Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum

Abstract

Rectal prolapse is associated with diminished anal sensitivity and rectal motor activity. Both sensory and motor functions are controlled by the extrinsic and intrinsic (enteric nervous system) innervation of the gastrointestinal tract. Studies of changes in intestinal innervation in humans and in animal models with rectal prolapse are extremely scarce. The Winnie mouse model of spontaneous chronic colitis closely represents human inflammatory bowel disease and is prone to develop rectal prolapse. We have investigated changes in the myenteric and inhibitory motor neurons and evaluated changes in the density of sensory afferent, sympathetic, and parasympathetic fibers in the rectal colon of Winnie mice with and without rectal prolapse. Our results demonstrate that rectal prolapse in Winnie mice with chronic colitis is correlated with enhanced levels of inflammation, gross morphological damage, and muscular hypertrophy of the rectum. Animals with prolapse have more severe damage to the rectal innervation compared with Winnie mice without prolapse. This includes more severe neuronal loss in the myenteric plexus, involving a decrease in nNOS-immunoreactive neurons (not observed in Winnie mice without prolapse) and a more pronounced loss of VAChT-immunoreactive fibers. Both Winnie mice with and without prolapse have comparable levels of noradrenergic and sensory fiber loss in the rectum. This is the first study providing evidence that the damage and death of enteric neurons, including nitrergic neurons in myenteric ganglia and the loss of cholinergic nerve fibers, are important factors in structural changes in the rectum of mice with rectal prolapse.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Antao B, Bradley V, Roberts JP, Shawis R (2005) Management of rectal prolapse in children. Dis Colon Rectum 48:1620–1625

    CAS  Article  PubMed  Google Scholar 

  2. Assas BM, Pennock JI, Miyan JA (2014) Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front Neurosci 8:23

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bernard CE, Gibbons SJ, Gomez-Pinilla PJ, Lurken MS, Schmalz PF, Roeder JL, Linden D, Cima RR, Dozois EJ, Larson DW, Camilleri M, Zinsmeister AR, Pozo MJ, Hicks GA, Farrugia G (2009) Effect of age on the enteric nervous system of the human colon. Neurogastroenterol Motil 21:746–e46

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Boyer L, Ghoreishi M, Templeman V, Vallance BA, Buchan AM, Jevon G, Jacobson K (2005) Myenteric plexus injury and apoptosis in experimental colitis. Auton Neurosci 117:41–53

    CAS  Article  PubMed  Google Scholar 

  5. Brookes SJ (2001) Classes of enteric nerve cells in the guinea-pig small intestine. Anat Rec 262:58–70

    CAS  Article  PubMed  Google Scholar 

  6. Brumovsky PR, La JH, Gebhart GF (2014) Distribution across tissue layers of extrinsic nerves innervating the mouse colorectum—an in vitro anterograde tracing study. Neurogastroenterol Motil 26:1494–1507

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Cervi AL, Lukewich MK, Lomax AE (2014) Neural regulation of gastrointestinal inflammation: role of the sympathetic nervous system. Auton Neurosci 182:83–88

    CAS  Article  PubMed  Google Scholar 

  8. Choi S, Parajuli SP, Yeum CH, Park CG, Kim MY, Kim YD, Cha KH, Park YB, Park JS, Jeong HS, Jun JY (2008) Calcitonin gene-related peptide suppresses pacemaker currents by nitric oxide/cGMP-dependent activation of ATP-sensitive K(+) channels in cultured interstitial cells of Cajal from the mouse small intestine. Mol Cell 26:181–185

    CAS  Google Scholar 

  9. de Lorijn F, de Jonge WJ, Wedel T, Vanderwinden JM, Benninga MA, Boeckxstaens GE (2005) Interstitial cells of Cajal are involved in the afferent limb of the rectoanal inhibitory reflex. Gut 54:1107–1113

    Article  PubMed  PubMed Central  Google Scholar 

  10. de Souza RR, Moratelli HB, Borges N, Liberti EA (1993) Age-induced nerve cell loss in the myenteric plexus of the small intestine in man. Gerontology 39:183–188

    Article  PubMed  Google Scholar 

  11. de Tayrac R, Sentilhes L (2013) Complications of pelvic organ prolapse surgery and methods of prevention. Int Urogynecol J 24:1859–1872

    Article  PubMed  Google Scholar 

  12. Depoortere I, Thijs T, Peeters TL (2002) Generalized loss of inhibitory innervation reverses serotonergic inhibition into excitation in a rabbit model of TNBS-colitis. Br J Pharmacol 135:2011–2019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Domoto T, Yang H, Bishop AE, Polak JM, Oki M (1992) Distribution and origin of extrinsic nerve fibers containing calcitonin gene-related peptide, substance P and galanin in the rat upper rectum. Neurosci Res 15:64–73

    CAS  Article  PubMed  Google Scholar 

  14. Eri RD, Adams RJ, Tran TV, Tong H, Das I, Roche DK, Oancea I, Png CW, Jeffery PL, Radford-Smith GL, Cook MC, Florin TH, McGuckin MA (2011) An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol 4:354–364

    CAS  Article  PubMed  Google Scholar 

  15. Eysselein VE, Reinshagen M, Cominelli F, Sternini C, Davis W, Patel A, Nast CC, Bernstein D, Anderson K, Khan H, Snape WJ (1991) Calcitonin gene-related peptide and substance P decrease in the rabbit colon during colitis. A time study. Gastroenterology 101:1211–1219

    CAS  Article  PubMed  Google Scholar 

  16. Eysselein VE, Reinshagen M, Patel A, Davis W, Nast C, Sternini C (1992) Calcitonin gene-related peptide in inflammatory bowel disease and experimentally induced colitis. Ann N Y Acad Sci 657:319–327

    CAS  Article  PubMed  Google Scholar 

  17. Farouk R, Duthie GS (1998) Rectal prolapse and rectal invagination. Eur J Surg 164:323–332

    CAS  Article  PubMed  Google Scholar 

  18. Felt-Bersma RJ, Poen AC, Cuesta MA, Meuwissen SG (1997) Anal sensitivity test: what does it measure and do we need it? Cause or derivative of anorectal complaints. Dis Colon Rectum 40:811–816

    CAS  Article  PubMed  Google Scholar 

  19. Fox A, Tietze PH, Ramakrishnan K (2014) Anorectal conditions: rectal prolapse. FP Essent 419:28–34

    PubMed  Google Scholar 

  20. Furness JB (2012) The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 9:286–294

    CAS  Article  PubMed  Google Scholar 

  21. Goyal RK (2013) Revised role of interstitial cells of Cajal in cholinergic neurotransmission in the gut. J Physiol (Lond) 591:5413–5414

    CAS  Article  Google Scholar 

  22. Grider JR (2003) Neurotransmitters mediating the intestinal peristaltic reflex in the mouse. J Pharmacol Exp Ther 307:460–467

    CAS  Article  PubMed  Google Scholar 

  23. Hammond K, Beck DE, Margolin DA, Whitlow CB, Timmcke AE, Hicks TC (2007) Rectal prolapse: a 10-year experience. Ochsner J 7:24–32

    PubMed  PubMed Central  Google Scholar 

  24. Heazlewood CK, Cook MC, Eri R, Price GR, Tauro SB, Taupin D, Thornton DJ, Chin WP, Crockford TL, Cornall RJ, Adams R, Kato M, Nelms KA, Hong NA, Florin THJ, Goodnow CC, McGuckin MA (2008) Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 5:e54

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jacobs LK, Lin YJ, Orkin BA (1997) The best operation for rectal prolapse. Surg Clin North Am 77:49–70

    CAS  Article  PubMed  Google Scholar 

  26. Jonsson M, Norrgard O, Forsgren S (2007) Presence of a marked nonneuronal cholinergic system in human colon: study of normal colon and colon in ulcerative colitis. Inflamm Bowel Dis 13:1347–1356

    Article  PubMed  Google Scholar 

  27. Kairaluoma MV, Kellokumpu IH (2005) Epidemiologic aspects of complete rectal prolapse. Scand J Surg 94:207–210

    CAS  PubMed  Google Scholar 

  28. Kajimoto Y, Hashimoto T, Shirai Y, Nishino N, Kuno T, Tanaka C (1992) cDNA cloning and tissue distribution of a rat ubiquitin carboxyl-terminal hydrolase PGP9.5. J Biochem 112:28–32

    CAS  PubMed  Google Scholar 

  29. Kim DS, Tsang CB, Wong WD, Lowry AC, Goldberg SM, Madoff RD (1999) Complete rectal prolapse: evolution of management and results. Dis Colon Rectum 42:460–469

    CAS  Article  PubMed  Google Scholar 

  30. Kono T, Chisato N, Ebisawa Y, Asama T, Sugawara M, Ayabe T, Kohgo Y, Kasai S, Yoneda M, Takahashi T (2004) Impaired nitric oxide production of the myenteric plexus in colitis detected by a new bioimaging system. J Surg Res 117:329–338

    CAS  Article  PubMed  Google Scholar 

  31. Kressel M, Berthoud HR, Neuhuber WL (1994) Vagal innervation of the rat pylorus: an anterograde tracing study using carbocyanine dyes and laser scanning confocal microscopy. Cell Tissue Res 275:109–123

    CAS  Article  PubMed  Google Scholar 

  32. Kumar MJM, Nagarajan P, Venkatesan R, Juyal RC (2004) Case report and short communication: rectal prolapse associated with an unusual combination of pinworms and citrobacter species infection in FVB mice colony. Scand J Lab Anim Sci 31:221–223

    CAS  Google Scholar 

  33. Lecci A, Santicioli P, Maggi CA (2002) Pharmacology of transmission to gastrointestinal muscle. Curr Opin Pharmacol 2:630–641

    CAS  Article  PubMed  Google Scholar 

  34. Li ZS, Pham TD, Tamir H, Chen JJ, Gershon MD (2004) Enteric dopaminergic neurons: definition, developmental lineage, and effects of extrinsic denervation. J Neurosci 24:1330–1339

    CAS  Article  PubMed  Google Scholar 

  35. Lies B, Beck K, Keppler J, Saur D, Groneberg D, Friebe A (2015) Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon. J Physiol (Lond) 593:4589–4601

    CAS  Article  Google Scholar 

  36. Lin A, Lourenssen S, Stanzel RDP, Blennerhassett MG (2005) Selective loss of NGF-sensitive neurons following experimental colitis. Exp Neurol 191:337–343

    CAS  Article  PubMed  Google Scholar 

  37. Linden DR, Couvrette JM, Ciolino A, McQuoid C, Blaszyk H, Sharkey KA, Mawe GM (2005) Indiscriminate loss of myenteric neurones in the TNBS-inflamed guinea-pig distal colon. Neurogastroenterol Motil 17:751–760

    CAS  Article  PubMed  Google Scholar 

  38. Lomax AE, Sharkey KA, Furness JB (2010) The participation of the sympathetic innervation of the gastrointestinal tract in disease states. Neurogastroenterol Motil 22:7–18

    CAS  PubMed  Google Scholar 

  39. Lourenssen S, Wells RW, Blennerhassett MG (2005) Differential responses of intrinsic and extrinsic innervation of smooth muscle cells in rat colitis. Exp Neurol 195:497–507

    CAS  Article  PubMed  Google Scholar 

  40. Luckensmeyer GB, Keast JR (1998) Projections of pelvic autonomic neurons within the lower bowel of the male rat: an anterograde labelling study. Neuroscience 84:263–280

    CAS  Article  PubMed  Google Scholar 

  41. Madiba TE, Baig MK, Wexner SD (2005) Surgical management of rectal prolapse. Arch Surg 140:63–73

    Article  PubMed  Google Scholar 

  42. Marceau C, Parc Y, Debroux E, Tiret E, Parc R (2005) Complete rectal prolapse in young patients: psychiatric disease a risk factor of poor outcome. Colorectal Dis 7:360–365

    CAS  Article  PubMed  Google Scholar 

  43. Matsumoto K, Hosoya T, Tashima K, Namiki T, Murayama T, Horie S (2011) Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: relationship to peptidergic and nitrergic neurons. Neuroscience 172:518–534

    CAS  Article  PubMed  Google Scholar 

  44. Matteoli G, Boeckxstaens GE (2013) The vagal innervation of the gut and immune homeostasis. Gut 62:1214–1222

    CAS  Article  PubMed  Google Scholar 

  45. McGuckin MA, Eri RD, Das I, Lourie R, Florin TH (2011) Intestinal secretory cell ER stress and inflammation. Biochem Soc Trans 39:1081–1085

    CAS  Article  PubMed  Google Scholar 

  46. McIntyre AS, Thompson DG (1992) Review article: adrenergic control of motor and secretory function in the gastrointestinal tract. Aliment Pharmacol Ther 6:125–142

    CAS  Article  PubMed  Google Scholar 

  47. Miampamba M, Sharkey KA (1998) Distribution of calcitonin gene-related peptide, somatostatin, substance P and vasoactive intestinal polypeptide in experimental colitis in rats. Neurogastroenterol Motil 10:315–329

    CAS  Article  PubMed  Google Scholar 

  48. Miampamba M, Chery-Croze S, Chayvialle JA (1992) Spinal and intestinal levels of substance P, calcitonin gene-related peptide and vasoactive intestinal polypeptide following perendoscopic injection of formalin in rat colonic wall. Neuropeptides 22:73–80

    CAS  Article  PubMed  Google Scholar 

  49. Miller CL, Muthupalani S, Shen Z, Fox JG (2014) Isolation of Helicobacter spp. from mice with rectal prolapses. Comp Med 64:171–178

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Moszkowicz D, Peschaud F, Bessede T, Benoit G, Alsaid B (2012) Internal anal sphincter parasympathetic-nitrergic and sympathetic-adrenergic innervation: a 3-dimensional morphological and functional analysis. Dis Colon Rectum 55:473–481

    Article  PubMed  Google Scholar 

  51. Nagatsu T (1989) The human tyrosine hydroxylase gene. Cell Mol Neurobiol 9:313–321

    CAS  Article  PubMed  Google Scholar 

  52. Nurgali K, Nguyen TV, Matsuyama H, Thacker M, Robbins HL, Furness JB (2007) Phenotypic changes of morphologically identified guinea-pig myenteric neurons following intestinal inflammation. J Physiol (Lond) 583:593–609

    CAS  Article  Google Scholar 

  53. Nurgali K, Qu Z, Hunne B, Thacker M, Pontell L, Furness JB (2011) Morphological and functional changes in guinea-pig neurons projecting to the ileal mucosa at early stages after inflammatory damage. J Physiol (Lond) 589:325–339

    CAS  Article  Google Scholar 

  54. O’Brien DP (2007) Rectal prolapse. Clin Colon Rectal Surg 20:125–132

    Article  PubMed  PubMed Central  Google Scholar 

  55. Olsson C, Chen BN, Jones S, Chataway TK, Costa M, Brookes SJ (2006) Comparison of extrinsic efferent innervation of guinea pig distal colon and rectum. J Comp Neurol 496:787–801

    Article  PubMed  Google Scholar 

  56. Pelletier AM, Venkataramana S, Miller KG, Bennett BM, Nair DG, Lourenssen S, Blennerhassett MG (2010) Neuronal nitric oxide inhibits intestinal smooth muscle growth. Am J Physiol Gastrointest Liver Physiol 298:G896–G907

    CAS  Article  PubMed  Google Scholar 

  57. Qu Z, Apel ED, Doherty CA, Hoffman PW, Merlie JP, Huganir RL (1996) The synapse-associated protein rapsyn regulates tyrosine phosphorylation of proteins colocalized at nicotinic acetylcholine receptor clusters. Mol Cell Neurosci 8:171–184

    CAS  Article  Google Scholar 

  58. Qu ZD, Thacker M, Castelucci P, Bagyánszki M, Epstein ML, Furness JB (2008) Immunohistochemical analysis of neuron types in the mouse small intestine. Cell Tissue Res 334:147–161

    CAS  Article  PubMed  Google Scholar 

  59. Rahman AA, Robinson AM, Jovanovska V, Eri R, Nurgali K (2015) Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 362:497–512

    CAS  Article  PubMed  Google Scholar 

  60. Rattan S, Regan RF, Patel CA, De Godoy MA (2005) Nitric oxide not carbon monoxide mediates nonadrenergic noncholinergic relaxation in the murine internal anal sphincter. Gastroenterology 129:1954–1966

    CAS  Article  PubMed  Google Scholar 

  61. Renzi D, Mantellini P, Calabro A, Panerai C, Amorosi A, Paladini I, Salvadori G, Garcea MR, Surrenti C (1998) Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis. Ital J Gastroenterol Hepatol 30:62–70

    CAS  PubMed  Google Scholar 

  62. Ridolfi TJ, Tong WD, Takahashi T, Kosinski L, Ludwig KA (2009) Sympathetic and parasympathetic regulation of rectal motility in rats. J Gastrointest Surg 13:2027–2033

    Article  PubMed  Google Scholar 

  63. Rivera LR, Poole DP, Thacker M, Furness JB (2011) The involvement of nitric oxide synthase neurons in enteric neuropathies. Neurogastroenterol Motil 23:980–988

    CAS  Article  PubMed  Google Scholar 

  64. Rogala AR, Morgan AP, Christensen AM, Gooch TJ, Bell TA, Miller DR, Godfrey VL, de Villena FP (2014) The collaborative cross as a resource for modeling human disease: CC011/Unc, a new mouse model for spontaneous colitis. Mamm Genome 25:95–108

    Article  PubMed  PubMed Central  Google Scholar 

  65. Sainio AP, Voutilainen PE, Husa AI (1991) Recovery of anal sphincter function following transabdominal repair of rectal prolapse: cause of improved continence? Dis Colon Rectum 34:816–821

    CAS  Article  PubMed  Google Scholar 

  66. Sanders KM, Hwang SJ, Ward SM (2010) Neuroeffector apparatus in gastrointestinal smooth muscle organs. J Physiol (Lond) 588:4621–4639

    CAS  Article  Google Scholar 

  67. Sanovic S, Lamb DP, Blennerhassett MG (1999) Damage to the enteric nervous system in experimental colitis. Am J Pathol 155:1051–1057

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Sharrad DF, Hibberd TJ, Kyloh MA, Brookes SJ, Spencer NJ (2015) Quantitative immunohistochemical co-localization of TRPV1 and CGRP in varicose axons of the murine oesophagus, stomach and colorectum. Neurosci Lett 599:164–171

    CAS  Article  PubMed  Google Scholar 

  69. Snooks SJ, Henry MM, Swash M (1985) Anorectal incontinence and rectal prolapse: differential assessment of the innervation to puborectalis and external anal sphincter muscles. Gut 26:470–476

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Spencer NJ, Smith TK (2001) Simultaneous intracellular recordings from longitudinal and circular muscle during the peristaltic reflex in guinea-pig distal colon. J Physiol (Lond) 533:787–799

    CAS  Article  Google Scholar 

  71. Straub RH, Grum F, Strauch U, Capellino S, Bataille F, Bleich A, Falk W, Scholmerich J, Obermeier F (2008) Anti-inflammatory role of sympathetic nerves in chronic intestinal inflammation. Gut 57:911–921

    CAS  Article  PubMed  Google Scholar 

  72. Taffs LF (1976) Pinworm infections in laboratory rodents: a review. Lab Anim 10:1–13

    CAS  Article  PubMed  Google Scholar 

  73. Terauchi A, Kobayashi D, Mashimo H (2005) Distinct roles of nitric oxide synthases and interstitial cells of Cajal in rectoanal relaxation. Am J Physiol Gastrointest Liver Physiol 289:G291–G299

    CAS  Article  PubMed  Google Scholar 

  74. Wafai L, Taher M, Jovanovska V, Bornstein JC, Dass CR, Nurgali K (2013) Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci 7:1–8

    Article  Google Scholar 

  75. Wakabayashi K, Takahashi H, Ohama E, Ikuta F (1989) Tyrosine hydroxylase-immunoreactive intrinsic neurons in the Auerbach’s and Meissner’s plexuses of humans. Neurosci Lett 96:259–263

    CAS  Article  PubMed  Google Scholar 

  76. Ward SM, Beckett EA, Wang X, Baker F, Khoyi M, Sanders KM (2000) Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 20:1393–1403

    CAS  PubMed  Google Scholar 

  77. Weihe E, Tao-Cheng JH, Schäfer MKH, Erickson JD, Eiden LE (1996) Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles. Proc Natl Acad Sci U S A 93:3547–3552

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Zaitouna M, Alsaid B, Diallo D, Benoit G, Bessede T (2013) Identification of the origin of adrenergic and cholinergic nerve fibers within the superior hypogastric plexus of the human fetus. J Anat 223:14–21

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Zhao A, Bossone C, Pineiro-Carrero V, Shea-Donohue T (2001) Colitis-induced alterations in adrenergic control of circular smooth muscle in vitro in rats. J Pharmacol Exp Ther 299:768–774

    CAS  PubMed  Google Scholar 

  80. Zorenkov D, Otto S, Bottner M, Hedderich J, Vollrath O, Ritz JP, Buhr H, Wedel T (2011) Morphological alterations of the enteric nervous system in young male patients with rectal prolapse. Int J Colorectal Dis 26:1483–1491

    Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kulmira Nurgali.

Ethics declarations

Conflict of interest

The authors of this manuscript do not have any potential conflicts to disclose.

Role of authors

AAR and AMR performed experiments, analyzed data, and wrote the manuscript. KN, RE, and SJHB developed the concept, obtained funding, and edited manuscript. KN supervised the study.

Additional information

Ahmed A. Rahman and Ainsley M. Robinson contributed equally to this work.

This study was supported by the Australian National Health & Medical Research Council project grant 1032414 and a Victoria University research support grant.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1
figure8

Changes in the innervation of the distal colon (non-prolapsed regions). Total number of myenteric neurons (a), nNOS-IR neurons (b), and VAChT-IR fibers (c) in cross sections, of VAChT-IR fibers in wholemount preparations (d), of TH-IR fibers in wholemount preparations (e), and of CGRP-IR fibers in cross sections (f) of the distal colon (non-prolapsed regions) of Winnie-prolapse mice compared with data from the same regions of the distal colon from Winnie and C57/BL6 mice (Rahman et al. 2015). (GIF 79 kb)

High Resolution Image (TIF 1277 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rahman, A.A., Robinson, A.M., Brookes, S.J.H. et al. Rectal prolapse in Winnie mice with spontaneous chronic colitis: changes in intrinsic and extrinsic innervation of the rectum. Cell Tissue Res 366, 285–299 (2016). https://doi.org/10.1007/s00441-016-2465-z

Download citation

Keywords

  • Rectal prolapse
  • Enteric neurons
  • Spontaneous chronic colitis
  • Winnie mice
  • Rectum innervation