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Physiology, Motilin

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Last Update: September 29, 2020.

Introduction

Gastrointestinal hormones are peptides released into the portal system targeting specific cells. Gastrointestinal hormones are an essential part of the digestive system since they regulate smooth muscle contractions of the gastrointestinal system allowing the food to move throughout the gastrointestinal tract. Motilin is the hormone that is cyclically released during the fasted state and is released by the entero-endocrine cells (Mo cells) in the upper small intestine. Motilin stimulates gastric and small intestine motility, causing undigested food in these regions to move into the large intestine. This movement is also known as the migrating motor complex (MMC), or the interdigestive myoelectric complex. Motilin also stimulates the production of pepsin in the stomach chief cells, as well as the release of pancreatic polypeptide and somatostatin.  Motilin has been associated with disturbed gastrointestinal motility. [1]  Motilin is reduced in pregnancy, during which there is gastrointestinal tract hypomotility. Furthermore, the motilin level is sensitive to the food ingested. Motilin levels decrease with the ingestion of glucose and decrease with fat.

Issues of Concern

The gastrointestinal peristalsis is increased hormonally by cholecystokinin, gastrin, serotonin, insulin, and motilin. The gastrointestinal motility is decreased hormonally by glucagon and secretin. The current thinking is that secretin decreases the motility of the digestive tract by reducing the level of plasma motilin.[2]

Cellular

Motilin is 22 amino acid oligopeptide secreted by M cells, which are present in the epithelium of the mucosa of the duodenum mainly.[3] 

Motilin binds to the motilin receptors, which are G protein-coupled receptors.[4]  The motilin receptors stimulate phospholipase C which synthesizes inositol-trisphosphate. When the motilin receptors get activated, the smooth muscles get contracted. Motilin works via actions on the enteric neurons, smooth muscle cells, and vagal afferents. Smooth muscle contraction mediation occurs by increased intracellular calcium and diacylglycerol.[3] Motilin has homology with ghrelin and its receptor, but ghrelin does not bind to the motilin receptor.

Development

In the fourth week of pregnancy, the distal part of the foregut and the proximal portion of the midgut form the origin of the duodenum. The junction of the two parts of the duodenum is just distal to the origin of the liver bud.

In the fifth week of the pregnancy, the epithelial cells proliferate, making the duodenal lumen smaller.

Organ Systems Involved

The target cells of motilin are large intestine, small intestine, stomach, lower esophageal sphincter, and gallbladder.[5] The expression of the motilin receptor is differential throughout the gastrointestinal tract in dogs, and researchers found that duodenum and ileum have the most robust immunoreactivity to mRNA expression of the motilin receptor.[6]

Function

Motilin acts on several organs. It increases gall bladder emptying, increased insulin release from the pancreas, GI tract mobility, and increased hunger. [1] Motilin acts on the movement of the gastrointestinal tract by regulating the migrating motor complex, called hunger contraction.[7] The migrating motor complex occurs in the fasting, interdigestive periods. The migrating motor complex moves from the stomach to the terminal ileum, occurs at 1.5 to 2-hour intervals. [1] The migrating motor complexes facilitate the transportation of the undigested foods, aids bacterial transport from the small intestine into the large intestine, and inhibit the bacterial migration from the large intestine into the terminal ileum. The migrating motor complexes consist of three phases. [1] Phase I is when the smooth muscle of the gastrointestinal tract is quiescent. Phase II has increasing peristaltic activity of the digestive tract. Phase III, has the most contractile activity and is the characteristic phase of the migrating motor complex. In phase III, the pylorus of the stomach remains open, allowing undigested food to move into the small intestine. 

Motilin is considered recently as a primary orexigenic hormone by modulating the neurocircuit in the brain.[7]

Motilin raises pepsin output and the acid secretion in the stomach.[8] The motilin effect in the lower esophageal sphincter is the contraction of the sphincter and increased resting pressure the sphincter. Motilin causes contraction of the stomach and the lower esophageal sphincter, whereas it does not affect the contraction of the esophagus. The level of motilin is directly proportional to the number of the contractions of the stomach and the number of the contractions of the lower esophageal sphincter.[9]

Mechanism

Motilin is released periodically and increased during the fasting period.[10] During the interdigestive period, motility increases water and protein secretion through the pancreas.[11] Motilin secretion is enhanced by the food that contains fat, whereas suppressed by the food that contains glucose.[12] Acidification of the duodenum can increase motilin release.[13]

Pathophysiology

Motilin has been associated with disturbed gastointestinal motility. [1] A study measured motilin levels during pregnancy, and levels of motilin demonstrated significant reduction. The motilin level returned to its average level one week postpartum. This phenomenon can be advanced to explain why pregnant women have gastrointestinal hypomotility partially. Gastrointestinal hypomotility in pregnant women can manifest as constipation, heartburn, and gallbladder stasis.[5]

Clinical Significance

Erythromycin activates the motilin receptors, which are G protein-coupled receptors. Such compounds have the name motilides. Using erythromycin can cause concentration-dependent contractions of the stomach and promote gastric emptying significantly. However, erythromycin has less potency compared to motilin.[4] Erythromycin, the motilin receptor agonist, increases the hunger sensation.[7] There is considerable interest in motilides in the drug discovery and more importantly, small molecule motilin receptor agonists, given their prokinetic effect; this could usher in more focused therapies for diabetic gastroparesis.

A study examined patients who underwent T tube after choledochotomy and cholecystectomy have duodenal-biliary reflux. The level of motilin was measured in patients after having a T tube after choledochotomy and cholecystectomy. Researchers divided the patients into two groups, which were the reflux group and control group. The level of motilin of reflux group patients had a much lower motilin level compared to the control group. This observation could probably explain the cause of the duodenal-biliary reflux. The lower level of motilin causes hypomotility of the sphincter of Oddi.[14][1]

Continuing Education / Review Questions

References

1.
Deloose E, Verbeure W, Depoortere I, Tack J. Motilin: from gastric motility stimulation to hunger signalling. Nat Rev Endocrinol. 2019 Apr;15(4):238-250. [PubMed: 30675023]
2.
Mitznegg P, Bloom SR, Domschke W, Haecki WH, Domschke S, Belohlavek D, Wünsch E, Demling L. Effect of secretin on plasma motilin in man. Gut. 1977 Jun;18(6):468-71. [PMC free article: PMC1411507] [PubMed: 17563]
3.
Kitazawa T, Kaiya H. Regulation of Gastrointestinal Motility by Motilin and Ghrelin in Vertebrates. Front Endocrinol (Lausanne). 2019;10:278. [PMC free article: PMC6533539] [PubMed: 31156548]
4.
Kato S, Takahashi A, Shindo M, Yoshida A, Kawamura T, Matsumoto K, Matsuura B. Characterization of the gastric motility response to human motilin and erythromycin in human motilin receptor-expressing transgenic mice. PLoS One. 2019;14(2):e0205939. [PMC free article: PMC6383879] [PubMed: 30789939]
5.
Christofides ND, Ghatei MA, Bloom SR, Borberg C, Gillmer MD. Decreased plasma motilin concentrations in pregnancy. Br Med J (Clin Res Ed). 1982 Nov 20;285(6353):1453-4. [PMC free article: PMC1500630] [PubMed: 6814598]
6.
He Y, Wang H, Yang D, Wang C, Yang L, Jin C. Differential expression of motilin receptor in various parts of gastrointestinal tract in dogs. Gastroenterol Res Pract. 2015;2015:970940. [PMC free article: PMC4396909] [PubMed: 25918525]
7.
Zhao D, Meyer-Gerspach AC, Deloose E, Iven J, Weltens N, Depoortere I, O'daly O, Tack J, Van Oudenhove L. The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study. Sci Rep. 2018 Jan 29;8(1):1819. [PMC free article: PMC5789052] [PubMed: 29379095]
8.
Konturek SJ, Dembinski A, Krol R, Wünsch E. Effect of 13-NLE-motilin on gastric secretion, serum gastrin level and mucosal blood flow in dogs. J Physiol. 1977 Jan;264(3):665-72. [PMC free article: PMC1307785] [PubMed: 321755]
9.
Meissner AJ, Bowes KL, Zwick R, Daniel EE. Effect of motilin on the lower oesophageal sphincter. Gut. 1976 Dec;17(12):925-32. [PMC free article: PMC1411234] [PubMed: 1017712]
10.
Korimilli A, Parkman HP. Effect of atilmotin, a motilin receptor agonist, on esophageal, lower esophageal sphincter, and gastric pressures. Dig Dis Sci. 2010 Feb;55(2):300-6. [PMC free article: PMC2832181] [PubMed: 19997977]
11.
Magee DF, Naruse S. The role of motilin in periodic interdigestive pancreatic secretion in dogs. J Physiol. 1984 Oct;355:441-7. [PMC free article: PMC1193501] [PubMed: 6491998]
12.
Christofides ND, Bloom SR, Besterman HS, Adrian TE, Ghatei MA. Release of motilin by oral and intravenous nutrients in man. Gut. 1979 Feb;20(2):102-6. [PMC free article: PMC1419440] [PubMed: 428820]
13.
Modlin IM, Mitznegg P, Bloom SR. Motilin release in the pig. Gut. 1978 May;19(5):399-402. [PMC free article: PMC1412103] [PubMed: 658771]
14.
Zhang ZH, Wu SD, Wang B, Su Y, Jin JZ, Kong J, Wang HL. Sphincter of Oddi hypomotility and its relationship with duodenal-biliary reflux, plasma motilin and serum gastrin. World J Gastroenterol. 2008 Jul 07;14(25):4077-81. [PMC free article: PMC2725349] [PubMed: 18609694]
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