.
[http://dx.doi.org/10.1016/S0140-6736(12)60026-9 ] [PMID:  22914295] 
[4] 
Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest  2007; 117(3): 514-21.
[http://dx.doi.org/10.1172/JCI30587 ] [PMID:  17332878] 
[5] 
Landgren AM, Landgren O, Gridley G, Dores GM, Linet MS, Morton LM. Autoimmune disease and subsequent risk of developing alimentary tract cancers among 4.5 million US male veterans. Cancer  2011; 117(6): 1163-71.
[http://dx.doi.org/10.1002/cncr.25524 ] [PMID:  21381009] 
[6] 
Rungoe C, Basit S, Ranthe MF, Wohlfahrt J, Langholz E, Jess T. Risk of ischaemic heart disease in patients with inflammatory bowel disease: a nationwide Danish cohort study. Gut  2013; 62(5): 689-94.
[http://dx.doi.org/10.1136/gutjnl-2012-303285 ] [PMID:  22961677] 
[7] 
de Ridder L, Turner D, Wilson DC, et al. Malignancy and mortality in pediatric patients with inflammatory bowel disease: a multinational study from the porto pediatric IBD group. Inflamm Bowel Dis  2014; 20(2): 291-300.
[http://dx.doi.org/10.1097/01.MIB.0000439066.69340.3c ] [PMID:  24374875] 
[8] 
Jussila A, Virta LJ, Pukkala E, Färkkilä MA. Mortality and causes of death in patients with inflammatory bowel disease: a nationwide register study in Finland. J Crohn’s Colitis  2014; 8(9): 1088-96.
[http://dx.doi.org/10.1016/j.crohns.2014.02.015 ] [PMID:  24630486] 
[9] 
Pithadia AB, Jain S. Treatment of inflammatory bowel disease (IBD). Pharmacol Rep  2011; 63(3): 629-42.
[http://dx.doi.org/10.1016/S1734-1140(11)70575-8 ] [PMID:  21857074] 
[10] 
Chernajovsky Y, Robbins PD. Gene Therapy for autoimmune and inflammatory diseases. Springer Basel 2010.
[http://dx.doi.org/10.1007/978-3-0346-0165-8] 
[11] 
Lemmens B, de Buck van Overstraeten A, Arijs I, et al. Submucosal plexitis as a predictive factor for postoperative endoscopic recurrence in patients with crohn’s disease undergoing a resection with ileocolonic anastomosis: results from a prospective single-centre study. J Crohn’s Colitis  2017; 11(2): 212-20.
[http://dx.doi.org/10.1093/ecco-jcc/jjw135 ] [PMID:  27466173] 
[12] 
Gklavas A, Dellaportas D, Papaconstantinou I. Risk factors for postoperative recurrence of Crohn’s disease with emphasis on surgical predictors. Ann Gastroenterol  2017; 30(6): 598-612.
[http://dx.doi.org/10.20524/aog.2017.0195 ] [PMID:  29118554] 
[13] 
Ferrante M, de Hertogh G, Hlavaty T, et al. The value of myenteric plexitis to predict early postoperative Crohn’s disease recurrence. Gastroenterology  2006; 130(6): 1595-606.
[http://dx.doi.org/10.1053/j.gastro.2006.02.025 ] [PMID:  16697723] 
[14] 
Ng SC, Lied GA, Kamm MA, Sandhu F, Guenther T, Arebi N. Predictive value and clinical significance of myenteric plexitis in Crohn’s disease. Inflamm Bowel Dis  2009; 15(10): 1499-507.
[http://dx.doi.org/10.1002/ibd.20932 ] [PMID:  19338051] 
[15] 
Sokol H, Polin V, Lavergne-Slove A, et al. Plexitis as a predictive factor of early postoperative clinical recurrence in Crohn’s disease. Gut  2009; 58(9): 1218-25.
[http://dx.doi.org/10.1136/gut.2009.177782 ] [PMID:  19625280] 
[16] 
Bressenot A, Chevaux JB, Williet N, et al. Submucosal plexitis as a predictor of postoperative surgical recurrence in Crohn’s disease. Inflamm Bowel Dis  2013; 19(8): 1654-61.
[http://dx.doi.org/10.1097/MIB.0b013e318281f336 ] [PMID:  23751396] 
[17] 
Misteli H, Koh CE, Wang LM, Mortensen NJ, George B, Guy R. Myenteric plexitis at the proximal resection margin is a predictive marker for surgical recurrence of ileocaecal Crohn’s disease. Colorectal Dis  2015; 17(4): 304-10.
[http://dx.doi.org/10.1111/codi.12896 ] [PMID:  25581299] 
[18] 
Decousus S, Boucher A-L, Joubert J, et al. Myenteric plexitis is a risk factor for endoscopic and clinical postoperative recurrence after ileocolonic resection in Crohn’s disease. Dig Liver Dis  2016; 48(7): 753-8.
[http://dx.doi.org/10.1016/j.dld.2016.02.023 ] [PMID:  27005857] 
[19] 
Milassin Á, Sejben A, Tiszlavicz L, et al. Analysis of risk factors - especially different types of plexitis - for postoperative relapse in Crohn’s disease. World J Gastrointest Surg  2017; 9(7): 167-73.
[http://dx.doi.org/10.4240/wjgs.v9.i7.167 ] [PMID:  28824749] 
[20] 
Drokhlyansky E, Smillie CS, Van Wittenberghe N, et al. The enteric nervous system of the human and mouse colon at a single-cell resolution. bioRxiv 2019. 746743
[21] 
Furness JB. The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol  2012; 9(5): 286-94.
[http://dx.doi.org/10.1038/nrgastro.2012.32 ] [PMID:  22392290] 
[22] 
Smolilo DJ, Costa M, Hibberd TJ, Wattchow DA, Spencer NJ. Morphological evidence for novel enteric neuronal circuitry in guinea pig distal colon. J Comp Neurol  2018; 526(10): 1662-72.
[http://dx.doi.org/10.1002/cne.24436 ] [PMID:  29574743] 
[23] 
Costa M, Brookes SH. Architecture of enteric neural circuits involved in intestinal motility. Eur Rev Med Pharmacol Sci  2008; 12(Suppl. 1): 3-19.
[PMID:  18924440] 
[24] 
Gross ER, Gershon MD, Margolis KG, Gertsberg ZV, Li Z, Cowles RA. Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology  2012; 143(2): 408-17.e2.
[http://dx.doi.org/10.1053/j.gastro.2012.05.007 ] [PMID:  22609381] 
[25] 
Spencer NJ, Hennig GW, Smith TK. A rhythmic motor pattern activated by circumferential stretch in guinea-pig distal colon. J Physiol  2002; 545(2): 629-48.
[http://dx.doi.org/10.1113/jphysiol.2002.028647 ] [PMID:  12456839] 
[26] 
Spencer NJ, Hennig GW, Smith TK. Stretch-activated neuronal pathways to longitudinal and circular muscle in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol  2003; 284(2): G231-41.
[http://dx.doi.org/10.1152/ajpgi.00291.2002 ] [PMID:  12388186] 
[27] 
Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst  2000; 81(1-3): 87-96.
[http://dx.doi.org/10.1016/S0165-1838(00)00127-2 ] [PMID:  10869706] 
[28] 
Iino S, Ward SM, Sanders KM. Interstitial cells of Cajal are functionally innervated by excitatory motor neurones in the murine intestine. J Physiol  2004; 556(Pt 2): 521-30.
[http://dx.doi.org/10.1113/jphysiol.2003.058792 ] [PMID:  14754997] 
[29] 
Sanders KM, Koh SD, Ward SM. Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol  2006; 68: 307-43.
[http://dx.doi.org/10.1146/annurev.physiol.68.040504.094718 ] [PMID:  16460275] 
[30] 
Iino S, Horiguchi K, Nojyo Y. Interstitial cells of Cajal are innervated by nitrergic nerves and express nitric oxide-sensitive guanylate cyclase in the guinea-pig gastrointestinal tract. Neuroscience  2008; 152(2): 437-48.
[http://dx.doi.org/10.1016/j.neuroscience.2007.12.044 ] [PMID:  18280665] 
[31] 
Sanders KM, Ward SM, Koh SD. Interstitial cells: regulators of smooth muscle function. Physiol Rev  2014; 94(3): 859-907.
[http://dx.doi.org/10.1152/physrev.00037.2013 ] [PMID:  24987007] 
[32] 
Mawe GM. Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon. J Clin Invest  2015; 125(3): 949-55.
[http://dx.doi.org/10.1172/JCI76306 ] [PMID:  25729851] 
[33] 
Spear ET, Mawe GM. Enteric neuroplasticity and dysmotility in inflammatory disease: key players and possible therapeutic targets. Am J Physiol Gastrointest Liver Physiol  2019; 317(6): G853-61.
[http://dx.doi.org/10.1152/ajpgi.00206.2019 ] [PMID:  31604034] 
[34] 
Tsuchida Y, Hatao F, Fujisawa M, et al. Neuronal stimulation with 5-hydroxytryptamine 4 receptor induces anti-inflammatory actions via α7nACh receptors on muscularis macrophages associated with postoperative ileus. Gut  2011; 60(5): 638-47.
[http://dx.doi.org/10.1136/gut.2010.227546 ] [PMID:  21115544] 
[35] 
Matteoli G, Gomez-Pinilla PJ, Nemethova A, et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut  2014; 63(6): 938-48.
[http://dx.doi.org/10.1136/gutjnl-2013-304676 ] [PMID:  23929694] 
[36] 
Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune interactions in the gut and their significance for intestinal immunity. Cells  2019; 8(7): 670.
[http://dx.doi.org/10.3390/cells8070670 ] [PMID:  31269754] 
[37] 
Pochard C, Coquenlorge S, Freyssinet M, et al. The multiple faces of inflammatory enteric glial cells: is Crohn’s disease a gliopathy? Am J Physiol Gastrointest Liver Physiol  2018; 315(1): G1-G11.
[http://dx.doi.org/10.1152/ajpgi.00016.2018 ] [PMID:  29517926] 
[38] 
Poli E, Lazzaretti M, Grandi D, Pozzoli C, Coruzzi G. Morphological and functional alterations of the myenteric plexus in rats with TNBS-induced colitis. Neurochem Res  2001; 26(8-9): 1085-93.
[http://dx.doi.org/10.1023/A:1012313424144 ] [PMID:  11699935] 
[39] 
Hansen MB. The enteric nervous system III: a target for pharmacological treatment. Pharmacol Toxicol  2003; 93(1): 1-13.
[http://dx.doi.org/10.1034/j.1600-0773.2003.930101.x ] [PMID:  12828568] 
[40] 
Lomax AE, Fernández E, Sharkey KA. Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol Motil  2005; 17(1): 4-15.
[http://dx.doi.org/10.1111/j.1365-2982.2004.00607.x ] [PMID:  15670258] 
[41] 
De Giorgio R, Barbara G, Furness JB, Tonini M. Novel therapeutic targets for enteric nervous system disorders. Trends Pharmacol Sci  2007; 28(9): 473-81.
[http://dx.doi.org/10.1016/j.tips.2007.08.003 ] [PMID:  17764756] 
[42] 
Lakhan SE, Kirchgessner A. Neuroinflammation in inflammatory bowel disease. J Neuroinflammation  2010; 7: 37.
[http://dx.doi.org/10.1186/1742-2094-7-37 ] [PMID:  20615234] 
[43] 
Bishop AE, Polak JM, Bryant MG, Bloom SR, Hamilton S. Abnormalities of vasoactive intestinal polypeptide-containing nerves in Crohn’s disease. Gastroenterology  1980; 79(5 Pt 1): 853-60.
[http://dx.doi.org/10.1016/0016-5085(80)90441-2 ] [PMID:  7419008] 
[44] 
Bernardini N, Segnani C, Ippolito C, et al. Immunohistochemical analysis of myenteric ganglia and interstitial cells of Cajal in ulcerative colitis. J Cell Mol Med  2012; 16(2): 318-27.
[http://dx.doi.org/10.1111/j.1582-4934.2011.01298.x ] [PMID:  21426484] 
[45] 
Boyer L, Ghoreishi M, Templeman V, et al. Myenteric plexus injury and apoptosis in experimental colitis. Auton Neurosci  2005; 117(1): 41-53.
[http://dx.doi.org/10.1016/j.autneu.2004.10.006 ] [PMID:  15620569] 
[46] 
Lin A, Lourenssen S, Stanzel RDP, Blennerhassett MG. Selective loss of NGF-sensitive neurons following experimental colitis. Exp Neurol  2005; 191(2): 337-43.
[http://dx.doi.org/10.1016/j.expneurol.2004.10.003 ] [PMID:  15649490] 
[47] 
Linden DR, Couvrette JM, Ciolino A, et al. Indiscriminate loss of myenteric neurones in the TNBS-inflamed guinea-pig distal colon. Neurogastroenterol Motil  2005; 17(5): 751-60.
[http://dx.doi.org/10.1111/j.1365-2982.2005.00703.x ] [PMID:  16185315] 
[48] 
Sarnelli G, De Giorgio R, Gentile F, et al. Myenteric neuronal loss in rats with experimental colitis: role of tissue transglutaminase-induced apoptosis. Dig Liver Dis  2009; 41(3): 185-93.
[http://dx.doi.org/10.1016/j.dld.2008.06.004 ] [PMID:  18635410] 
[49] 
Nurgali K, Qu Z, Hunne B, Thacker M, Pontell L, Furness JB. Morphological and functional changes in guinea-pig neurons projecting to the ileal mucosa at early stages after inflammatory damage. J Physiol  2011; 589(Pt 2): 325-39.
[http://dx.doi.org/10.1113/jphysiol.2010.197707 ] [PMID:  21098001] 
[50] 
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): 600-4.
[http://dx.doi.org/10.1038/nm.2679 ] [PMID:  22426419] 
[51] 
Bhave S, Arciero E, Baker C, et al. Enteric neuronal cell therapy reverses architectural changes in a novel diphtheria toxin-mediated model of colonic aganglionosis. Sci Rep  2019; 9(1): 18756.
[http://dx.doi.org/10.1038/s41598-019-55128-4 ] [PMID:  31822721] 
[52] 
Yu H, Cao N-J, Pan W-K, et al. Correlation of spatio-temporal characteristics of intestinal inflammation with IL-17 in a rat model of hypoganglionosis. Biochem Biophys Res Commun  2018; 506(4): 956-61.
[http://dx.doi.org/10.1016/j.bbrc.2018.10.129 ] [PMID:  30401564] 
[53] 
Schneider J, Jehle EC, Starlinger MJ, et al. Neurotransmitter coding of enteric neurones in the submucous plexus is changed in non-inflamed rectum of patients with Crohn’s disease. Neurogastroenterol Motil  2001; 13(3): 255-64.
[http://dx.doi.org/10.1046/j.1365-2982.2001.00265.x ] [PMID:  11437988] 
[54] 
Neunlist M, Aubert P, Toquet C, et al. Changes in chemical coding of myenteric neurones in ulcerative colitis. Gut  2003; 52(1): 84-90.
[http://dx.doi.org/10.1136/gut.52.1.84 ] [PMID:  12477766] 
[55] 
Boyer L, Sidpra D, Jevon G, Buchan AM, Jacobson K. Differential responses of VIPergic and nitrergic neurons in paediatric patients with Crohn’s disease. Auton Neurosci  2007; 134(1-2): 106-14.
[http://dx.doi.org/10.1016/j.autneu.2007.03.001 ] [PMID:  17466601] 
[56] 
Winston JH, Li Q, Sarna SK. Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn’s colitis and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol  2013; 305(4): G295-302.
[http://dx.doi.org/10.1152/ajpgi.00052.2013 ] [PMID:  23681475] 
[57] 
de Fontgalland D, Brookes SJ, Gibbins I, Sia TC, Wattchow DA. The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in ulcerative colitis and Crohn’s disease. Neurogastroenterol Motil  2014; 26(5): 731-44.
[http://dx.doi.org/10.1111/nmo.12327 ] [PMID:  24597665] 
[58] 
Arnold SJ, Facer P, Yiangou Y, et al. Decreased potassium channel IK1 and its regulator neurotrophin-3 (NT-3) in inflamed human bowel. Neuroreport  2003; 14(2): 191-5.
[http://dx.doi.org/10.1097/00001756-200302100-00006 ] [PMID:  12598727] 
[59] 
Linden DR, Sharkey KA, Mawe GM. Enhanced excitability of myenteric AH neurones in the inflamed guinea-pig distal colon. J Physiol  2003; 547(Pt 2): 589-601.
[http://dx.doi.org/10.1113/jphysiol.2002.035147 ] [PMID:  12562910] 
[60] 
Nurgali K, Nguyen TV, Matsuyama H, Thacker M, Robbins HL, Furness JB. Phenotypic changes of morphologically identified guinea-pig myenteric neurons following intestinal inflammation. J Physiol  2007; 583(Pt 2): 593-609.
[http://dx.doi.org/10.1113/jphysiol.2007.135947 ] [PMID:  17615102] 
[61] 
Hons IM, Burda JE, Grider JR, Mawe GM, Sharkey KA. Alterations to enteric neural signaling underlie secretory abnormalities of the ileum in experimental colitis in the guinea pig. Am J Physiol Gastrointest Liver Physiol  2009; 296(4): G717-26.
[http://dx.doi.org/10.1152/ajpgi.90472.2008 ] [PMID:  19221017] 
[62] 
Nurgali K, Nguyen TV, Thacker M, Pontell L, Furness JB. Slow synaptic transmission in myenteric AH neurons from the inflamed guinea pig ileum. Am J Physiol Gastrointest Liver Physiol  2009; 297(3): G582-93.
[http://dx.doi.org/10.1152/ajpgi.00026.2009 ] [PMID:  19556360] 
[63] 
Krauter EM, Strong DS, Brooks EM, Linden DR, Sharkey KA, Mawe GM. 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  2007; 19(12): 990-1000.
[http://dx.doi.org/10.1111/j.1365-2982.2007.00986.x ] [PMID:  17973636] 
[64] 
Lomax AE, O’Hara JR, Hyland NP, Mawe GM, Sharkey KA. Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis. Am J Physiol Gastrointest Liver Physiol  2007; 292(2): G482-91.
[http://dx.doi.org/10.1152/ajpgi.00355.2006 ] [PMID:  17008554] 
[65] 
Mawe GM, Sharkey KA. The intrinsic reflex circuitry of the inflamed colon. Adv Exp Med Biol  2016; 891: 153-7.
[http://dx.doi.org/10.1007/978-3-319-27592-5_15 ] [PMID:  27379643] 
[66] 
Sharkey KA, Kroese AB. Consequences of intestinal inflammation on the enteric nervous system: neuronal activation induced by inflammatory mediators. Anat Rec  2001; 262(1): 79-90.
[http://dx.doi.org/10.1002/1097-0185(20010101)262:1<79::AID AR1013>3.0.CO;2-K ] [PMID:  11146431] 
[67] 
Schemann M, Michel K, Ceregrzyn M, Zeller F, Seidl S, Bischoff SC. Human mast cell mediator cocktail excites neurons in human and guinea-pig enteric nervous system. Neurogastroenterol Motil  2005; 17(2): 281-9.
[http://dx.doi.org/10.1111/j.1365-2982.2004.00591.x ] [PMID:  15787948] 
[68] 
Kraneveld AD, Rijnierse A, Nijkamp FP, Garssen J. Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: future therapeutic targets. Eur J Pharmacol  2008; 585(2-3): 361-74.
[http://dx.doi.org/10.1016/j.ejphar.2008.02.095 ] [PMID:  18417115] 
[69] 
de Jonge WJ. The gut’s little brain in control of intestinal immunity. ISRN Gastroenterol 2013. 2013630159
[http://dx.doi.org/10.1155/2013/630159 ] [PMID:  23691339] 
[70] 
Tixier E, Galmiche JP, Neunlist M. Intestinal neuro-epithelial interactions modulate neuronal chemokines production. Biochem Biophys Res Commun  2006; 344(2): 554-61.
[http://dx.doi.org/10.1016/j.bbrc.2006.03.159 ] [PMID:  16620783] 
[71] 
Neunlist M, Van Landeghem L, Mahé MM, Derkinderen P, des Varannes SB, Rolli-Derkinderen M. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat Rev Gastroenterol Hepatol  2013; 10(2): 90-100.
[http://dx.doi.org/10.1038/nrgastro.2012.221 ] [PMID:  23165236] 
[72] 
Bedoui S, Kawamura N, Straub RH, Pabst R, Yamamura T, von Hörsten S. Relevance of neuropeptide Y for the neuroimmune crosstalk. J Neuroimmunol  2003; 134(1-2): 1-11.
[http://dx.doi.org/10.1016/S0165-5728(02)00424-1 ] [PMID:  12507767] 
[73] 
Sanovic S, Lamb DP, Blennerhassett MG. Damage to the enteric nervous system in experimental colitis. Am J Pathol  1999; 155(4): 1051-7.
[http://dx.doi.org/10.1016/S0002-9440(10)65207-8 ] [PMID:  10514387] 
[74] 
Kinoshita K, Horiguchi K, Fujisawa M, et al. Possible involvement of muscularis resident macrophages in impairment of interstitial cells of Cajal and myenteric nerve systems in rat models of TNBS-induced colitis. Histochem Cell Biol  2007; 127(1): 41-53.
[http://dx.doi.org/10.1007/s00418-006-0223-0 ] [PMID:  16871386] 
[75] 
Sayani FA, Keenan CM, Van Sickle MD, et al. The expression and role of fas ligand in intestinal inflammation. Neurogastroenterol Motil  2004; 16(1): 61-74.
[http://dx.doi.org/10.1046/j.1365-2982.2003.00457.x ] [PMID:  14764206] 
[76] 
Filippone RT, Robinson AM, Jovanovska V, et al. Targeting eotaxin-1 and CCR3 receptor alleviates enteric neuropathy and colonic dysfunction in TNBS-induced colitis in guinea pigs. Neurogastroenterol Motil  2018; 30(11) e13391
[http://dx.doi.org/10.1111/nmo.13391 ] [PMID:  29968270] 
[77] 
De Schepper S, Stakenborg N, Matteoli G, Verheijden S, Boeckxstaens GE. Muscularis macrophages: Key players in intestinal homeostasis and disease. Cell Immunol  2018; 330: 142-50.
[http://dx.doi.org/10.1016/j.cellimm.2017.12.009 ] [PMID:  29291892] 
[78] 
Muller PA, Koscsó B, Rajani GM, et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell  2014; 158(2): 300-13.
[http://dx.doi.org/10.1016/j.cell.2014.04.050 ] [PMID:  25036630] 
[79] 
Avetisyan M, Rood JE, Huerta Lopez S, et al. Muscularis macrophage development in the absence of an enteric nervous system. Proc Natl Acad Sci USA  2018; 115(18): 4696-701.
[http://dx.doi.org/10.1073/pnas.1802490115 ] [PMID:  29666241] 
[80] 
Kulkarni S, Micci M-A, Leser J, et al. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis. Proceedings of the National Academy
of Sciences 114, E3709-E3718 
[81] 
Meroni E, Stakenborg N, Viola MF, Boeckxstaens GE. Intestinal macrophages and their interaction with the enteric nervous system in health and inflammatory bowel disease. Acta Physiol (Oxf)  2019; 225(3) e13163
[http://dx.doi.org/10.1111/apha.13163 ] [PMID:  29998613] 
[82] 
Stavely R, Robinson AM, Miller S, Boyd R, Sakkal S, Nurgali K. Allogeneic guinea pig mesenchymal stem cells ameliorate neurological changes in experimental colitis. Stem Cell Res Ther  2015; 6: 263.
[http://dx.doi.org/10.1186/s13287-015-0254-3 ] [PMID:  26718461] 
[83] 
Stavely R, Robinson AM, Miller S, Boyd R, Sakkal S, Nurgali K. Human adult stem cells derived from adipose tissue and bone marrow attenuate enteric neuropathy in the guinea-pig model of acute colitis. Stem Cell Res Ther  2015; 6: 244.
[http://dx.doi.org/10.1186/s13287-015-0231-x ] [PMID:  26652292] 
[84] 
Rahman AA, Robinson AM, Brookes SJH, Eri R, Nurgali K. Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum. Cell Tissue Res  2016; 366(2): 285-99.
[http://dx.doi.org/10.1007/s00441-016-2465-z ] [PMID:  27477670] 
[85] 
Oehmichen M, Reifferscheid P. Intramural ganglion cell degeneration in inflammatory bowel disease. Digestion  1977; 15(6): 482-96.
[http://dx.doi.org/10.1159/000198039 ] [PMID:  913914] 
[86] 
Riemann JF, Schmidt H. Ultrastructural changes in the gut autonomic nervous system following laxative abuse and in other conditions. Scand J Gastroenterol Suppl  1982; 71: 111-24.
[PMID:  6176011] 
[87] 
Storsteen KA, Kernohan JW, Bargen JA. The myenteric plexus in chronic ulcerative colitis. Surg Gynecol Obstet  1953; 97(3): 335-43.
[PMID:  13090060] 
[88] 
Villanacci V, Bassotti G, Nascimbeni R, et al. Enteric nervous system abnormalities in inflammatory bowel diseases. Neurogastroenterol Motil  2008; 20(9): 1009-16.
[http://dx.doi.org/10.1111/j.1365-2982.2008.01146.x ] [PMID:  18492026] 
[89] 
Bassotti G, Villanacci V, Nascimbeni R, et al. Enteric neuroglial apoptosis in inflammatory bowel diseases. J Crohn’s Colitis  2009; 3(4): 264-70.
[http://dx.doi.org/10.1016/j.crohns.2009.06.004 ] [PMID:  21172285] 
[90] 
Martin JC, Boschetti G, Chang C, et al. Single-cell analysis of
Crohn’s disease lesions identifies a pathogenic cellular module
associated with resistance to anti-TNF therapy. bioRxiv 2018;
•••503102. 
[91] 
Martin JC, Chang C, Boschetti G, et al. Single-cell analysis of crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-tnf therapy. Cell  2019; 178(6): 1493-1508.e20.
[http://dx.doi.org/10.1016/j.cell.2019.08.008 ] [PMID:  31474370] 
[92] 
Godlewski J. 2010.Morphological changes in the enteric nervous system caused by carcinoma of the human large intestine 
[http://dx.doi.org/10.2478/v10042-010-0029-8] 
[93] 
Vera G, Castillo M, Cabezos PA, et al. 2011.Enteric neuropathy evoked by repeated cisplatin in the rat 
[http://dx.doi.org/10.1111/j.1365-2982.2011.01674.x] 
[94] 
McQuade RM, Carbone SE, Stojanovska V, et al. Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice. Br J Pharmacol  2016; 173(24): 3502-21.
[http://dx.doi.org/10.1111/bph.13646 ] [PMID:  27714760] 
[95] 
Vicentini GE, Fracaro L, de Souza SRG, Martins HA, Guarnier FA, Zanoni JN. Experimental cancer cachexia changes neuron numbers and peptide levels in the intestine: partial protective effects after dietary supplementation with l-glutamine. PLoS One  2016; 11(9) e0162998
[http://dx.doi.org/10.1371/journal.pone.0162998 ] [PMID:  27635657] 
[96] 
Bassotti G, Villanacci V, Fisogni S, Cadei M, Di Fabio F, Salerni B. Apoptotic phenomena are not a major cause of enteric neuronal loss in constipated patients with dementia. Neuropathology  2007; 27(1): 67-72.
[http://dx.doi.org/10.1111/j.1440-1789.2006.00740.x ] [PMID:  17319285] 
[97] 
Domènech A, Pasquinelli G, De Giorgio R, et al. Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNβ transgenic mice. Int J Exp Pathol  2011; 92(6): 400-12.
[http://dx.doi.org/10.1111/j.1365-2613.2011.00789.x ] [PMID:  22050417] 
[98] 
Uesaka T, Jain S, Yonemura S, Uchiyama Y, Milbrandt J, Enomoto H. Conditional ablation of GFRalpha1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung’s disease phenotype. Development  2007; 134(11): 2171-81.
[http://dx.doi.org/10.1242/dev.001388 ] [PMID:  17507417] 
[99] 
Venkataramana S, Lourenssen S, Miller KG, Blennerhassett MG. Early inflammatory damage to intestinal neurons occurs via inducible nitric oxide synthase. Neurobiol Dis  2015; 75: 40-52.
[http://dx.doi.org/10.1016/j.nbd.2014.12.014 ] [PMID:  25562655] 
[100] 
Yakovlev AG, Faden AI. Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies. NeuroRx  2004; 1(1): 5-16.
[http://dx.doi.org/10.1602/neurorx.1.1.5 ] [PMID:  15717003] 
[101] 
Belkind-Gerson J, Hotta R, Nagy N, et al. Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism. Inflamm Bowel Dis  2015; 21(4): 870-8.
[http://dx.doi.org/10.1097/MIB.0000000000000326 ] [PMID:  25742399] 
[102] 
Bertrand PP, Barajas-Espinosa A, Neshat S, Bertrand RL, Lomax AE. Analysis of real-time serotonin (5-HT) availability during experimental colitis in mouse. Am J Physiol Gastrointest Liver Physiol  2010; 298(3): G446-55.
[http://dx.doi.org/10.1152/ajpgi.00318.2009 ] [PMID:  20019165] 
[103] 
Robinson AM, Gondalia SV, Karpe AV, et al. Fecal microbiota and metabolome in a mouse model of spontaneous chronic colitis: Relevance to human inflammatory bowel disease. Inflamm Bowel Dis  2016; 22(12): 2767-87.
[http://dx.doi.org/10.1097/MIB.0000000000000970 ] [PMID:  27824648] 
[104] 
De Vadder F, Grasset E, Mannerås Holm L, et al. Gut microbiota regulates maturation of the adult enteric nervous system via enteric serotonin networks. Proc Natl Acad Sci USA  2018; 115(25): 6458-63.
[http://dx.doi.org/10.1073/pnas.1720017115 ] [PMID:  29866843] 
[105] 
Stavely R, Fraser S, Sharma S, et al. The onset and progression of chronic colitis parallels increased mucosal serotonin release via enterochromaffin cell hyperplasia and downregulation of the serotonin reuptake transporter. Inflamm Bowel Dis  2018; 24(5): 1021-34.
[http://dx.doi.org/10.1093/ibd/izy016 ] [PMID:  29668991] 
[106] 
Rolig AS, Mittge EK, Ganz J, et al. The enteric nervous system promotes intestinal health by constraining microbiota composition. PLoS Biol  2017; 15(2) e2000689
[http://dx.doi.org/10.1371/journal.pbio.2000689 ] [PMID:  28207737] 
[107] 
Thorpe D, Stringer A, Butler R. Chemotherapy-induced mucositis: the role of mucin secretion and regulation, and the enteric nervous system. Neurotoxicology  2013; 38: 101-5.
[http://dx.doi.org/10.1016/j.neuro.2013.06.007 ] [PMID:  23827812] 
[108] 
Busch RA, Heneghan AF, Pierre JF, Wang X, Kudsk KA. The enteric nervous system neuropeptide, bombesin, reverses innate immune impairments during parenteral nutrition. Ann Surg  2014; 260(3): 432-43.
[http://dx.doi.org/10.1097/SLA.0000000000000871 ] [PMID:  25115419] 
[109] 
Puzan M, Hosic S, Ghio C, Koppes A. Enteric nervous system regulation of intestinal stem cell differentiation and epithelial monolayer function. Sci Rep  2018; 8(1): 6313.
[http://dx.doi.org/10.1038/s41598-018-24768-3 ] [PMID:  29679034] 
[110] 
Neunlist M, Toumi F, Oreschkova T, et al. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol  2003; 285(5): G1028-36.
[http://dx.doi.org/10.1152/ajpgi.00066.2003 ] [PMID:  12881224] 
[111] 
Andersen YS, Gillin FD, Eckmann L. Adaptive immunity-dependent intestinal hypermotility contributes to host defense against Giardia spp. Infect Immun  2006; 74(4): 2473-6.
[http://dx.doi.org/10.1128/IAI.74.4.2473-2476.2006 ] [PMID:  16552082] 
[112] 
Inoue A, Ikoma K, Morioka N, et al. Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system. J Neurochem  1999; 73(5): 2206-13.
[PMID:  10537081] 
[113] 
Xia Y, Hu H-Z, Liu S, Ren J, Zafirov DH, Wood JD. IL-1β and IL-6 excite neurons and suppress nicotinic and noradrenergic neurotransmission in guinea pig enteric nervous system. J Clin Invest  1999; 103(9): 1309-16.
[http://dx.doi.org/10.1172/JCI5823 ] [PMID:  10225974] 
[114] 
Kelles A, Janssens J, Tack J. IL-1β and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea pig. Neurogastroenterol Motil  2000; 12(6): 531-8.
[http://dx.doi.org/10.1046/j.1365-2982.2000.00228.x ] [PMID:  11123708] 
[115] 
Coquenlorge S, Duchalais E, Chevalier J, Cossais F, Rolli-Derkinderen M, Neunlist M. Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system. J Neuroinflammation  2014; 11: 202.
[http://dx.doi.org/10.1186/s12974-014-0202-7 ] [PMID:  25497784] 
[116] 
Pacheco R, Riquelme E, Kalergis AM. Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands. Cent Nerv Syst Agents Med Chem  2010; 10(1): 65-83.
[http://dx.doi.org/10.2174/187152410790780154 ] [PMID:  20236043] 
[117] 
Delgado M. VIP: a very important peptide in T helper differentiation. Trends Immunol  2003; 24(5): 221-4.
[http://dx.doi.org/10.1016/S1471-4906(03)00069-3 ] [PMID:  12738408] 
[118] 
Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol  2008; 154(8): 1558-71.
[http://dx.doi.org/10.1038/bjp.2008.185 ] [PMID:  18500366] 
[119] 
Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide substance P and the immune response. Cell Mol Life Sci  2016; 73(22): 4249-64.
[http://dx.doi.org/10.1007/s00018-016-2293-z ] [PMID:  27314883] 
[120] 
Fujii T, Mashimo M, Moriwaki Y, et al. Expression and Function of the Cholinergic System in Immune Cells. Front Immunol  2017; 8: 1085.
[http://dx.doi.org/10.3389/fimmu.2017.01085 ] [PMID:  28932225] 
[121] 
Gabanyi I, Muller PA, Feighery L, Oliveira TY, Costa-Pinto FA, Mucida D. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell  2016; 164(3): 378-91.
[http://dx.doi.org/10.1016/j.cell.2015.12.023 ] [PMID:  26777404] 
[122] 
Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity  2017; 46(6): 927-42.
[http://dx.doi.org/10.1016/j.immuni.2017.06.008 ] [PMID:  28636960] 
[123] 
Robinson AM, Rahman AA, Carbone SE, et al. Alterations of colonic function in the Winnie mouse model of spontaneous chronic colitis. Am J Physiol Gastrointest Liver Physiol  2017; 312(1): G85-G102.
[http://dx.doi.org/10.1152/ajpgi.00210.2016 ] [PMID:  27881401] 
[124] 
Rahman AA, Robinson AM, Jovanovska V, Eri R, Nurgali K. Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res  2015; 362(3): 497-512.
[http://dx.doi.org/10.1007/s00441-015-2251-3 ] [PMID:  26227258] 
[125] 
Robinson AM, Miller S, Payne N, Boyd R, Sakkal S, Nurgali K. Neuroprotective potential of mesenchymal stem cell-based therapy in acute stages of tnbs-induced colitis in guinea-pigs. PLoS One  2015; 10(9) e0139023
[http://dx.doi.org/10.1371/journal.pone.0139023 ] [PMID:  26397368] 
[126] 
Zijlstra FJ. Smoking and nicotine in inflammatory bowel disease: good or bad for cytokines? Mediators Inflamm  1998; 7(3): 153-5.
[http://dx.doi.org/10.1080/09629359891072 ] [PMID:  9705601] 
[127] 
McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004; (4):  CD004722
[http://dx.doi.org/10.1002/14651858.CD004722.pub2 ] [PMID:  15495126] 
[128] 
Thomas GAO, Rhodes J, Ingram JR. Mechanisms of disease: nicotine--a review of its actions in the context of gastrointestinal disease. Nat Clin Pract Gastroenterol Hepatol  2005; 2(11): 536-44.
[http://dx.doi.org/10.1038/ncpgasthep0316 ] [PMID:  16355159] 
[129] 
Cosnes J. What is the link between the use of tobacco and IBD? Inflamm Bowel Dis  2008; 14(Suppl. 2): S14-5.
[http://dx.doi.org/10.1097/00054725-200810001-00007 ] [PMID:  18816683] 
[130] 
Berkowitz L, Schultz BM, Salazar GA, et al. Impact of cigarette smoking on the gastrointestinal tract inflammation: opposing effects in crohn’s disease and ulcerative colitis. Front Immunol  2018; 9: 74.
[http://dx.doi.org/10.3389/fimmu.2018.00074 ] [PMID:  29441064] 
[131] 
Galeazzi F, Blennerhassett PA, Qiu B, O’Byrne PM, Collins SM. Cigarette smoke aggravates experimental colitis in rats. Gastroenterology  1999; 117(4): 877-83.
[http://dx.doi.org/10.1016/S0016-5085(99)70346-X ] [PMID:  10500070] 
[132] 
Grandi A, Zini I, Flammini L, et al. α7 Nicotinic agonist ar-r17779 protects mice against 2,4,6-trinitrobenzene sulfonic acid-induced colitis in a spleen-dependent Way. Front Pharmacol  2017; 8: 809.
[http://dx.doi.org/10.3389/fphar.2017.00809 ] [PMID:  29167641] 
[133] 
Snoek SA, Verstege MI, van der Zanden EP, et al. Selective alpha7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis. Br J Pharmacol  2010; 160(2): 322-33.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00699.x ] [PMID:  20423343] 
[134] 
Beck PL, Xavier R, Wong J, et al. Paradoxical roles of different nitric oxide synthase isoforms in colonic injury. Am J Physiol Gastrointest Liver Physiol  2004; 286(1): G137-47.
[http://dx.doi.org/10.1152/ajpgi.00309.2003 ] [PMID:  14665440] 
[135] 
Mashimo H, He XD, Huang PL, Fishman MC, Goyal RK. Neuronal constitutive nitric oxide synthase is involved in murine enteric inhibitory neurotransmission. J Clin Invest  1996; 98(1): 8-13.
[http://dx.doi.org/10.1172/JCI118781 ] [PMID:  8690808] 
[136] 
Chandrasekharan B, Bala V, Kolachala VL, et al. Targeted deletion of neuropeptide Y (NPY) modulates experimental colitis. PLoS One  2008; 3(10) e3304
[http://dx.doi.org/10.1371/journal.pone.0003304 ] [PMID:  18836554] 
[137] 
Engel MA, Leffler A, Niedermirtl F, et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology  2011; 141(4): 1346-58.
[http://dx.doi.org/10.1053/j.gastro.2011.07.002 ] [PMID:  21763243] 
[138] 
Engel MA, Khalil M, Siklosi N, et al. Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis. Dig Liver Dis  2012; 44(1): 24-9.
[http://dx.doi.org/10.1016/j.dld.2011.08.030 ] [PMID:  22018693] 
[139] 
Stanisz AM. Neurogenic inflammation: Role of substance PNeuroImmune Biology.  Elsevier 2001; pp. 373-8.
[http://dx.doi.org/10.1016/S1567-7443(01)80033-8] 
[140] 
Assas BM, Pennock JI, Miyan JA. Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front Neurosci  2014; 8: 23.
[http://dx.doi.org/10.3389/fnins.2014.00023 ] [PMID:  24592205] 
[141] 
Goldin E, Karmeli F, Selinger Z, Rachmilewitz D. Colonic substance P levels are increased in ulcerative colitis and decreased in chronic severe constipation. Dig Dis Sci  1989; 34(5): 754-7.
[http://dx.doi.org/10.1007/BF01540348 ] [PMID:  2469561] 
[142] 
Li F-J, Zou Y-Y, Cui Y, Yin Y, Guo G, Lu F-G. Calcitonin gene-related peptide is a promising marker in ulcerative colitis. Dig Dis Sci  2013; 58(3): 686-93.
[http://dx.doi.org/10.1007/s10620-012-2406-y ] [PMID:  23010746] 
[143] 
Filippone RT, Sahakian L, Apostolopoulos V, Nurgali K. Eosinophils in inflammatory bowel disease. Inflamm Bowel Dis  2019; 25(7): 1140-51.
[http://dx.doi.org/10.1093/ibd/izz024 ] [PMID:  30856253] 
[144] 
Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer Metastasis Rev  1998; 17(1): 7-23.
[http://dx.doi.org/10.1023/A:1005940202801 ] [PMID:  9544420] 
[145] 
Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci  2007; 8(10): 766-75.
[http://dx.doi.org/10.1038/nrn2214 ] [PMID:  17882254] 
[146] 
Balez R, Ooi L. Getting to no alzheimer’s disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxid Med Cell Longev 2016. 20163806157
[http://dx.doi.org/10.1155/2016/3806157 ] [PMID:  26697132] 
[147] 
Shang B, Shi H, Wang X, et al. Protective effect of melatonin on myenteric neuron damage in experimental colitis in rats. Fundam Clin Pharmacol  2016; 30(2): 117-27.
[http://dx.doi.org/10.1111/fcp.12181 ] [PMID:  26787455] 
[148] 
Ibiza S, García-Cassani B, Ribeiro H, et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature  2016; 535(7612): 440-3.
[http://dx.doi.org/10.1038/nature18644 ] [PMID:  27409807] 
[149] 
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): 2824-40.
[http://dx.doi.org/10.1172/JCI120261 ] [PMID:  31205031] 
[150] 
Han TY, Lourenssen S, Miller KG, Blennerhassett MG. Intestinal smooth muscle phenotype determines enteric neuronal survival via GDNF expression. Neuroscience  2015; 290: 357-68.
[http://dx.doi.org/10.1016/j.neuroscience.2015.01.056 ] [PMID:  25655216] 
[151] 
Liu GX, Yang YX, Yan J, et al. Glial-derived neurotrophic factor reduces inflammation and improves delayed colonic transit in rat models of dextran sulfate sodium-induced colitis. Int Immunopharmacol  2014; 19(1): 145-52.
[http://dx.doi.org/10.1016/j.intimp.2014.01.008 ] [PMID:  24462388] 
[152] 
López-Pérez AE, Nurgali K, Abalo R. Painful neurotrophins and their role in visceral pain Behav Pharmacol 2018; 29(2 and 3-Spec
 Issue): 120-39.. 
[http://dx.doi.org/10.1097/FBP.0000000000000386] [PMID: 29543647] 
[153] 
Brun P, Zamuner A, Peretti A, et al. 3D synthetic peptide-based architectures for the engineering of the enteric nervous system. Sci Rep  2019; 9(1): 5583.
[http://dx.doi.org/10.1038/s41598-019-42071-7 ] [PMID:  30944410] 
[154] 
Metzger M, Caldwell C, Barlow AJ, Burns AJ, Thapar N. Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders Gastroenterology 2009; 136(7): 2214-25.e1, 3.. 
[http://dx.doi.org/10.1053/j.gastro.2009.02.048] [PMID: 19505425] 
[155] 
Hotta R, Stamp LA, Foong JP, et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J Clin Invest  2013; 123(3): 1182-91.
[http://dx.doi.org/10.1172/JCI65963 ] [PMID:  23454768] 
[156] 
Workman MJ, Mahe MM, Trisno S, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med  2017; 23(1): 49-59.
[http://dx.doi.org/10.1038/nm.4233 ] [PMID:  27869805] 
[157] 
Margolis KG, Stevanovic K, Karamooz N, et al. 2011.Enteric neuronal density contributes to the severity of intestinal inflammation 
[http://dx.doi.org/10.1053/j.gastro.2011.04.047] 
[158] 
Burns AJ, Goldstein AM, Newgreen DF, et al. White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Dev Biol  2016; 417(2): 229-51.
[http://dx.doi.org/10.1016/j.ydbio.2016.04.001 ] [PMID:  27059883] 
[159] 
Robinson AM, Sakkal S, Park A, et al. Mesenchymal stem cells and conditioned medium avert enteric neuropathy and colon dysfunction in guinea pig TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol  2014; 307(11): G1115-29.
[http://dx.doi.org/10.1152/ajpgi.00174.2014 ] [PMID:  25301186] 
[160] 
Robinson AM, Rahman AA, Miller S, Stavely R, Sakkal S, Nurgali K. The neuroprotective effects of human bone marrow mesenchymal stem cells are dose-dependent in TNBS colitis. Stem Cell Res Ther  2017; 8(1): 87.
[http://dx.doi.org/10.1186/s13287-017-0540-3 ] [PMID:  28420434] 
[161] 
Prakash MD, Miller S, Randall-Demllo S, Nurgali K. Mesenchymal stem cell treatment of inflammation-induced cancer. Inflamm Bowel Dis  2016; 22(11): 2694-703.
[http://dx.doi.org/10.1097/MIB.0000000000000900 ] [PMID:  27753693] 
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DOI https://dx.doi.org/10.2174/1389450121666200516173242	Print ISSN 1389-4501
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Targeting Enteric Neurons and Plexitis for the Management of Inflammatory Bowel Disease

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