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Alterations of the enteric smooth musculature in diverticular disease

  • Original Article—Alimentary Tract
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Abstract

Background

The pathogenesis of diverticular disease (DD) is considered to be multifactorial and involves intestinal motor disturbances and an underlying enteric neuromuscular pathology. While an enteric neuropathy has been well documented, actual studies on concomitant alterations of the enteric musculature are limited. This study is aimed at reassessing the smooth muscle tissue by histological, ultrastructural and molecular-biological approaches.

Methods

Full-thickness sigmoid specimens were obtained from patients with DD (n = 20) and controls (n = 19). Morphometric analysis was performed to evaluate the thickness and connective tissue index of the circular and longitudinal muscle layers as well as the myenteric plexus. Structural alterations were determined by light and transmission electron microscopy. mRNA profiles of components of the contractile smooth muscle apparatus including smooth muscle α-actin, smoothelin, histone deacetylase 8, and smooth muscle myosin heavy chain (SMMHC) were assessed by qPCR. Altered gene expression levels were confirmed at protein level by immunohistochemistry.

Results

Compared to controls, patients with DD showed (1) increased thickness of the circular and longitudinal muscle layers, (2) architectural alterations of smooth muscle cells, (3) increased connective tissue index of the longitudinal muscle layer, (4) focally reduced density of myofilaments at ultrastructural level, (5) specific down-regulation of SMMHC mRNA levels, (6) decreased immunoreactivity of SMMHC, (7) oligo-neuronal hypoganglionosis.

Conclusions

DD is associated with distinct structural and functional alterations of the enteric musculature. The enteric myopathy is characterized by disturbed muscular architecture, connective tissue replacement and loss of specific myofilaments and thus may contribute to the pathogenesis and progression of DD.

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Abbreviations

α-SMA:

α-Smooth muscle actin

DD:

Diverticular disease

ENS:

Enteric nervous system

HDAC8:

Histone deacetylase 8

qPCR:

Quantitative PCR

SM:

Smoothelin

SMMHC:

Smooth muscle myosin heavy chain

References

  1. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500–11.

    Article  PubMed  Google Scholar 

  2. Simpson J, Spiller R. Colonic diverticular disease. Clin Evid. 2002;8:436–44.

    PubMed  Google Scholar 

  3. Milner P, Crowe R, Kamm MA, et al. Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease. Gastroenterology. 1990;99:666–75.

    CAS  PubMed  Google Scholar 

  4. Bassotti G, Battaglia E, Spinozzi F, et al. Twenty-four hour recordings of colonic motility in patients with diverticular disease: evidence for abnormal motility and propulsive activity. Dis Colon Rectum. 2001;44:1814–20.

    Article  CAS  PubMed  Google Scholar 

  5. Golder M, Burleigh DE, Belai A, et al. Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. Lancet. 2003;361:1945–51.

    Article  CAS  PubMed  Google Scholar 

  6. Knowles CH, De Giorgio R, Kapur RP, et al. The London classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group. Gut. 2010;59:882–7.

    Article  PubMed  Google Scholar 

  7. Golder M, Burleigh DE, Ghali L, et al. Longitudinal muscle shows abnormal relaxation responses to nitric oxide and contains altered levels of NOS1 and elastin in uncomplicated diverticular disease. Colorectal Dis. 2007;9:218–28.

    Article  CAS  PubMed  Google Scholar 

  8. Bottner M, Barrenschee M, Hellwig I et al. The enteric serotonergic system is altered in patients with diverticular disease. Gut. 2012. doi:10.1136/gutjnl-2012-302660.

  9. Simpson J, Sundler F, Humes DJ, et al. Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms. Neurogastroenterol Motil. 2009;21:e847–58.

    Article  Google Scholar 

  10. Humes DJ, Simpson J, Smith J et al. Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation. Neurogastroenterol Motil. 2012;24:318–e163.

    Google Scholar 

  11. Deduchovas O, Saladzinskas Z, Tamelis A, et al. Morphologic pattern of myenteric neural plexus in colonic diverticular disease. A whole-mount study employing histochemical staining for acetylcholinesterase. Ann Anat. 2008;190:525–30.

    Article  PubMed  Google Scholar 

  12. Painter NS, Truelove SC, Ardran GM, et al. Effect of morphine, prostigmine, pethidine, and probanthine on the human colon in diverticulosis studied by intraluminal pressure recording and cineradiography. Gut. 1965;6:57–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Parks TG, Connell AM. Motility studies in diverticular disease of the colon. Gut. 1969;10:534–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Cortesini C, Pantalone D. Usefulness of colonic motility study in identifying patients at risk for complicated diverticular disease. Dis Colon Rectum. 1991;34:339–42.

    Article  CAS  PubMed  Google Scholar 

  15. Hughes LE. Postmortem survey of diverticular disease of the colon. II. The muscular abnormality of the sigmoid colon. Gut. 1969;10:344–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Painter NS, Burkitt DP. Diverticular disease of the colon, a 20th century problem. Clin Gastroenterol. 1975;4:3–21.

    CAS  PubMed  Google Scholar 

  17. Stelzner F. Abnormality of the muscular structure of the colon: a possible cause of diverticulosis (author’s transl). Langenbecks Arch Chir. 1976;342:411–2.

    Article  CAS  PubMed  Google Scholar 

  18. Morson BC. The muscle abnormality in diverticular disease of the colon. Proc R Soc Med. 1963;56:798–800.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Whiteway J, Morson BC. Pathology of the ageing–diverticular disease. Clin Gastroenterol. 1985;14:829–46.

    CAS  PubMed  Google Scholar 

  20. Raguse T, Kuhnel W. Pathogenesis of colon diverticular disease (author’s transl). Leber Magen Darm. 1981;11:147–58.

    CAS  PubMed  Google Scholar 

  21. Wedel T, Van Eys GJ, Waltregny D, et al. Novel smooth muscle markers reveal abnormalities of the intestinal musculature in severe colorectal motility disorders. Neurogastroenterol Motil. 2006;18:526–38.

    Article  CAS  PubMed  Google Scholar 

  22. Wedel T, Busing V, Heinrichs G, et al. Diverticular disease is associated with an enteric neuropathy as revealed by morphometric analysis. Neurogastroenterol Motil. 2010;22:407–14 (e493–404).

    Article  CAS  PubMed  Google Scholar 

  23. Arfwidsson S, Knock NG, Lehmann L, et al. Pathogenesis of multiple diverticula of the sogmoid colon in diverticular disease. Acta Chir Scand Suppl. 1964;63(SUPPL 342):341–68.

    Google Scholar 

  24. Whiteway J, Morson BC. Elastosis in diverticular disease of the sigmoid colon. Gut. 1985;26:258–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Wess L, Eastwood MA, Wess TJ, et al. Cross linking of collagen is increased in colonic diverticulosis. Gut. 1995;37:91–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Stumpf M, Cao W, Klinge U, et al. Increased distribution of collagen type III and reduced expression of matrix metalloproteinase 1 in patients with diverticular disease. Int J Colorectal Dis. 2001;16:271–5.

    Article  CAS  PubMed  Google Scholar 

  27. Mimura T, Bateman AC, Lee RL, et al. Up-regulation of collagen and tissue inhibitors of matrix metalloproteinase in colonic diverticular disease. Dis Colon Rectum. 2004;47:371–8 (discussion 378–379).

    Article  PubMed  Google Scholar 

  28. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487–517.

    CAS  PubMed  Google Scholar 

  29. Rensen SS, Doevendans PA, van Eys GJ. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J. 2007;15:100–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Iwase H, Sadahiro S, Mukoyama S, et al. Morphology of myenteric plexuses in the human large intestine: comparison between large intestines with and without colonic diverticula. J Clin Gastroenterol. 2005;39:674–8.

    Article  PubMed  Google Scholar 

  31. Bottner M, Barrenschee M, Hellwig I, et al. The GDNF system is altered in diverticular disease—implications for pathogenesis. PLoS One. 2013;8:e66290.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Rieder F, Fiocchi C. Intestinal fibrosis in IBD–a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol. 2009;6:228–35.

    Article  CAS  PubMed  Google Scholar 

  33. Powell DW, Mifflin RC, Valentich JD, et al. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol. 1999;277:C183–201.

    CAS  PubMed  Google Scholar 

  34. Pucilowska JB, Williams KL, Lund PK. Fibrogenesis. IV. Fibrosis and inflammatory bowel disease: cellular mediators and animal models. Am J Physiol Gastrointest Liver Physiol. 2000;279:G653–9.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Jürgen Hedderich and Oliver Vollrath (Institute of Medical Informatics and Statistics, University Hospital Schleswig–Holstein, Campus Kiel) for statistical advice and Karin Stengel, Inka Geurink, Miriam Lemmer, Frank Lichte, Bettina Facompré and Clemens Franke (Institute of Anatomy, Christian-Albrecht′s University in Kiel) for their excellent technical assistance. The study was supported by a research grant from the German Research Foundation (DFG, WE 2366/4-2) and the Faculty of Medicine, Christian Albrechts University of Kiel (F347022). The funding source has no role in study design, management of data and writing of the paper.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anatomy, Christian-Albrecht′s University in Kiel, Otto-Hahn-Platz 8, 24118, Kiel, Germany

    Ines Hellwig, Martina Böttner, Martina Barrenschee, Jonas Harde & Thilo Wedel

  2. Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig–Holstein, Campus Kiel, Arnold-Heller-Straße 7, 24105, Kiel, Germany

    Jan-Hendrik Egberts & Thomas Becker

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  1. Ines Hellwig
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  2. Martina Böttner
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  3. Martina Barrenschee
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  4. Jonas Harde
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  5. Jan-Hendrik Egberts
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  6. Thomas Becker
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  7. Thilo Wedel
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Corresponding author

Correspondence to Ines Hellwig.

Additional information

Ines Hellwig, Martina Böttner authors contributed equally to this study.

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Hellwig, I., Böttner, M., Barrenschee, M. et al. Alterations of the enteric smooth musculature in diverticular disease. J Gastroenterol 49, 1241–1252 (2014). https://doi.org/10.1007/s00535-013-0886-y

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  • DOI: https://doi.org/10.1007/s00535-013-0886-y

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