Immunohistochemical study of the sympathetic innervation of the colon in chronic slow-transit constipation

The purpose of this study is to determine the distribution and features of sympathetic innervation of the tissues of the human colon wall in chronic slow-transit constipation using immunohistochemical methods. Materials and methods. Immunohistochemical study of large intestine segments (colon and sigmoid colon) obtained as a result of surgical treatment of patients with chronic slow-transit constipation was carried out using neural markers (PGP 9.5 protein, tyrosine hydroxylase, synaptophysin). Results. It has been shown that the majority of postganglionic sympathetic nerve fibers are localized in the Auerbach and Meissner plexuses. Their terminal axons form pericellular synaptic apparatuses around cholinergic neurons. Another part of the sympathetic fibers is involved in the innervation of the muscular plate of the mucous membrane and the walls of the venous vessels of the submucosa; their terminal varicose axons can be seen on smooth muscle cells as distant synapses en passant. Significant features of sympathetic innervation disorders of the large intestine of the studied patients were established; morphological evidence for the reactive, dystrophic and degenerative changes in the sympathetic apparatuses in the ganglionic plexuses were found. The regularities of the absence of sympathetic innervation in two muscle layers (longitudinal and circular), as well as in the mucous membrane, were revealed. Sympathetic neurons were not found in the studied sections of the large intestine. Conclusion. It is assumed that the identified pathological changes in sympathetic innervation in chronic slow-transit constipation can serve as one of the main causes of disruption of normal bowel functions.

human colon, human sigmoid colon, chronic slow-transit constipation, tyrosine hydroxylase, PGP 9.5 protein, immunohistochemistry

1. Nozdrachev A. D. Physiology of the autonomic nervous system. L., Medicine Publ., 1983. (In Russ.)@@ Ноздрачев А. Д. Физиология вегетативной нервной системы. - Л.: Медицина,1983.

2. Nozdrachev A.D., Chumasov E. I. Peripheral nervous system. St. Petersburg, Nauka Publ., 1999. (In Russ.)@@ Ноздрачев А. Д., Чумасов Е. И. Периферическая нервная система. - СПб.: Наука, 1999.

3. Pokrovsky V.M., Korotko G. F. Human physiology. Moscow. Medicine Publ., 2003. (In Russ.)@@ Покровский В. М., Коротько Г. Ф. Физиология человека. - М.: Медицина, 2003.

4. Furness J. B. Types of neurons in the enteric nervous system. J Auton Nerv Syst. 2000 Jul 3;81(1-3):87-96. doi: 10.1016/s0165-1838(00)00127-2.

5. Lomax A.E., Sharkey K. A., Furness J. B. The participation of the sympathetic innervation of the gastrointestinal tract in disease states. Neurogastroenterol Motil. 2010 Jan;22(1):7-18. doi: 10.1111/j.1365-2982.2009.01381.x.

6. Galeisya E.N., Lychkova A. E. Nervous regulation of the colon. Experimental and clinical gastroenterology. 2013(8):54-60. (In Russ.)@@ Галейся Е. Н., Лычкова А. Э. Нервная регуляция толстой кишки // Экспериментальная и клиническая гастроэнтерология. - 2013. - № 8. - С. 54-60.

7. Gabella G. Structure of the autonomic nervous system. London. Chapman and Hall, 1979.

8. Lolova I., Itzev D., Davidoff M. Z. Innervation of the smooth muscle in human large intestine during ontogenesis. Mikrosk Anat Forsch. 1987;101(5):871-80. PMID: 3328440.

9. Shultz J.M., Resnikoff H., Bondarenko V. et al. Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys. J Alzheimers Dis Parkinsonism. 2016 Nov;6(6):279. doi: 10.4172/2161-0460.1000279.

10. Stojanovska V., McQuade R.M., Miller S., Nurgali K. Effects of Oxaliplatin Treatment on the Myenteric Plexus Innervation and Glia in the Murine Distal Colon. J Histochem Cytochem. 2018 Oct;66(10):723-736. doi: 10.1369/0022155418774755.

11. Rahman A.A., Robinson A. M., Jovanovska V., Eri R., Nurgali K. Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res. 2015 Dec;362(3):497-512. doi: 10.1007/s00441-015-2251-3.

12. Korzhevskii D.E., Sukhorukova E. G., Gilerovich E. G., et al. Advantages and disadvantages of zinc-ethanol-formaldehyde as a fixative for immunocytochemical studies and confocal laser microscopy. Neuroscience and Behavioral Physiology. 2014;44(5):542-545. doi: 10.1007/s11055-014-9948-8.

13. Chumasov E.I., Kolos E. A., Petrova E. S., Korzhevsky D. E. Immunohistochemistry of the peripheral nervous system. St. Petersburg. SpecLit Publ., 2020. (In Russ.)@@ Чумасов Е. И., Колос Е. А., Петрова Е. С., Коржевский Д. Э. Иммуногистохимия периферической нервной системы. - СПб.: СпецЛит, 2020.

14. Mizoguchi A. Animal models of inflammatory bowel disease. Prog Mol Biol Transl Sci. 2012;105:263-320. doi: 10.1016/B978-0-12-394596-9.00009-3.

15. Straub R.H., Stebner K., Härle P., et al. Key role of the sympathetic microenvironment for the interplay of tumour necrosis factor and interleukin 6 in normal but not in inflamed mouse colon mucosa. Gut. 2005 Aug;54(8):1098-106. doi: 10.1136/gut.2004.062877.

16. Swain M.G., Blennerhassett P. A., Collins S. M. Impaired sympathetic nerve function in the inflamed rat intestine. Gastroenterology. 1991 Mar;100(3):675-82. doi: 10.1016/0016-5085(91)80011-w.

17. Wirtz S., Neufert C., Weigmann B., Neurath M. F. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2(3):541-6. doi: 10.1038/nprot.2007.41.

18. Raethjen J., Pilo A. M., Knowles C., et al. Selective autonomic and sensory deficits in slow transit constipation. Journal of the Autonomic Nervous System. 1997 Sep 10;66(1-2):46-52. doi: 10.1016/s0165-1838(97)00043-x.

19. Tillou J., Poylin V. Functional Disorders: Slow-Transit Constipation. Clin Colon Rectal Surg. 2017 Feb;30(1):76-86. doi: 10.1055/s-0036-1593436.

20. Yeh K.M., Johansson O., Le H., et al. Cystic fibrosis transmembrane conductance regulator modulates enteric cholinergic activities and is abnormally expressed in the enteric ganglia of patients with slow transit constipation. J Gastroenterol. 2019 Nov;54(11):994-1006. doi: 10.1007/s00535-019-01610-9.

21. Zhong Z.H., Yang S., Zhao Y., et al.Comparison of laparoscopic selective colectomy based on barium-strip examination and subtotal colectomy for adult slow-transit constipation. Gastroenterol Rep (Oxf). 2019 Jul 16;7(5):361-366. doi: 10.1093/gastro/goz020.

22. Bassotti G. Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out. World Journal of Gastroenterology. 2013 Jul 14;19(26):4099-105. doi: 10.3748/wjg.v19.i26.4099.

23. Ghoshal U.C., Sachdeva S., Pratap N., et al. Indian consensus on chronic constipation in adults: A joint position statement of the Indian Motility and Functional Diseases Association and the Indian Society of Gastroenterology // Indian J Gastroenterol. 2018 Nov;37(6):526-544. doi: 10.1007/s12664-018-0894-1.

24. Spencer N.J., Kyloh M., Duffield M. Identification of different types of spinal afferent nerve endings that encode noxious and innocuous stimuli in the large intestine using a novel anterograde tracing technique. PLoS One. 2014 Nov 10;9(11): e112466. doi: 10.1371/journal.pone.0112466.

25. Chumasov E.I., Romashchenko P. N., Maistrenko N. A. et al. Pathohistological study of the ganglionic plexuses of the sigmoid colon in patients with chronic slow-transit constipation. Bulletin of the Russian Military Medical Academy. 2021;3(75):117-124. (In Russ.) doi: 10.17816/brmma75673.@@ Чумасов Е. И., Ромащенко П. Н., Майстренко Н. А. и др. Патогистологическое исследование ганглиозных сплетений сигмовидной кишки больных хроническим медленно-транзитным запором // Вестник Российской Военно-медицинской академии. - 2021. - № 3(75). - С. 117-124. doi: 10.17816/brmma75673.