Role of guanylate cyclase-C in the occurrence and treatment of digestive system diseases_West China Medical Journal

Authors：

WANG Bing ^1,2 , SUN Hongyu ^1,3 ,  TANG Lijun ^1,2,3

1. Department of General Surgery, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P. R. China;
2. College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan 610031, P. R. China;
3. Key Laboratory of Pancreas Injury and Repair in Sichuan Province, Chengdu, Sichuan 610083, P. R. China;

Corresponding author：

TANG Lijun, Email: tanglj2016@163.com

Keywords：

Guanylate cyclase-C; Guanylin; Uroguanylin; Cyclic guanosine monophosphate

DOI：

10.7507/1002-0179.202004038

Video：

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In recent years, the importance of guanylate cyclase-C (GC-C) in digestive system diseases has received more and more attention. It plays a key role in regulating water and electrolyte balance, maintaining gastrointestinal function, relieving abdominal pain, controlling inflammation, regulating intestinal microecology, inhibiting tumor growth and regulating cell proliferation, and is considered as a potential therapeutic target for digestive tract diseases. This article reviews the role of GC-C in digestive system diseases and related intervention studies of agonists linaclotide and plecanatide in recent years, in order to better understand its intrinsic function and further guide the diagnosis and treatment of related clinical diseases.

Citation： WANG Bing, SUN Hongyu, TANG Lijun. Role of guanylate cyclase-C in the occurrence and treatment of digestive system diseases. West China Medical Journal, 2021, 36(11): 1623-1627. doi: 10.7507/1002-0179.202004038 Copy

1.	Smith HW, Gyles CL. The relationship between two apparently different enterotoxins produced by enteropathogenic strains of Escherichia coli of porcine origin. J Med Microbiol, 1970, 3(3): 387-401.
2.	Kuhn M. Molecular physiology of membrane guanylyl cyclase receptors. Physiol Rev, 2016, 96(2): 751-804.
3.	Waldman SA, Camilleri M. Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut, 2018, 67(8): 1543-1552.
4.	Uranga JA, Castro M, Abalo R. Guanylate cyclase C: a current hot target, from physiology to pathology. Curr Med Chem, 2018, 25(16): 1879-1908.
5.	Pattison AM, Blomain ES, Merlino DJ, et al. Intestinal enteroids model guanylate cyclase C-dependent secretion induced by heat-stable enterotoxins. Infect Immun, 2016, 84(10): 3083-3091.
6.	Bijvelds MJ, Loos M, Bronsveld I, et al. Inhibition of heat-stable toxin-induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. J Infect Dis, 2015, 212(11): 1806-1815.
7.	Venglovecz V, Pallagi P, Kemény LV, et al. The importance of aquaporin 1 in pancreatitis and its relation to the CFTR Cl - channel. Front Physiol, 2018, 9: 854.
8.	Hegyi P, Wilschanski M, Muallem S, et al. CFTR: a new horizon in the pathomechanism and treatment of pancreatitis. Rev Physiol Bioch P, 2016, 170(4): 37-66.
9.	Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol, 2019, 16(8): 479-496.
10.	Kulaksiz H, Cetin Y. The electrolyte/fluid secretion stimulatory peptides guanylin and uroguanylin and their common functional coupling proteins in the rat pancreas: a correlative study of expression and cell-specific localization. Pancreas, 2002, 25(2): 170-175.
11.	Schulz S, Chrisman TD, Garbers DL. Cloning and expression of guanylin. Its existence in various mammalian tissues. J Biol Chem, 1992, 267(23): 16019-16021.
12.	Zhang ZH, Jow F, Numann R, et al. The airway-epithelium: a novel site of action by guanylin. Biochem Biophys Res Commun, 1998, 244(1): 50-56.
13.	Lan D, Niu J, Miao J, et al. Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index. Sci Rep, 2016, 6: 25034.
14.	Han X, Mann E, Gilbert S, et al. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS One, 2011, 6(1): e16139.
15.	Lin JE, Snook AE, Li P, et al. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS One, 2012, 7(2): e31686.
16.	Lin JE, Li P, Snook AE, et al. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology, 2010, 138(1): 241-254.
17.	Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med, 2011, 365(6): 527-536.
18.	Tchernychev B, Ge P, Kessler MM, et al. MRP4 modulation of the guanylate cyclase-C/cGMP pathway: effects on linaclotide-induced electrolyte secretion and cGMP efflux. J Pharmacol Exp Ther, 2015, 355(1): 48-56.
19.	Shailubhai K, Palejwala V, Arjunan KP, et al. Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis. World J Gastrointest Pharmacol Ther, 2015, 6(4): 213-222.
20.	Diop L, Raymond F, Fargeau H, et al. Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat. J Pharmacol Exp Ther, 2002, 302(3): 1013-1022.
21.	Boulete IM, Thadi A, Beaufrand C, et al. Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models. World J Gastroenterol, 2018, 24(17): 1888-1900.
22.	Silos-Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain, 2013, 154(9): 1820-1830.
23.	Chang WL, Masih S, Thadi A, et al. Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc⁺/Min-FCCC mice. World J Gastrointest Pharmacol Ther, 2017, 8(1): 47-59.
24.	Harmel-Laws E, Mann EA, Cohen MB, et al. Guanylate cyclase C deficiency causes severe inflammation in a murine model of spontaneous colitis. PLoS One, 2013, 8(11): e79180.
25.	Brenna Ø, Bruland T, Furnes MW, et al. The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease. Scand J Gastroenterol, 2015, 50(10): 1241-1252.
26.	Freihat LA, Wheeler JI, Wong A, et al. IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity. Sci Rep, 2019, 9(1): 15468.
27.	Amarachintha S, Harmel-Laws E, Steinbrecher KA. Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens. Sci Rep, 2018, 8(1): 1521.
28.	Tronstad RR, Kummen M, Holm K, et al. Guanylate cyclase C activation shapes the intestinal microbiota in patients with familial diarrhea and increased susceptibility for Crohn’s disease. Inflamm Bowel Dis, 2017, 23(10): 1752-1761.
29.	Kraft CL, Rappaport JA, Snook AE, et al. GUCY2C maintains intestinal LGR5⁺ stem cells by opposing ER stress. Oncotarget, 2017, 8(61): 102923-102933.
30.	Kastenhuber ER, Lowe SW. Putting p53 in context. Cell, 2017, 170(6): 1062-1078.
31.	Wilson C, Lin JE, Li P, et al. The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2014, 23(11): 2328-2337.
32.	McHugh DR, Cotton CU, Moss FJ, et al. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol, 2018, 315(5): G868-G878.
33.	Bassotti G, Usai-Satta P, Bellini M. Linaclotide for the treatment of chronic constipation. Expert Opin Pharmacother, 2018, 19(11): 1261-1266.
34.	Brenner DM, Argoff CE, Fox SM, et al. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain, 2020, 161(5): 1027-1036.
35.	Nee JW, Johnston JM, Shea EP, et al. Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled phase 3 analysis. Expert Rev Gastroenterol Hepatol, 2019, 13(4): 397-406.
36.	Busby RW, Kessler MM, Bartolini WP, et al. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther, 2013, 344(1): 196-206.
37.	Brancale A, Shailubhai K, Ferla S, et al. Therapeutically targeting guanylate cyclase-C: computational modeling of plecanatide, a uroguanylin analog. Pharmacol Res Perspect, 2017, 5(2): e00295.
38.	Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol, 2018, 113(5): 735-745.
39.	DeMicco M, Barrow L, Hickey B, et al. Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol, 2017, 10(11): 837-851.
40.	Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized phaseⅢ clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol, 2017, 112(4): 613-621.
41.	Collins SM. Peripheral mechanisms of symptom generation in irritable bowel syndrome. Can J Gastroenterol, 2001, 15(Suppl B): 14B-16B.
42.	Wald A. Constipation: advances in diagnosis and treatment. JAMA, 2016, 315(2): 185-191.

1. Smith HW, Gyles CL. The relationship between two apparently different enterotoxins produced by enteropathogenic strains of Escherichia coli of porcine origin. J Med Microbiol, 1970, 3(3): 387-401.
2. Kuhn M. Molecular physiology of membrane guanylyl cyclase receptors. Physiol Rev, 2016, 96(2): 751-804.
3. Waldman SA, Camilleri M. Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders. Gut, 2018, 67(8): 1543-1552.
4. Uranga JA, Castro M, Abalo R. Guanylate cyclase C: a current hot target, from physiology to pathology. Curr Med Chem, 2018, 25(16): 1879-1908.
5. Pattison AM, Blomain ES, Merlino DJ, et al. Intestinal enteroids model guanylate cyclase C-dependent secretion induced by heat-stable enterotoxins. Infect Immun, 2016, 84(10): 3083-3091.
6. Bijvelds MJ, Loos M, Bronsveld I, et al. Inhibition of heat-stable toxin-induced intestinal salt and water secretion by a novel class of guanylyl cyclase C inhibitors. J Infect Dis, 2015, 212(11): 1806-1815.
7. Venglovecz V, Pallagi P, Kemény LV, et al. The importance of aquaporin 1 in pancreatitis and its relation to the CFTR Cl - channel. Front Physiol, 2018, 9: 854.
8. Hegyi P, Wilschanski M, Muallem S, et al. CFTR: a new horizon in the pathomechanism and treatment of pancreatitis. Rev Physiol Bioch P, 2016, 170(4): 37-66.
9. Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol, 2019, 16(8): 479-496.
10. Kulaksiz H, Cetin Y. The electrolyte/fluid secretion stimulatory peptides guanylin and uroguanylin and their common functional coupling proteins in the rat pancreas: a correlative study of expression and cell-specific localization. Pancreas, 2002, 25(2): 170-175.
11. Schulz S, Chrisman TD, Garbers DL. Cloning and expression of guanylin. Its existence in various mammalian tissues. J Biol Chem, 1992, 267(23): 16019-16021.
12. Zhang ZH, Jow F, Numann R, et al. The airway-epithelium: a novel site of action by guanylin. Biochem Biophys Res Commun, 1998, 244(1): 50-56.
13. Lan D, Niu J, Miao J, et al. Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index. Sci Rep, 2016, 6: 25034.
14. Han X, Mann E, Gilbert S, et al. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS One, 2011, 6(1): e16139.
15. Lin JE, Snook AE, Li P, et al. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS One, 2012, 7(2): e31686.
16. Lin JE, Li P, Snook AE, et al. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology, 2010, 138(1): 241-254.
17. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med, 2011, 365(6): 527-536.
18. Tchernychev B, Ge P, Kessler MM, et al. MRP4 modulation of the guanylate cyclase-C/cGMP pathway: effects on linaclotide-induced electrolyte secretion and cGMP efflux. J Pharmacol Exp Ther, 2015, 355(1): 48-56.
19. Shailubhai K, Palejwala V, Arjunan KP, et al. Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis. World J Gastrointest Pharmacol Ther, 2015, 6(4): 213-222.
20. Diop L, Raymond F, Fargeau H, et al. Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat. J Pharmacol Exp Ther, 2002, 302(3): 1013-1022.
21. Boulete IM, Thadi A, Beaufrand C, et al. Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models. World J Gastroenterol, 2018, 24(17): 1888-1900.
22. Silos-Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain, 2013, 154(9): 1820-1830.
23. Chang WL, Masih S, Thadi A, et al. Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc⁺/Min-FCCC mice. World J Gastrointest Pharmacol Ther, 2017, 8(1): 47-59.
24. Harmel-Laws E, Mann EA, Cohen MB, et al. Guanylate cyclase C deficiency causes severe inflammation in a murine model of spontaneous colitis. PLoS One, 2013, 8(11): e79180.
25. Brenna Ø, Bruland T, Furnes MW, et al. The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease. Scand J Gastroenterol, 2015, 50(10): 1241-1252.
26. Freihat LA, Wheeler JI, Wong A, et al. IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity. Sci Rep, 2019, 9(1): 15468.
27. Amarachintha S, Harmel-Laws E, Steinbrecher KA. Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens. Sci Rep, 2018, 8(1): 1521.
28. Tronstad RR, Kummen M, Holm K, et al. Guanylate cyclase C activation shapes the intestinal microbiota in patients with familial diarrhea and increased susceptibility for Crohn’s disease. Inflamm Bowel Dis, 2017, 23(10): 1752-1761.
29. Kraft CL, Rappaport JA, Snook AE, et al. GUCY2C maintains intestinal LGR5⁺ stem cells by opposing ER stress. Oncotarget, 2017, 8(61): 102923-102933.
30. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell, 2017, 170(6): 1062-1078.
31. Wilson C, Lin JE, Li P, et al. The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2014, 23(11): 2328-2337.
32. McHugh DR, Cotton CU, Moss FJ, et al. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol, 2018, 315(5): G868-G878.
33. Bassotti G, Usai-Satta P, Bellini M. Linaclotide for the treatment of chronic constipation. Expert Opin Pharmacother, 2018, 19(11): 1261-1266.
34. Brenner DM, Argoff CE, Fox SM, et al. Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain, 2020, 161(5): 1027-1036.
35. Nee JW, Johnston JM, Shea EP, et al. Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled phase 3 analysis. Expert Rev Gastroenterol Hepatol, 2019, 13(4): 397-406.
36. Busby RW, Kessler MM, Bartolini WP, et al. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther, 2013, 344(1): 196-206.
37. Brancale A, Shailubhai K, Ferla S, et al. Therapeutically targeting guanylate cyclase-C: computational modeling of plecanatide, a uroguanylin analog. Pharmacol Res Perspect, 2017, 5(2): e00295.
38. Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol, 2018, 113(5): 735-745.
39. DeMicco M, Barrow L, Hickey B, et al. Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol, 2017, 10(11): 837-851.
40. Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized phaseⅢ clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol, 2017, 112(4): 613-621.
41. Collins SM. Peripheral mechanisms of symptom generation in irritable bowel syndrome. Can J Gastroenterol, 2001, 15(Suppl B): 14B-16B.
42. Wald A. Constipation: advances in diagnosis and treatment. JAMA, 2016, 315(2): 185-191.

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