Review Article | Published:

The migrating motor complex: control mechanisms and its role in health and disease

Nature Reviews Gastroenterology & Hepatology volume 9, pages 271285 (2012) | Download Citation

Abstract

The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupted by feeding. The MMC is present in the gastrointestinal tract of many species, including humans. The complex can be subdivided into four phases, of which phase III is the most active, with a burst of contractions originating from the antrum or duodenum and migrating distally. Control of the MMC is complex. Phase III of the MMC with an antral origin can be induced in humans through intravenous administration of motilin, erythromycin or ghrelin, whereas administration of serotonin or somatostatin induces phase III activity with duodenal origin. The role of the vagus nerve in control of the MMC seems to be restricted to the stomach, as vagotomy abolishes the motor activity in the stomach, but leaves the periodic activity in the small bowel intact. The physiological role of the MMC is incompletely understood, but its absence has been associated with gastroparesis, intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Measuring the motility of the gastrointestinal tract can be important for the diagnosis of gastrointestinal disorders. In this Review we summarize current knowledge of the MMC, especially its role in health and disease.

Key points

  • The migrating motor complex (MMC) is a cyclic motor pattern in the gastrointestinal tract that occurs during the interdigestive state in humans and other animals

  • Levels of endogenous motilin fluctuate together with the different MMC phases, and exogenously administered motilin can induce phase III contractions

  • Exogenously administered ghrelin induces phase III contractions; detailed studies of fluctuations of endogenous ghrelin levels with the MMC phases in humans are lacking

  • Serotonin and somatostatin inhibit the occurrence of antral phase III contractions and redirect the origin of these contractions towards the duodenum

  • Vagotomy abolishes the MMC pattern in the stomach, but has a minimal effect on the small bowel pattern

  • The activity of the MMC is a clinical marker for the functionality of the gastrointestinal tract, and several disorders are linked to a disturbed MMC

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References

  1. 1.

    Backwards and forwards with the migrating complex. Dig. Dis. Sci. 26, 641–666 (1981).

  2. 2.

    Periodic wave phenomena in the secretory function of the digestive tract. Gaz. Hop. Botkine 34, 1529–1542 (1902).

  3. 3.

    Le travail periodique de l'appareil digestif en dehors de la digestion [French]. Arch. Des Sci. Biol. 11, 1–157 (1905).

  4. 4.

    & An explanation of hunger. Am. J. Physiol. 29, 441–454 (1912).

  5. 5.

    A study of the mechanisms of the hunger contractions of the empty stomach by experiments on dogs. Am. J. Physiol. 32, 369–388 (1913).

  6. 6.

    A migrating electric complex of canine small intestine. Am. J. Physiol. 217, 1757–1763 (1969).

  7. 7.

    & The interdigestive myo-electric complex of the stomach and small bowel of dogs. J. Physiol. 246, 289–309 (1975).

  8. 8.

    , , & Disruptive effect of test meals on interdigestive motor complex in dogs. Am. J. Physiol. 235, E661–E665 (1978).

  9. 9.

    , & Nervous control of migratory myoelectric complex of the small bowel. Am. J. Physiol. 238, G102–G108 (1980).

  10. 10.

    & Insulin and jejunal electrical activity in dogs and sheep. Am. J. Physiol. 230, 1538–1544 (1976).

  11. 11.

    & The propagation of segmental contractions along the small intestine. J. Physiol. 227, 611–625 (1972).

  12. 12.

    & The effect of weaning on the motility of the small intestine in the calf. Br. J. Nutr. 30, 491–499 (1973).

  13. 13.

    & Electrical spiking activity and propulsion in small intestine in fed and fasted rats. Gastroenterology 68, 1500–1508 (1975).

  14. 14.

    & The effect of feeding on the motility of the stomach and small intestine in the pig. Br. J. Nutr. 35, 397–405 (1976).

  15. 15.

    & The migrating motor complex. Gastroenterol. Clin. Biol. 5, 681–690 (1981).

  16. 16.

    et al. Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J. Physiol. 550, 227–240 (2003).

  17. 17.

    , , , & Ghrelin regulates gastric phase III-like contractions in freely moving conscious mice. Neurogastroenterol. Motil. 21, 78–84 (2009).

  18. 18.

    et al. Dual effects of acupuncture on gastric motility in conscious rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R862–R872 (2003).

  19. 19.

    Migrating electrical spike activity in the fasting human small intestine. Am. J. Dig. Dis. 23, 769–775 (1978).

  20. 20.

    , , & The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J. Clin. Invest. 59, 1158–1166 (1977).

  21. 21.

    et al. Motilin and the interdigestive migrating motor complex in man. Dig. Dis. Sci. 24, 497–500 (1979).

  22. 22.

    , & Variability of migrating motor complex in humans. Dig. Dis. Sci. 37, 723–728 (1992).

  23. 23.

    , , , & Erythromycin induces migrating motor complex in human gastrointestinal tract. Dig. Dis. Sci. 31, 157–161 (1986).

  24. 24.

    , , & Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 43, 395–400 (1998).

  25. 25.

    et al. Gastrointestinal sounds and migrating motor complex in fasted humans. Am. J. Gastroenterol. 94, 374–381 (1999).

  26. 26.

    , & The secretory component of the interdigestive motor complex in man. Scand. J. Gastroenterol. 14, 663–667 (1979).

  27. 27.

    Meaningful or redundant complexity—mechanisms behind cyclic changes in gastroduodenal pH in the fasting state. Acta Physiol. (Oxf.) 201, 127–131 (2011).

  28. 28.

    & High-resolution analysis of the duodenal interdigestive phase III in humans. Neurogastroenterol. Motil. 13, 473–481 (2001).

  29. 29.

    , & The secretory component of the interdigestive migrating motor complex in man. Scand. J. Gastroenterol. 14, 663–667 (1979).

  30. 30.

    , , , & Effect of 13-norleucin motilin on water and ion transport in the human jejunum. Gastroenterology 87, 550–556 (1984).

  31. 31.

    , & Pressure and frequency dependent linkage between motility and epithelial secretion in human proximal small intestine. Gut 46, 376–384 (1999).

  32. 32.

    , & Circadian variation in the propagation velocity of the migrating motor complex. Gastroenterology 91, 926–930 (1986).

  33. 33.

    , & Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 98, 1208–1218 (1990).

  34. 34.

    et al. Relationship between enteric migrating motor complex and the sleep cycle. Am. J. Physiol. 259, G983–G990 (1990).

  35. 35.

    et al. Modulation of the duration of human postprandial motor activity by sleep. Am. J. Physiol. 256, G851–G855 (1989).

  36. 36.

    et al. Immunohistochemical localization of motilin in endocrine non-enterochromaffin cells of the small intestine of humans and monkey. Gastroenterology 76, 897–902 (1979).

  37. 37.

    et al. Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Regul. Pept. 124, 119–125 (2005).

  38. 38.

    , & Motilin, a gastric motor activity stimulating polypeptide: the complete amino acid sequence. Can. J. Biochem. 51, 533–537 (1973).

  39. 39.

    , & Motilin and ghrelin as prokinetic drug targets. Pharmacol. Ther. 123, 207–223 (2009).

  40. 40.

    , , , , & The rat lacks functional genes for motilin and the motilin recpetor. Neurogastroenterol. Motil. 16, 841 (2004).

  41. 41.

    , , & Molecular, functional and cross-species comparisons between the receptors for the prokinetic neuropeptides, motilin and ghrelin. Gastroenterology 122, A54 (2002).

  42. 42.

    et al. Motilin-induced mechanical activity in the canine alimentary tract. Scand. J. Gastroenterol. Suppl. 39, 93–110 (1976).

  43. 43.

    , , & Radioimmunoassay of motilin. Validation and studies on the relationship between plasma motilin and interdigestive myoelectric activity of the duodenum of dog. Am. J. Dig. Dis. 23, 789–795 (1978).

  44. 44.

    , & Fasting plasma motilin levels are related to the interdigestive motility complex. Gastroenterology 79, 716–719 (1980).

  45. 45.

    et al. Effect of motilin on the opossum upper gastrointestinal tract and sphincter of Oddi. Am. J. Physiol. 245, G476–G481 (1983).

  46. 46.

    , , , & Motilin secretion and the migrating myoelectric complex in the pig. Q. J. Exp. Physiol. 72, 51–60 (1987).

  47. 47.

    , , & Effects of motilin, somatostatin, and pancreatic polypeptide on the migrating myoelectric complex in pig and dog. Gastroenterology 82, 1395–1402 (1982).

  48. 48.

    , & Motilin and migrating myoelectric complexes in the pig and the dog. Q. J. Exp. Physiol. 69, 875–890 (1984).

  49. 49.

    , & Effect of rabbit antimotilin serum on myoelectric activity and plasma motilin concentration in fasting dog. Am. J. Physiol. 245, G547–G553 (1983).

  50. 50.

    Motilin is a digestive hormone in the dog. Gastroenterology 87, 909–913 (1984).

  51. 51.

    et al. In man, only activity fronts that originate in the stomach correlate with motilin peaks. Scand. J. Gastroenterol. 22, 781–784 (1987).

  52. 52.

    , , , & Plasma motilin variation during the interdigestive and digestive states in man. Neurogastroenterol. Motil. 2, 240–246 (1990).

  53. 53.

    et al. Effect of duodenectomy on gastric motility and gastric hormones in dogs. Ann. Surg. 233, 353–359 (2001).

  54. 54.

    , & The activity front of the migrating motor complex of the human stomach but not of the small intestine is motilin-dependent. Regul. Pept. 6, 363–369 (1983).

  55. 55.

    et al. Pancreatic polypeptide is not involved in the regulation of the migrating motor complex in man. Regul. Pept. 3, 41–49 (1982).

  56. 56.

    , , & Effect of pancreatic polypeptide on canine migrating motor complex and plasma motilin. Am. J. Physiol. 245, G178–G185 (1983).

  57. 57.

    et al. 5-hydroxytryptamine-3 receptors are involved in the initiation of gastric phase-3 motor activity in humans. Gastroenterology 105, 773–780 (1993).

  58. 58.

    , & Somatostatin and the interdigestive migrating motor complex in man. Regul. Pept. 5, 209–217 (1983).

  59. 59.

    & Duodenal pH governs interdigestive motility in humans. Am. J. Physiol. 268, G146–G152 (1995).

  60. 60.

    Relationship between acid secretory activity and gastroduodenal migrating motor complex. Hepatogastroenterology 43, 1288–1295 (1996).

  61. 61.

    et al. Cause-and-effect relationship between motilin and migrating myoelectric complexes. Am. J. Physiol. 245, G277–G284 (1983).

  62. 62.

    Morphine and gastroduodenal motility. Dig. Dis. Sci. 44, 2178–2186 (1999).

  63. 63.

    et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell. Metab. 10, 167–177 (2009).

  64. 64.

    et al. Increases in plasma motilin follow each episode of gallbladder emptying during the interdigestive period, and changes in serum bile acid concentration correlate to plasma motilin. Scand. J. Gastroenterol. 30, 122–127 (1995).

  65. 65.

    et al. Motor cycles with phase III in antrum are associated with high motilin levels and prolonged gallbladder emptying. Am. J. Physiol. 264, G596–G600 (1993).

  66. 66.

    et al. The relationship between interdigestive gallbladder and gastroduodenal motility in man. Gastroenterol. Jpn 25, 568–574 (1990).

  67. 67.

    et al. Altered antroduodenal motility after cholecystectomy. Am. J. Surg. 168, 609–614 (1994).

  68. 68.

    , , , & Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog. Am. J. Physiol. 247, G688–G694 (1984).

  69. 69.

    , , & Erythromycin and its derivatives with motilin-like biological activities inhibit the specific binding of 125I-motilin to duodenal muscle. Biochem. Biophys. Res. Commun. 150, 877–882 (1988).

  70. 70.

    et al. Erythromycin is a motilin receptor agonist. Am. J. Physiol. 257, G470–G474 (1989).

  71. 71.

    et al. The motilin antagonist ANQ-11125 blocks motilide-induced contractions in vitro in the rabbit. Biochem. Biophys. Res. Commun. 198, 411–416 (1994).

  72. 72.

    & Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle. Regul. Pept. 55, 227–235 (1995).

  73. 73.

    et al. Receptor for motilin identified in the human gastrointestinal system. Science 284, 2184–2188 (1999).

  74. 74.

    et al. Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis. Gastroenterology 103, 72–79 (1992).

  75. 75.

    , , , & Concentration-dependent stimulation of cholinergic motor nerves or smooth muscle by [Nle13]motilin in the isolated rabbit gastric antrum. Eur. J. Pharmacol. 337, 267–274 (1997).

  76. 76.

    , , & Gastrokinetic effects of erythromycin: myogenic and neurogenic mechanisms of action in rabbit stomach. Am. J. Physiol. 269, G418–G426 (1995).

  77. 77.

    , , , & Migrating motor complex recorded spontaneously and induced by motilin and erythromycin in an ex vivo rabbit intestinal preparation. Peptides 15, 1067–1077 (1994).

  78. 78.

    , , , & Actions of the 5-hydroxytryptamine 1 receptor agonist sumatriptan on interdigestive gastrointestinal motility in man. Gut 42, 36–41 (1998).

  79. 79.

    , , & Sumatriptan is an agonist at 5-HT receptors on myenteric neurones in the guinea-pig gastric antrum. Neurogastroenterol. Motil. 19, 39–46 (2007).

  80. 80.

    et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

  81. 81.

    , , , & Interaction of the growth hormone-releasing peptides ghrelin and growth hormone-releasing peptide-6 with the motilin receptor in the rabbit gastric antrum. J. Pharmacol. Exp. Ther. 305, 660–667 (2003).

  82. 82.

    et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc. Natl Acad. Sci. USA 105, 6320–6325 (2008).

  83. 83.

    et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141, 4255–4261 (2000).

  84. 84.

    et al. Investigation of the presence of ghrelin in the central nervous system of the rat and mouse. Neuroscience 193, 1–9 (2011).

  85. 85.

    et al. Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci. Lett. 321, 157–160 (2002).

  86. 86.

    et al. Distribution of ghrelin-immunoreactive neuronal networks in the human hypothalamus. Brain Res. 1125, 31–36 (2006).

  87. 87.

    et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661 (2003).

  88. 88.

    et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc. Natl Acad. Sci. USA 101, 8227–8232 (2004).

  89. 89.

    et al. The cholinergic system controls ghrelin release and ghrelin-induced growth hormone release in humans. J. Clin. Endocrinol. Metab. 89, 4729–4733 (2004).

  90. 90.

    et al. Acetylcholine regulates ghrelin secretion in humans. J. Clin. Endocrinol. Metab. 89, 2429–2433 (2004).

  91. 91.

    et al. Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proc. Natl Acad. Sci. USA 107, 15868–15873.

  92. 92.

    et al. Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem. Biophys. Res. Commun. 281, 1220–1225 (2001).

  93. 93.

    et al. Circulating ghrelin levels are decreased in human obesity. Diabetes 50, 707–709 (2001).

  94. 94.

    et al. Centrally and peripherally administered ghrelin potently inhibits water intake in rats. Endocrinology 148, 1638–1647 (2007).

  95. 95.

    et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141, 4325–4328 (2000).

  96. 96.

    & Inhibitory effects of gastric electrical stimulation on ghrelin-induced excitatory effects on gastric motility and food intake in dogs. Scand. J. Gastroenterol. 41, 903–909 (2006).

  97. 97.

    et al. Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur. J. Endocrinol. 158, 491–498 (2008).

  98. 98.

    et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur. J. Endocrinol. 150, 447–455 (2004).

  99. 99.

    et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001).

  100. 100.

    , , , & Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am. J. Physiol. Endocrinol. Metab. 287, E297–E304 (2004).

  101. 101.

    et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50, 1714–1719 (2001).

  102. 102.

    et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 55, 327–333 (2006).

  103. 103.

    et al. Ghrelin does not stimulate gastrointestinal motility and gastric emptying: an experimental study of conscious dogs. Neurogastroenterol. Motil. 18, 129–135 (2006).

  104. 104.

    et al. Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol. Motil. 19, 675–680 (2007).

  105. 105.

    et al. Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G403–G411 (2008).

  106. 106.

    , , , & Association between plasma ghrelin and motilin levels during MMC cycle in conscious dogs. Regul. Pept. 164, 78–82 (2010).

  107. 107.

    et al. Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach. Neurogastroenterol. Motil. 19, 675–680 (2007).

  108. 108.

    et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem. Biophys. Res. Commun. 276, 905–908 (2000).

  109. 109.

    et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310, 996–999 (2005).

  110. 110.

    , , & Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterol. Motil. 19, 211–217 (2007).

  111. 111.

    et al. Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract. Br. J. Pharmacol. 150, 58–64 (2007).

  112. 112.

    et al. Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents. Peptides 27, 2811–2819 (2006).

  113. 113.

    , , , & Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1210–G1218 (2008).

  114. 114.

    , , & Growth-hormone release-inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet 1, 1220–1222 (1975).

  115. 115.

    , & Somatostatin, 1976. S. Afr. Med. J. 50, 1471–1474 (1976).

  116. 116.

    et al. Cholinergic, somatostatin-immunoreactive interneurons in the guinea pig intestine: morphology, ultrastructure, connections and projections. J. Anat. 187 (Pt 2), 303–321 (1995).

  117. 117.

    , , , & Somatostatin suppresses secretin and pancreatic exocrine secretion. Science 190, 163–165 (1975).

  118. 118.

    , & Somatostatin inhibits motilin-induced interdigestive contractile activity in the dog. Am. J. Dig. Dis. 23, 781–788 (1978).

  119. 119.

    , , , & Effect of somatostatin on blood levels of motilin and the interdigestive myoelectric complex in dogs. Endocrinol. Jpn 27 (Suppl. 1), 163–166 (1980).

  120. 120.

    et al. Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J. Clin. Endocrinol. Metab. 87, 4829–4832 (2002).

  121. 121.

    et al. Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J. Clin. Endocrinol. Metab. 88, 2180–2184 (2003).

  122. 122.

    et al. Motilin controls cyclic release of insulin through vagal cholinergic muscarinic pathways in fasted dogs. Am. J. Physiol. 274, G87–G95 (1998).

  123. 123.

    , , , & Role of gastrin and insulin in postprandial disruption of migrating complex in dogs. Am. J. Physiol. 235, E666–E669 (1978).

  124. 124.

    , & Insulin and myoelectric activity of the small intestine of the pig. Dig. Dis. Sci. 26, 33–41 (1981).

  125. 125.

    et al. Relationship between intraduodenal 5-hydroxytryptamine release and interdigestive contractions in dogs. J. Smooth Muscle Res. 40, 75–84 (2004).

  126. 126.

    , & Serotonin regulation of the canine migrating motor complex. J. Pharmacol. Exp. Ther. 231, 436–440 (1984).

  127. 127.

    , , , & Effect of serotonin on small intestinal contractility in healthy volunteers. Physiol. Res. 57, 63–71 (2008).

  128. 128.

    & 5-Hydroxytryptamine: initiator of phase 3 of migrating motor complex. Acta Physiol. Scand. 155, 241–242 (1995).

  129. 129.

    , , , & Concentration-dependent stimulation of intestinal phase III of migrating motor complex by circulating serotonin in humans. Clin. Sci. (Lond.) 94, 663–670 (1998).

  130. 130.

    , & 5-Hydroxytryptamine and human small intestinal motility: effect of inhibiting 5-hydroxytryptamine reuptake. Gut 35, 496–500 (1994).

  131. 131.

    , & The influence of citalopram on interdigestive gastrointestinal motility in man. Aliment. Pharmacol. Ther. 32, 289–295 (2010).

  132. 132.

    et al. Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin. Biol. Psychiatry 65, 748–759 (2009).

  133. 133.

    , , & Cholecystokinin in the regulation of intestinal motility and pancreatic secretion in dogs. Am. J. Physiol. 255, G498–G504 (1988).

  134. 134.

    & Effects of CCK receptor blockade on intestinal motor activity in conscious dogs. Am. J. Physiol. 260, G315–G324 (1991).

  135. 135.

    , , , & Effect of cholecystokinin on myoelectric activity of small bowel of the dog. Am. J. Physiol. 232, E44–E47 (1977).

  136. 136.

    , , , & Identification of xenin, a xenopsin-related peptide, in the human gastric mucosa and its effect on exocrine pancreatic secretion. J. Biol. Chem. 267, 22305–22309 (1992).

  137. 137.

    , , & Evidence for the presence of xenopsin-related peptide(s) in the gastric mucosa of mammals. J. Clin. Invest. 76, 156–162 (1985).

  138. 138.

    , , & Xenin—a novel suppressor of food intake in rats. Brain Res. 800, 294–299 (1998).

  139. 139.

    , , & Xenin, a gastrointestinal peptide, regulates feeding independent of the melanocortin signaling pathway. Diabetes 58, 87–94 (2009).

  140. 140.

    et al. Phase III of the migrating motor complex: associated with endogenous xenin plasma peaks and induced by exogenous xenin. Neurogastroenterol. Motil. 13, 237–246 (2001).

  141. 141.

    & Migrating myoelectrical complex of the small intestine. An intrinsic activity mediated by the vagus. Gastroenterology 73, 1309–1314 (1977).

  142. 142.

    Effects of vagotomy on gastrointestinal myoelectric pattern of the conscious dog [Japanese]. Nippon Heikatsukin Gakkai Zasshi 18, 19–38 (1982).

  143. 143.

    , & Vagal control of migrating motor complex in the dog. Am. J. Physiol. 243, G276–G284 (1982).

  144. 144.

    & Small intestinal motility in fasted and postprandial states: effect of transient vagosympathetic blockade. Am. J. Physiol. 252, G301–G308 (1987).

  145. 145.

    , , , & Motilin and the vagus in dogs. Can. J. Physiol. Pharmacol. 62, 1092–1096 (1984).

  146. 146.

    et al. Variations in plasma motilin, somatostatin, and pancreatic polypeptide concentrations and the interdigestive myoelectric complex in dog. Can. J. Physiol. Pharmacol. 63, 1495–1500 (1985).

  147. 147.

    et al. The failure of truncal vagotomy to affect motilin release in dogs. J. Surg. Res. 38, 263–266 (1985).

  148. 148.

    , & Vagal control of canine postprandial upper gastrointestinal motility. Am. J. Physiol. 250, G501–G510 (1986).

  149. 149.

    , & Relationship of postprandial motilin, gastrin, and pancreatic polypeptide release to intestinal motility during vagal interruption. Can. J. Physiol. Pharmacol. 70, 1148–1153 (1992).

  150. 150.

    , , & Vagal control of migrating motor complex-related peaks in canine plasma motilin, pancreatic polypeptide, and gastrin. Can. J. Physiol. Pharmacol. 61, 1289–1298 (1983).

  151. 151.

    , & Vagal control of fasting somatostatin levels. Neurogastroenterol. Motil. 7, 73–78 (1995).

  152. 152.

    & Vagotomy in the treatment of peptic ulcer. Edinb. Med. J. 54, 540–544 (1947).

  153. 153.

    , & Studies on the effect of vagotomy on small intestinal motility using the radiotelemetering capsule. Gut 4, 77–81 (1963).

  154. 154.

    & Interstitial cells of Cajal-their role in pacing and signal transmission in the digestive system. Acta Physiol. Scand. 170, 177–190 (200).

  155. 155.

    Mechanisms controlling the gastrointestinal migrating motor complex. JPCCR 3, 11–19 (2009).

  156. 156.

    in Schuster Atlas of Gastrointestinal Motility in Health and Disease (eds Schuster, M. M., Crowell, M. D. & Koch, K. L.) 1–18 (Decker Publishing Inc., Hamilton, Canada, 2002).

  157. 157.

    , , & Intrinsic nervous control of migrating myoelectric complexes. Am. J. Physiol. 241, G16–G23 (1981).

  158. 158.

    , , & Intestinal motility. Its possible role in diarrhea. Acta Gastroenterol. Belg. 44, 34–42 (1981).

  159. 159.

    Gastrointestinal motility disorders and bacterial overgrowth. J. Intern. Med. 237, 419–427 (1995).

  160. 160.

    , , , & Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology 109, 1078–1089 (1995).

  161. 161.

    , & High interdigestive and postprandial motilin levels in patients with the irritable bowel syndrome. Neurogastroenterol. Motil. 17, 51–57 (2005).

  162. 162.

    , , , & Abnormal propagation pattern of duodenal pressure waves in the irritable bowel syndrome (IBS) [correction of (IBD)]. Dig. Dis. Sci. 45, 2151–2161 (2000).

  163. 163.

    et al. Ambulatory gastrojejunal manometry in severe motility-like dyspepsia: lack of correlation between dysmotility, symptoms, and gastric emptying. Gut 42, 235–242 (1998).

  164. 164.

    , , & Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: effect of metoclopramide and bethanechol. Gastroenterology 78, 286–293 (1980).

  165. 165.

    & Abnormal gastric and small intestinal motor function in diabetes mellitus. Dig. Dis. 15, 263–274 (1997).

  166. 166.

    & Erythromycin in the treatment of diabetic gastroparesis. Am. J. Ther. 1, 287–295 (1994).

  167. 167.

    , , , & Disorders of gastrointestinal motility: towards a new classification. J. Gastroenterol. Hepatol. 17 (Suppl.), S1–S14 (2002).

  168. 168.

    Chagas' disease: a model of denervation in the study of digestive tract motility. Braz. J. Med. Biol. Res. 18, 255–264 (1985).

  169. 169.

    , , , & Abnormalities of interdigestive motility of the small intestine in patients with Chagas' disease. Dig. Dis. Sci. 28, 294–299 (1983).

  170. 170.

    Chagas' disease and Chagas' syndromes: the pathology of American trypanosomiasis. Adv. Parasitol. 6, 63–116 (1968).

  171. 171.

    , , & Gastrointestinal manifestations of Chagas' disease. Am. J. Gastroenterol. 93, 884–889 (1998).

  172. 172.

    , , & Small bowel bacterial overgrowth syndrome in chagasic megajejunum: report of 2 cases [Portugese]. Arq. Gastroenterol. 32, 71–78 (1995).

  173. 173.

    , & Chronic idiopathic intestinal pseudo-obstruction: clinical and intestinal manometric findings. Gut 28, 5–12 (1987).

  174. 174.

    , , , & Antroduodenal motility in children with chronic intestinal pseudo-obstruction. J. Pediatr. 112, 899–905 (1988).

  175. 175.

    , & Jejunal manometry patterns in health, partial intestinal obstruction, and pseudoobstruction. Gastroenterology 85, 1290–1300 (1983).

  176. 176.

    & An explanation of hunger. 1911. Obes. Res. 1, 494–500 (1993).

  177. 177.

    Contributions to the physiology of the stomach.—II. The relation between the contractions of the empty stomach and the sensation of hunger. 1912. Obes. Res. 1, 501–509 (1993).

  178. 178.

    , , & in Proceedings of the Fifth International Symposium on Gastrointestinal Motility (ed. Vantrappen, G.) 48–55 (Typoff, Herentals, Belgium, 1975).

  179. 179.

    et al. Gastric phase 3 is a hunger signal in the interdigestive state in man. Gastroenterology 134, A314 (2008).

  180. 180.

    , , , & Interdigestive gastroduodenal motility and cycling of putative regulatory hormones in severe obesity. Scand. J. Gastroenterol. 27, 538–544 (1992).

  181. 181.

    & Gastric “hunger” contractions in anorexia nervosa. Br. J. Psychiatr. 113, 257–263 (1967).

  182. 182.

    , , , & Reversal of megaduodenum and duodenal dysmotility associated with improvement in nutritional status in primary anorexia nervosa. Dig. Dis. Sci. 39, 433–440 (1994).

  183. 183.

    & The patterns of motility are maintained in the human small intestine throughout the process of aging. Scand. J. Gastroenterol. 27, 397–404 (1992).

  184. 184.

    et al. High-resolution solid-state manometry of the antropyloroduodenal region. Neurogastroenterol. Motil. 19, 188–195 (2007).

  185. 185.

    et al. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment. Pharmacol. Ther. 31, 313–322 (2010).

  186. 186.

    et al. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol. Motil. 22, 527–533 (2010).

  187. 187.

    et al. American Neurogastroenterology and Motility Society consensus statement on intraluminal measurement of gastrointestinal and colonic motility in clinical practice. Neurogastroenterol. Motil. 20, 1269–1282 (2008).

  188. 188.

    et al. Prolonged ambulatory antroduodenal manometry in humans. Am. J. Gastroenterol. 89, 1489–95 (1994).

  189. 189.

    , , & Intestinal motility and jejunal feeding in children with chronic intestinal pseudo-obstruction. Gastroenterology 108, 1379–1385 (1995).

  190. 190.

    et al. Predicting the clinical response to cisapride in children with chronic intestinal pseudoobstruction. Am. J. Gastroenterol. 88, 832–836 (1993).

  191. 191.

    , , & Low-dose intravenous erythromycin: effects on postprandial and fasting motility of the small bowel. Aliment. Pharmacol. Ther. 14, 233–240 (2000).

  192. 192.

    , , , & Advantages of azithromycin over erythromycin in improving the gastric emptying half-time in adult patients with gastroparesis. J. Neurogastroenterol. Motil. 16, 407–413 (2010).

  193. 193.

    & What comes after macrolides and other motilin stimulants? Gut 49, 317–318 (2001).

  194. 194.

    et al. Identification of small molecule agonists of the motilin receptor. Bioorg. Med. Chem. Lett. 18, 6423–6428 (2008).

  195. 195.

    et al. Discovery of N.-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acety l]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate. J. Med. Chem. 52, 1180–1189 (2009).

  196. 196.

    et al. GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterol. Motil. 21, 657–664, e630–e651 (2009).

  197. 197.

    et al. GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs. Neurogastroenterol. Motil. 23, 958–e410 (2011).

  198. 198.

    et al. Pharmacokinetics, safety/tolerability, and effect on gastric emptying of the oral motilin receptor agonist, GSK962040, in healthy male and female volunteers [abstract 280]. Neurogastroenterol. Motil. 21 (Suppl. s1), 84 (2009).

  199. 199.

    et al. Evaluation of a new motilin receptor agonist, GSK962040, on the migrating motor complex and gastric pH in healthy human volunteers. Gastroenterology (in press).

  200. 200.

    et al. A double-blind, randomized placebo-controlled phase II study of the pharmacodynamics, safety/tolerability, and pharmacokinetics of single doses of the motilin agonist GSK962040, in patients with type I diabetes mellitus (T1DM) and gastroparesis [abstract 1389]. Gastroenterology 140, S-813 (2011).

  201. 201.

    , , , & PF-04548043, a novel motilin receptor agonist, increases gastric emptying in healthy volunteers and does not undergo tachyphyllaxis [abstract 235]. Gastroenterology 136, A-45 (2009).

  202. 202.

    et al. Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data. Aliment. Pharmacol. Ther. 33, 679–688 (2011).

  203. 203.

    et al. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment. Pharmacol. Ther. 29, 1179–87 (2009).

  204. 204.

    Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. Neurogastroenterol. Motil. 22, 1069–e281 (2010).

  205. 205.

    et al. TZP-102, ghrelin agonist phase 2 data: the improvement in symptoms of gastroparesis (nausea, early satiety, bloating and abdominal pain) significantly correlated with patient rating of overall treatment effect [abstract 1365]. Gastroenterology 140, S-807 (2011).

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Acknowledgements

The main draft of this manuscript was written when all authors worked at the Translational Research Center for Gastrointestinal Disorders (TARGID), Catholic University of Leuven, Belgium. Since that time P. Janssens has moved to work for Shire. See the article online for full author biographies.

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  1. Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, O&N1, Box 701, 3000 Leuven, Belgium

    • Eveline Deloose
    • , Inge Depoortere
    •  & Jan Tack
  2.  Shire, Veedijk 58 (1004), B-2300 Turnhout, Belgium

    • Pieter Janssen

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All authors contributed equally to all aspects of the manuscript.

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The authors declare no competing financial interests.

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Correspondence to Jan Tack.

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https://doi.org/10.1038/nrgastro.2012.57

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