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Hormones of the gut–brain axis as targets for the treatment of upper gastrointestinal disorders

Key Points

  • The gut is at the centre of an integrated gut–brain–energy axis, modulating appetite, metabolism and digestion.

  • During fasting, hormones contribute to the fasting pattern of gut motility (for example, motilin), the re-establishment of appetite (for example, orexin, ghrelin) and drive marked changes in these and other functions (for example, ghrelin), possibly to prepare for eating.

  • During eating and digestion, hormones (for example, gastrin, cholecystokinin (CCK), pancreatic polypeptide) contribute to satiety and regulate gastric emptying. Others (for example, peptide YY) are released from the intestine in response to poorly digested material, slowing down gastrointestinal motility and increasing satiety ('ileal break').

  • Upper gut disorders can disturb gastric movements and influence food preference, appetite or eating behaviours, in part by mechanisms by which the gut defends itself against ingestion of toxic material (for example, nausea, vomiting). Emesis, hunger, satiety and nausea are points on the same physiological spectrum; each can be regulated by hormones normally released during fasting, eating and digestion.

  • In the development of drugs to modulate the hormonal gut–brain axis, areas currently receiving attention are motilin receptor agonists (gastric prokinetics), and ghrelin and CCK1 receptor agonists. The latter exert multiple activities and possibly represent a more complete treatment of complex disorders such as functional dyspepsia.

  • Eating and digestion rely on an integrated gut–brain–energy axis. The recognition of complex hormonal links is creating a paradigm shift in how drug targets are identified to deliver more effective treatments for complex disorders. For example, drugs that modulate gastric motility can also represent targets for gastric prokinetc drugs. Those that modify eating behaviours can also represent targets for treatment of nausea, currently a serious clinical problem.


The concept of the gut forming the centre of an integrated gut–brain–energy axis — modulating appetite, metabolism and digestion — opens up new paradigms for drugs that can tackle multiple symptoms in complex upper gastrointestinal disorders. These include eating disorders, nausea and vomiting, gastroesophageal reflux disease, gastroparesis, dyspepsia and irritable bowel syndrome. The hormones that modulate gastric motility represent targets for gastric prokinetic drugs, and peptides that modify eating behaviours may be targeted to develop drugs that reduce nausea, a currently poorly treated condition. The gut–brain axis may therefore provide a range of therapeutic opportunities that deliver a more holistic treatment of upper gastrointestinal disorders.

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Figure 1: Illustration of the main features of the enteric nervous system (ENS).


  1. 1

    Broberger, C. Brain regulation of food intake and appetite: molecules and networks. J. Intern. Med. 258, 301–327 (2005).

    CAS  PubMed  Google Scholar 

  2. 2

    Luckman, S. M. & Lawrence, C. B. Anorectic brainstem peptides: more pieces to the puzzle. Trends Endocrinol. Metab. 14, 60–65 (2003).

    CAS  PubMed  Google Scholar 

  3. 3

    Havel, P. J. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp. Biol. Med. 226, 963–977 (2001).

    CAS  Google Scholar 

  4. 4

    Bray, G. A. Afferent signals regulating food intake. Proc. Nutri. Soc. 59, 373–384 (2000).

    CAS  Google Scholar 

  5. 5

    Murphy, K. G. Bloom, S. R. Gut peptides and the regulation of energy homeostasis. Nature 444, 854–859 (2006).

    CAS  PubMed  Google Scholar 

  6. 6

    Zafra, M. A., Molina, F. & Puerto, A. The neural/cephalic phase reflexes in the physiology of nutrition. Neurosci. Biobehav. Rev. 30, 1032–1044 (2006).

    PubMed  Google Scholar 

  7. 7

    Stern, R. M., Jokerst, M. D., Levine, M. E. & Koch, K. L. The stomach's response to unappetizing food: cephalic–vagal effects on gastric myoelectric activity. Neurogastroenterol. Motil. 13, 151–154 (2001).

    CAS  PubMed  Google Scholar 

  8. 8

    Naslund, E. & Hellstrom, P. M. The gut and food intake: an update for surgeons. J. Gastrointest. Surg. 5, 556–567 (2001).

    CAS  PubMed  Google Scholar 

  9. 9

    Camilleri, M. & Grudell, A. B. Appetite and obesity: a gastroenterologist's perspective. Neurogastroenterol. Motil. 19, 333–341 (2007).

    CAS  PubMed  Google Scholar 

  10. 10

    Sarna, S. K. Cyclic motor activity; migrating motor complex: 1985. Gastroenterol. 89, 894–913 (1985).

    CAS  Google Scholar 

  11. 11

    Husebye, E. The patterns of small bowel motility: physiology and implications in organic disease and functional disorders. Neurogastroenterol. Motil. 11, 141–161 (1999).

    CAS  PubMed  Google Scholar 

  12. 12

    Nieuwenhuijs, V. B. et al. The role of interdigestive small bowel motility in the regulation of gut microflora, bacterial overgrowth, and bacterial translocation in rats. Ann. Surg. 228, 188–193 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Furness, J. B. The Enteric Nervous System. 1–288 (Blackwell, Oxford, 2006).

    Google Scholar 

  14. 14

    Thomas, E. A., Sjovall, H. & Bornstein, J. C. Computational model of the migrating motor complex of the small intestine. Am. J. Physiol. 286, G564–G572 (2004).

    CAS  Google Scholar 

  15. 15

    Powley, T. L., Chi, M. M., Schier, L. A. & Phillips, R. J. Obesity: should treatments target visceral afferents? Physiol. Behav. 86, 698–708 (2005).

    CAS  PubMed  Google Scholar 

  16. 16

    Andrews, P. L. & Sanger, G. J. Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr. Opin. Pharmacol. 2, 650–656 (2002).

    CAS  PubMed  Google Scholar 

  17. 17

    Wood, J. D. Enteric nervous control of motility in the upper gastrointestinal tract in defensive states. Dig. Dis. Sci. 44 (Suppl. 8), 44–52 (1999).

    Google Scholar 

  18. 18

    Konturek, S. J. et al. Brain–gut axis in pancreatic secretion and appetite control. J. Physiol. Pharmacol. 54, 293–317 (2003).

    CAS  PubMed  Google Scholar 

  19. 19

    Takahashi, T. & Owyang, C. Characterization of vagal pathways mediating gastric accommodation reflex in rats. J. Physiol. 504, 479–488 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Banks, W. A. The blood–brain barrier as a regulatory interface in the gut–brain axes. Physiol. Behav. 89, 472–476. (2006).

    CAS  PubMed  Google Scholar 

  21. 21

    Rees, W. D., Malagelada, J. R., Miller, L. J. & Go, V. L. Human interdigestive and postprandial gastrointestinal motor and gastrointestinal hormone patterns. Dig. Dis. Sci. 27, 321–329 (1982).

    CAS  PubMed  Google Scholar 

  22. 22

    Naslund E., Backman, L., Theodorsson, E. & Hellstrom, P. M. Intraduodenal neuropeptide levels, but not plasma levels, vary in a cyclic fashion with the migrating motor complex. Acta Physiol. Scand. 164, 317–323 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    Feng, X., Peeters, T. L. & Tang, M. Motilin activates neurons in the rat amygdale and increases gastric motility. Peptides 28, 625–631 (2007).

    CAS  PubMed  Google Scholar 

  24. 24

    Bassil, A., Murray, C., Dass, N. M., Muir, A. & Sanger, G. J. Prokineticin-2, motilin, ghrelin and metoclopramide: prokinetic utility in mouse stomach and colon. Eur. J. Pharmacol. 524, 138–144. (2005).

    CAS  PubMed  Google Scholar 

  25. 25

    Hill, J., Szekeres, P., Muir, A. & Sanger, G. J. Molecular, functional and cross-species comparisons between the receptors for the prokinetic neuropeptides, motilin and ghrelin. Gastroenterol. 122 (Suppl. 1), A54 (2002).

    Google Scholar 

  26. 26

    Aerssens, J. et al. The rat lacks functional genes for motilin and for the motilin receptor. Neurogastroenterol. Motil. 16, 841 (2004).

    Google Scholar 

  27. 27

    Andrews, P. L. & Horn, C. C. Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases. Auton. Neurosci. 125, 100–115 (2006). Highlights the fact that although vomiting can be successfully treated, the sensation of nausea is poorly treated and remains a serious clinical problem.

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Karnovsky, A. M. et al. A cluster of novel serotonin receptor 3-like genes on human chromosome 3. Gene 319, 137–148 (2003).

    CAS  PubMed  Google Scholar 

  29. 29

    Ehrstrom, M. et al. Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin. Regul. Pept. 132, 9–16 (2005).

    PubMed  Google Scholar 

  30. 30

    Asakawa, A. et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterol. 120, 337–345 (2001).

    CAS  Google Scholar 

  31. 31

    Arnold, M., Mura, A., Langhans, W. & Geary, N. Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J. Neurosci. 26, 11052–11060 (2006).

    CAS  PubMed  Google Scholar 

  32. 32

    le Roux., C. W. et al. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J. Clin. Endocrinol. Metabol. 90, 4521–4524 (2005).

    CAS  Google Scholar 

  33. 33

    Date, Y. et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123, 1120–1128 (2002).

    CAS  PubMed  Google Scholar 

  34. 34

    Sakata, I. et al. Growth hormone secretagogue receptor expression in the cells of the stomach-projected afferent nerve in the rat nodose ganglion. Neurosci. Lett. 342, 183–186 (2003).

    CAS  PubMed  Google Scholar 

  35. 35

    Dass, N. B. et al. Growth hormone secretagogue receptors in the rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience 120, 443–453 (2003).

    CAS  PubMed  Google Scholar 

  36. 36

    Edholm, T., Levin, F., Hellstrom, P. M. & Schmidt, P. T. Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul. Pept. 121, 25–30 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Burdyga, G., Varro, A., Dimaline, R., Thompson, D. G. & Dockray, G. J. Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance. Am. J. Physiol. 290, G1289–G1297 (2006).

    CAS  Google Scholar 

  38. 38

    Sibilia, V. et al. Ghrelin protects against ethanol induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology 144, 353–359 (2003).

    CAS  PubMed  Google Scholar 

  39. 39

    Brzozowski, T. et al. Exogenous and endogenous ghrelin in gastroprotection against stress-induced damage. Regul. Pept. 120, 39–51 (2004).

    CAS  PubMed  Google Scholar 

  40. 40

    Shimizu, Y. et al. Increased plasma ghrelin level in lung cancer cachexia. Clin. Cancer Res. 9, 774–778 (2003).

    CAS  PubMed  Google Scholar 

  41. 41

    Folwaczny, C., Chang, J. K. & Tschop, M. Ghrelin and motilin: two sides of one coin? Eur. J. Endocrinol. 144, R1–R3 (2001).

    CAS  PubMed  Google Scholar 

  42. 42

    Ueno, N., Uemoto, M., Komatsu, Y., Sato, Y. & Inui, A. A motilin agonist, erythromycin, decreases circulating growth hormone levels in normal subjects but not in diabetic subjects. J. Diabetes Complicat. 20, 380–383 (2006).

    PubMed  Google Scholar 

  43. 43

    Dass, N. B. et al. The rabbit motilin receptor: molecular characterisation and pharmacology. Br. J. Pharmacol. 140, 948–954 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Lankarani, K. B., Moghadami, M., Masoumpoor, M., Geramizadeh, B. & Omrani, G. R. Serum leptin level in patients with functional dyspepsia. Dig. Liver Dis. 36, 717–721 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Rudd, J. A. et al. Anti-emetic activity of ghrelin in ferrets exposed to the cytotoxic anti-cancer agent cisplatin. Neurosci. Lett. 392, 79–83 (2006).

    CAS  PubMed  Google Scholar 

  46. 46

    Boivin, M. A., Carey, M. C. & Levy, H. Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects. Pharmacotherapy 23, 5–8 (2003).

    PubMed  Google Scholar 

  47. 47

    Zhang, J. V. et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310, 996–986 (2005).

    CAS  PubMed  Google Scholar 

  48. 48

    Zhang, J. V. et al. Response to comment on “Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake”. Science 315, 766 (2007).

    CAS  Google Scholar 

  49. 49

    Sibilia, V. et al. Intracerebroventricular acute and chronic administration of obestatin minimally affect food intake but not weight gain in the rat. J. Endocrinol. Invest. 29, RC31–RC34 (2006).

    CAS  PubMed  Google Scholar 

  50. 50

    Bresciani, E. et al. Obestatin inhibits feeding but does not modulate GH and corticosterone secretion in the rat. J. Endocrinol. Invest. 29, RC16–RC18 (2006).

    CAS  PubMed  Google Scholar 

  51. 51

    Lagaud, G. J. et al. Obestatin reduces food intake and suppresses body weight gain in rodents. Biochem. Biophys. Res. Commun. 357, 264–269 (2007).

    CAS  PubMed  Google Scholar 

  52. 52

    Seoane, L. M., Al-Massadi, O., Pazos, Y., Pagotto, U. & Casanueva, F. F. Central obestatin administration does not modify either spontaneous or ghrelin-induced food intake in rats. J. Endocrinol. Invest. 29, RC13–RC15 (2006).

    CAS  PubMed  Google Scholar 

  53. 53

    Samson, W. K., White, M. M., Price, C. & Ferguson, A. V. Obestatin acts in brain to inhibit thirst. Am. J. Physiol. 292, R637–R643 (2007).

    CAS  Google Scholar 

  54. 54

    Bassil, A. K. 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).

    CAS  PubMed  Google Scholar 

  55. 55

    De Smet, B., Thijs, T., Peeters, T. L. & Depoortere, I. Effect of peripheral obestatin on gastric emptying and intestinal contractility in rodents. Neurogastroenterol. Motil. 19, 211–217 (2007).

    CAS  PubMed  Google Scholar 

  56. 56

    Dun, S. L. et al. Distribution and biological activity of obestatin in the rat. J. Endocrinol. 191, 481–489 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Tremblay, F. et al. Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology 148, 501–506 (2007).

    CAS  PubMed  Google Scholar 

  58. 58

    Moechars, D. et al. Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse. Gastroenterology 131, 1131–1141 (2006). Following the recognition that obestatin does not activate the GPR39 receptor, this study illustrates the potential role of the receptor in the control of GI function in knockout mice lacking the GPR39 receptor. A cognate ligand for GPR39 may have profound effects on GI functions.

    CAS  PubMed  Google Scholar 

  59. 59

    Sun, K. & Ferguson, A. V. Cholecystokinin activates area postrema neurons in rat brain slices. Am. J. Physiol. 272, R1625–R1630 (1997).

    CAS  PubMed  Google Scholar 

  60. 60

    Sakurai, G. et al. Lack of ghrelin secretion in response to fasting in cholecystokinin-A (-1), -B (-2) receptor-deficient mice. J. Physiol. Sci. 56, 441–447 (2006).

    CAS  PubMed  Google Scholar 

  61. 61

    Baldwin, B. A., Parrott, R. F. & Ebenezer, I. S. Food for thought: a critique on the hypothesis that endogenous cholecystokinin acts as a physiological satiety factor. Prog. Neurobiol. 55, 477–507 (1998).

    CAS  PubMed  Google Scholar 

  62. 62

    Weiland, T. J. & Voudouris, N. J. Kent, S. CCK2 receptor nullification attenuates lipopolysaccharide-induced sickness behaviour. Am. J. Physiol. 292, R112–R123 (2007).

    CAS  Google Scholar 

  63. 63

    Huda, M. S., Wilding, J. P. & Pinkney, J. H. Gut peptides and the regulation of appetite. Obes. Rev. 7, 163–182 (2006).

    CAS  PubMed  Google Scholar 

  64. 64

    Bado, A. et al. The stomach is a source of leptin. Nature 394, 790–793 (1998).

    CAS  PubMed  Google Scholar 

  65. 65

    Camilleri, M. Integrated upper gastrointestinal response to food intake. Gastroenterology 131, 640–658 (2006). An important introduction to the role of gut hormones in regulating the response to eating.

    CAS  PubMed  Google Scholar 

  66. 66

    Pico, C., Oliver, P., Sanchez, J. & Palou, A. Gastric leptin: a putative role in the short-term regulation of food intake. Br. J. Nutr. 90, 735–741 (2003). Demonstrates that leptin can be produced by the stomach, where it is rapidly released in response to food intake, vagal-nerve stimulation, CCK and secretin.

    CAS  PubMed  Google Scholar 

  67. 67

    Peters, J. H., Simasko, S. M. & Ritter, R. C. Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin. Physiol. Behav. 89, 477–485 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    El Homsi, M. et al. Leptin modulates the expression of secreted and membrane-associated mucins in colonic epithelial cells by targeting PKC, PI3K, and MAPK pathways. Am. J. Physiol. 293, G365–G373 (2007).

    CAS  Google Scholar 

  69. 69

    Murphy, K. G., Dhillo, W. S. & Bloom, S. R. Gut peptides in the regulation of food intake and energy homeostasis. Endocr. Rev. 27, 719–727 (2006).

    CAS  PubMed  Google Scholar 

  70. 70

    Glatzle, J. et al. Apolipoprotein A-IV stimulates duodenal vagal afferent activity to inhibit gastric motility via a CCK1 pathway. Am. J. Physiol. 287, R354–R359 (2004).

    CAS  Google Scholar 

  71. 71

    Degen, L. et al. Effect of peptide YY3–36 on food intake in humans. Gastroenterol. 129, 1430–1436 (2005).

    CAS  Google Scholar 

  72. 72

    Greenough, A., Cole, G., Lewis, J., Lockton, A. & Blundell, J. Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion. Physiol. Behav. 65, 303–310 (1998). Introduces the concept that hunger, satiety and nausea are all points on the same physiological spectrum. It suggests that drugs that increase appetite may also reduce nausea.

    CAS  PubMed  Google Scholar 

  73. 73

    Ritz, M. A., Fraser, R., Tam, W. & Dent, J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am. J. Gastroenterol. 95, 3044–3052 (2000).

    CAS  PubMed  Google Scholar 

  74. 74

    Sanger, G. J. in 5-HT4 Receptors in the Brain and Periphery. (ed. Eglen, R. M.) 213–226 (Springer, Berlin,1998).

    Google Scholar 

  75. 75

    Davis, M. P., Walsh, D., Lagman, R. & Yavuzsen, T. Early satiety in cancer patients: a common and important but underrecognized symptom. Support. Care Cancer 14, 693–698 (2006).

    PubMed  Google Scholar 

  76. 76

    Bisschops, R. & Tack, J. Dysaccommodation of the stomach: therapeutic nirvana? Neurogastroenterol. Motil. 19, 85–93 (2007).

    CAS  PubMed  Google Scholar 

  77. 77

    Firth, M. & Prather, C. M. Gastrointestinal motility problems in the elderly patient. Gastroenterology 122, 1688–1700 (2002).

    PubMed  Google Scholar 

  78. 78

    Zipfel, S. et al. Gastrointestinal disturbances in eating disorders: clinical and neurobiological aspects. Auton. Neurosci. 129, 99–106 (2006).

    CAS  PubMed  Google Scholar 

  79. 79

    Faris, P. L. et al. Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms. J. Affective Dis. 92, 79–90 (2006).

    Google Scholar 

  80. 80

    Hellstrom, P. M. et al. Peripheral and central signals in the control of eating in normal, obese and binge-eating human subjects. Br. J. Nutr. 92 (Suppl. 1), 47–57 (2004).

    Google Scholar 

  81. 81

    Bullard, J. & Page, N. E. Cyclic vomiting syndrome: a disease in disguise. Pediatr. Nurs. 31, 27–29 (2005).

    PubMed  Google Scholar 

  82. 82

    Foubert, J. & Vaessen, G. Nausea: the neglected symptom? Eur. J. Oncol. Nurs. 9, 21–32 (2005).

    PubMed  Google Scholar 

  83. 83

    Sanger, G. J. & Andrews, P. L. Treatment of nausea and vomiting: gaps in our knowledge. Auton. Neurosci. 129, 3–16 (2006).

    CAS  PubMed  Google Scholar 

  84. 84

    Levine, A. S. The animal model in food intake regulation: examples from the opioid literature. Physiol. Behav. 89, 92–96 (2006).

    CAS  PubMed  Google Scholar 

  85. 85

    Jones, R., Armstrong, D., Malfertheiner, P. & Ducrotte, P. Does the treatment of gastroesophageal reflux disease (GERD) meet patients' needs? A survey-based study. Curr. Med. Res. Opin. 22, 657–662 (2006).

    PubMed  Google Scholar 

  86. 86

    Raybould, H. E. Nutrient tasting and signaling mechanisms in the gut. I. Sensing of lipid by the intestinal mucosa. Am. J. Physiol. 277, G751–G755 (1999).

    CAS  PubMed  Google Scholar 

  87. 87

    Omari, T. I. et al. Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: a randomized controlled trial. J. Pediatr. 149, 468–474 (2006).

    CAS  PubMed  Google Scholar 

  88. 88

    Meneghetti, A. T., Tedesco, P., Damani, T. & Patti, M. G. Esophageal mucosal damage may promote dysmotility and worsen esophageal acid exposure. J. Gastrointest. Surg. 9, 1313–1317 (2005).

    PubMed  Google Scholar 

  89. 89

    Vittal, H., Farrugia, G., Gomez, G. & Pasricha, P. J. Mechanisms of disease: the pathological basis of gastroparesis — a review of experimental and clinical studies. Nature Clin. Pract. Gastroenterol. Hepatol. 4, 336–346 (2007).

    CAS  Google Scholar 

  90. 90

    Tack, J. The difficult patient with gastroparesis. Best Pract. Res. Clin. Gastroenterol. 21, 379–391 (2007).

    PubMed  Google Scholar 

  91. 91

    Horowitz, M., Su, Y.-C., Rayner, C. K. & Jones, K. L. Gastroparesis: prevalence, clinical significance and treatment. Can. J. Gastroenterol. 15, 805–813 (2001).

    CAS  PubMed  Google Scholar 

  92. 92

    Allescher, H. D. Functional dyspepsia — a multicausal disease and its therapy. Phytomedicine 13 (Suppl. 5), 2–11 (2006).

    CAS  PubMed  Google Scholar 

  93. 93

    Liu, Y.-L., Malik, N., Sanger, G. J. & Andrews, P. L. Ghrelin alleviates cancer chemotherapy-associated dyspepsia in mice. Cancer Chemother. Pharmacol. 58, 326–333 (2006). Illustrates the potential ability of ghrelin to affect multiple components associated with dyspepsia.

    CAS  PubMed  Google Scholar 

  94. 94

    Drossman, D. A. & Dumitrascu, D. L. Rome III: new standard for functional gastrointestinal disorders. J. Gastrointest. Liver Dis. 15, 237–241 (2006).

    Google Scholar 

  95. 95

    Cremonini, F., Delgado-Aros, S. & Talley, N. J. Functional dyspepsia: drugs for new (and old) therapeutic targets. Best Pract. Res. Clin. Gastroenterol. 18, 717–733 (2004).

    CAS  PubMed  Google Scholar 

  96. 96

    Nishizawa, T. et al. Enhanced plasma ghrelin levels in patients with functional dyspepsia. Aliment. Pharmacol. Ther. 24 (Suppl. 4), 104–110 (2006).

    Google Scholar 

  97. 97

    Suzuki, H. et al. Increased levels of plasma ghrelin in peptic ulcer disease. Aliment. Pharmacol. Ther. 24 (Suppl. 4), 120–126 (2006).

    Google Scholar 

  98. 98

    Simren, M., Bjornsson, E. S. & Abrahamsson, H. High interdigestive and postprandial motilin levels in patients with the irritable bowel syndrome. Neurogastroenterol. Motil. 17, 51–57 (2005).

    CAS  PubMed  Google Scholar 

  99. 99

    Peeters, T. L. Erythromycin and other macrolides as prokinetic agents. Gastroenterology 105, 1886–1899 (1993).

    CAS  PubMed  Google Scholar 

  100. 100

    Annese, V. et al. Cisapride and erythromycin prokinetic effects in gastroparesis due to type 1 (insulin-dependent) diabetes mellitus. Aliment. Pharmacol. Ther. 11, 599–603 (1997).

    CAS  PubMed  Google Scholar 

  101. 101

    Sturm, A., Holtmann, G., Goebell, H. & Gerken, G. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 60, 422–427 (1999).

    CAS  PubMed  Google Scholar 

  102. 102

    Jarvie, E. M., North Laidler, V., Corcoran, S., Bassil, A. & Sanger, G. J. Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitro. Br. J. Pharmacol. 150, 455–462 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Mochiki, E., Inui, A., Satoh, M., Mizumoto, A. & Itoh, Z. Motilin is a biosignal controlling cyclic release of pancreatic polypeptide via the vagus in fasted dogs. Am. J. Physiol. 272, G224–G232 (1997).

    CAS  PubMed  Google Scholar 

  104. 104

    Takeshita, E., Matsuura, B., Dong, M., Miller, L. J. & Matsui, H. Molecular characterisation and distribution of motilin family receptors in the human gastrointestinal tract. J. Gastroenterol. 41, 223–230 (2006).

    CAS  PubMed  Google Scholar 

  105. 105

    Depoortere, I., Thijs, T., Thielemans, L., Robberecht, P. & Peeters, T. L. 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).

    CAS  PubMed  Google Scholar 

  106. 106

    Coulie, B., Tack, J., Peeters, T. & Janssens, J. Involvement of two different pathways in the motor effects of erythromycin on the gastric antrum in humans. Gut 43, 395–400 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Cuomo, R. et al. Influence of motilin on gastric fundus tone and on meal-induced satiety in man: role of cholinergic pathways. Am. J. Gastroenterol. 101, 804–811 (2006).

    PubMed  Google Scholar 

  108. 108

    Matsuura, B., Dong, M., Naik, S., Miller, L. J. & Onji, M. Differential contributions of motilin receptor extracellular domains for peptide and non-peptidyl agonist binding and activity. J. Biol. Chem. 281, 12390–12396 (2006).

    CAS  PubMed  Google Scholar 

  109. 109

    Richards, R. D., Davenport, K. & Mccallum, R. W. The treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin. Am. J. Gastroenterol. 88, 203–207 (1993).

    CAS  PubMed  Google Scholar 

  110. 110

    Dhir, R. & Richter, J. E. Erythromycin in the short- and long-term control of dyspepsia symptoms in patients with gastroparesis. J. Clin. Gastroenterol. 38, 237–242 (2004).

    CAS  PubMed  Google Scholar 

  111. 111

    Dibaise, J. K. & Quigley, E. M. Efficacy of prolonged administration of intravenous erythromycin in an ambulatory setting as treatment of severe gastroparesis: one centre's experience. J. Clin. Gastroenterol. 28, 131–134 (1999).

    CAS  PubMed  Google Scholar 

  112. 112

    Ritz, M. A. et al. Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200 mg in the critically ill. Intensive Care Med. 31, 949–954 (2005).

    PubMed  Google Scholar 

  113. 113

    Gonlachanvit, S. et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Dig. Dis. Sci. 48, 488–497 (2003).

    CAS  PubMed  Google Scholar 

  114. 114

    Maganti, K., Onyemere, K. & Jones, M. P. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am. J. Gastroenterol. 98, 259–263 (2003).

    CAS  PubMed  Google Scholar 

  115. 115

    Hawkyard, C. V. & Koerner, R. J. The use of erythromycin as a gastrointestinal prokinetic agent in adult critical care: benefits versus risks. J. Antimicrob. Chemother. 59, 347–358 (2007).

    CAS  PubMed  Google Scholar 

  116. 116

    Trudel, L. et al. Two new peptides to improve post-operative gastric ileus in dog. Peptides 24, 531–534 (2003).

    CAS  PubMed  Google Scholar 

  117. 117

    De Winter, B. Y. et al. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterol. Motil. 16, 439–446 (2004).

    CAS  PubMed  Google Scholar 

  118. 118

    Neary, N. M. et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J. Clin. Endocrinol. Metab. 89, 2832–2836 (2004).

    CAS  PubMed  Google Scholar 

  119. 119

    Leite-Moreira, A. F. & Soares, J.-B. Physiological, pathophysiological and potential therapeutic roles of ghrelin. Drug Discov. Today 12, 276–288 (2007).

    CAS  PubMed  Google Scholar 

  120. 120

    Vestergaard, E. T. et al. Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects. Am. J. Physiol. 292, E1829–E1836 (2007). The need for caution when considering ghrelin receptor agonists for the treatment of GI disorders is exemplified by this study, which shows that constant intravenous infusion of ghrelin can provoke a fall in insulin sensitivity.

    CAS  Google Scholar 

  121. 121

    Varga, G. Dexloxiglumide Rotta Research Lab. Curr. Opin. Invest. Drugs 3, 621–626 (2002).

    CAS  Google Scholar 

  122. 122

    Roberts, D. J., Banh, H. L. & Hall, R. I. Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients. Curr. Opin. Crit. Care. 12, 295–302 (2006). A demonstration of a clinical role for the CCK 1 receptor antagonist dexloxiglumide, which improved the rate of gastric emptying and hence the nutritional input in critically ill patients receiving enteral feeding.

    PubMed  Google Scholar 

  123. 123

    Zerbib, F., Piche, T., Charles, F., Galmiche, J. P. & Bruley des Varannes, S. SR 48692, a specific neurotensin receptor antagonist, has no effect on oesophageal motility in humans. Aliment. Pharmacol. Ther. 19, 931–939 (2004).

    CAS  PubMed  Google Scholar 

  124. 124

    Katz, D. B., Miguel, A. L., Nicolelis, A. L. & Simon, S. A. Nutrient tasting and signalling mechanisms in the gut. IV. There is more to taste than meets the tongue. Am. J. Physiol. 278, G6–G9 (2000).

    CAS  Google Scholar 

  125. 125

    Nebel, O. T. & Castell, D. O. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 63, 778–783 (1972).

    CAS  PubMed  Google Scholar 

  126. 126

    Hellstrom, P. M., Gryback, P. & Jacobsson, H. The physiology of gastric emptying. Best Prac. Res. Clin. Anaesthesiol. 20, 397–407 (2006).

    Google Scholar 

  127. 127

    Hyland, N. P., Abrahams, T. P., Fuchs, K., Burmeister, M. A. & Hornby, P. J. Organisation and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets. J. Comp. Neurol. 430, 222–234 (2001).

    CAS  PubMed  Google Scholar 

  128. 128

    Massey, B. T. Potential control of gastroesophageal reflux by local modulation of transient lower esophageal sphincter relaxations. Am. J. Med. 111 (Suppl. 8A), 186–189 (2001).

    Google Scholar 

  129. 129

    Schulze, K. Imaging and modelling of digestion in the stomach and the duodenum. Neurogastroenterol. Motil. 18, 172–183 (2006).

    CAS  PubMed  Google Scholar 

  130. 130

    Naslund, E. & Hellstrom, P. M. Appetite signaling: from gut peptides and enteric nerves to brain. Physiol. Behav. 92, 256–262 (2007).

    PubMed  Google Scholar 

  131. 131

    Banks, W. A., Tschop, M., Robinson, S. M. & Heiman, M. L. Extent and direction of ghrelin transport across the blood–brain barrier is determined by its unique primary structure. J. Pharmacol. Exp. Ther. 302, 822–827 (2002).

    CAS  PubMed  Google Scholar 

  132. 132

    Powley, T. L. & Phillips, R. J. Gastric satiation is volumetric, intestinal satiation is nutritive. Physiol. Behav. 82, 69–74, (2004).

    CAS  PubMed  Google Scholar 

  133. 133

    Hellstrom, P. M. & Naslund, E. Interactions between gastric emptying and satiety, with special reference to glucagon-like peptide-1. Physiol. Behav. 74, 735–741 (2001).

    CAS  PubMed  Google Scholar 

  134. 134

    Langhans, W. & Hrupka, B. Interleukins and tumor necrosis factor as inhibitors of food intake. Neuropeptides 33, 415–424 (1999). The study illustrates how food intake can present a high antigen exposure requiring host defence. It is argued that this will enhance the local production of proinflammatory cytokines to limit the antigen 'impact', at least partly, by inhibiting further ingestion.

    CAS  PubMed  Google Scholar 

  135. 135

    Kelles, A., Janssens, J. & Tack, J. IL-1β and IL-6 excite neurones and suppress cholinergic neurotransmission in the myenteric plexus of the guinea-pig. Neurogastroenterol. Motil. 12, 531–538 (2000).

    CAS  PubMed  Google Scholar 

  136. 136

    Ohwada, S. et al. Low-dose erythromycin reduces delayed gastric emptying and improves gastric motility after billroth I pylorus-preserving pancreaticoduodenectomy. Ann. Surg. 234, 668–674 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Park, M.-I. et al. Effect of atilmotin on gastrointestinal transit in healthy subjects: a randomised, placebo-controlled study. Neurogastroenterol. Motil. 18, 28–36 (2006).

    PubMed  Google Scholar 

  138. 138

    Peeters, T. L., Janssens, J. & Vantrappen, G. R. Somatostatin and the interdigestive migrating motor complex in man. Regul. Pept. 5, 209–217 (1983).

    CAS  PubMed  Google Scholar 

  139. 139

    Medhus, A. W., Sandstad, O., Naslund, E., Hellstrom, P. M. & Husebye, E. The influence of the migrating motor complex on the postprandial endocrine response. Scand. J. Gastroenterol. 34, 1012–1018 (1999).

    CAS  PubMed  Google Scholar 

  140. 140

    Feurle, G. E. 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).

    CAS  PubMed  Google Scholar 

  141. 141

    Nakabayashi, M. et al. Orexin-A expression in human peripheral tissues. Mol. Cell Endocrinol. 205, 43–50 (2003).

    CAS  PubMed  Google Scholar 

  142. 142

    Katayama, Y., Hirai, K., Homma, T., Noda, Y. & Honda, K. Actions of orexins on individual myenteric neurons of the guinea-pig ileum: orexin A or B? Neuroreport 16, 745–749 (2005).

    CAS  PubMed  Google Scholar 

  143. 143

    Burdyga, G. et al. Localization of orexin-1 receptors to vagal afferent neurons in the rat and humans. Gastroenterology 124, 129–139 (2003).

    CAS  PubMed  Google Scholar 

  144. 144

    Higgins, S. C., Gueorguiev, M. & Korbonits, M. Ghrelin, the peripheral hunger hormone. Ann. Med. 39, 116–136 (2007).

    CAS  PubMed  Google Scholar 

  145. 145

    Scott, V., McDade, D. M. & Luckman, S. M. Rapid changes in the sensitivity of arcuate nucleus neurons to central ghrelin in relation to feeding status. Physiol. Behav. 90, 180–185 (2007).

    CAS  PubMed  Google Scholar 

  146. 146

    Levin, F. et al. Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J. Clin. Endocrinol. Metab. 91, 3296–3302 (2006).

    CAS  PubMed  Google Scholar 

  147. 147

    Murray, C. D. et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 54, 1693–1698 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Tack, J. et al. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment. Pharmacol. Ther. 22, 847–853 (2005).

    CAS  PubMed  Google Scholar 

  149. 149

    Binn, M. et al. Ghrelin gastrokinetic action in patients with neurogenic gastroparesis. Peptides 27, 1603–1606 (2006).

    CAS  PubMed  Google Scholar 

  150. 150

    Hervieu, G., Volant, K., Grishina, O., Descroix-Vagne, M. & Nahon, J. L. Similarities in cellular expression and functions of melanin-concentrating hormone and atrial natriuretic factor in the rat digestive tract. Endocrinology 137, 561–571 (1996).

    CAS  PubMed  Google Scholar 

  151. 151

    Burdyga, G., Varro, A., Dimaline, R., Thompson, D. G. & Dockray, G. J. Feeding-dependent depression of melanin-concentrating hormone and melanin-concentrating hormone receptor-1 expression in vagal asfferent neurones. Neuroscience 137, 1405–1415 (2006).

    CAS  PubMed  Google Scholar 

  152. 152

    Straathof, J. W., Lamers, C. B. & Masclee, A. A. Effect of gastrin-17 on lower esophageal sphincter characteristics in man. Dig. Dis. Sci. 42, 2547–2551 (1997).

    CAS  PubMed  Google Scholar 

  153. 153

    Lal, S. et al. Cholecystokinin pathways modulate sensations induced by gastric distension in humans. Am. J. Physiol. 287, G72–G79 (2004).

    CAS  Google Scholar 

  154. 154

    Ballantyne, G. H. Peptide YY(1–36) and peptide YY(3–36): Part 1: distribution, release and actions. Obes. Surg. 16, 651–658 (2006).

    PubMed  Google Scholar 

  155. 155

    Moran, T. H. Pancreatic polypeptide: more than just another gut hormone? Gastroenterology 124, 1542–1544 (2003).

    PubMed  Google Scholar 

  156. 156

    Schirra, J. et al. Endogenous GLP-1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut 55, 243–251 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Tomita, R., Igarashi, S., Tanjoh, K. & Fujisaki, S. Role of recombinant human glicentin in the normal human jejunum: an in vitro study. Hepatogastroenterology 52, 1459–1462 (2005).

    CAS  PubMed  Google Scholar 

  158. 158

    Schmidt, P. T. et al. A role for pancreatic polypeptide in the regulation of gastric emptying and short-term metabolic control. J. Clin. Endocrinol. Metab. 90, 5241–5246 (2005).

    CAS  PubMed  Google Scholar 

  159. 159

    Lutz, T. A. Amylinergic control of food intake. Physiol. Behav. 89, 465–471 (2006).

    CAS  PubMed  Google Scholar 

  160. 160

    Gedulin, B. R., Jodka, C. M., Herrmann, K. & Young, A. A. Role of endogenous amylin in glucagons secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul. Pept. 137, 121–127 (2006).

    CAS  PubMed  Google Scholar 

  161. 161

    McCallum, R. W., Cynshi, O. & US Investigative Team. Efficacy of mitemcinal, a motilin agonist, on gastrointestinal symptoms in patients with symptoms suggesting diabetic gastropathy: a randomized, multi-center, placebo-controlled trial. Aliment. Pharmacol. Ther. 26, 107–116 (2007). Describes a non-antibiotic motilin receptor antagonist, reported to improve symptoms in patients with diabetic gastroparesis.

    CAS  PubMed  Google Scholar 

  162. 162

    Peeters, T. L. New motilin agonists: a long and winding road. Neurogastroenterol. Motil. 18, 1–5 (2006).

    CAS  PubMed  Google Scholar 

  163. 163

    Talley, N. J. et al. Failure of a motilin receptor agonist (ABT-229) to relieve the symptoms of functional dyspepsia in patients with and without delayed gastric emptying: a randomized double-blind placebo-controlled trial. Aliment. Pharmacol. Ther. 14, 1653–1661 (2000).

    CAS  PubMed  Google Scholar 

  164. 164

    Talley, N. J. et al. Effects of a motilin receptor agonist (ABT-229) on upper gastrointestinal symptoms in type 1 diabetes mellitus: a randomised, double blind, placebo controlled trial. Gut 49, 395–401 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Nieuwenhuijs, V. B. et al. The effects of ABT-229 and octreotide on interdigestive small bowel motility, bacterial overgrowth and bacterial translocation in rats. Eur. J. Clin. Invest. 29, 33–40 (1999).

    CAS  PubMed  Google Scholar 

  166. 166

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

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Madsen, J. L. et al. Ghrelin agonist (TZP-101) gastroprokinetic action in diabetic patients with gastroparesis: a pilot study. Abstract number 0599-P. American Diabetes Association web site[online], (2007).

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The authors gratefully acknowledge the many contributions made by colleagues and collaborators, which have helped to shape the ideas expressed in this review.

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Correspondence to Gareth J. Sanger.

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cyclic vomiting syndrome



Upper GI disorders

These are disorders that involve the oesophageal, stomach and upper small intestinal regions and are manifested as changes in appetite, satiety, nausea, abdominal pain or discomfort, bloating and other symptoms. Examples include, eating disorders, nausea and vomiting, gastroesophageal reflux, dyspepsia and gastroparesis.

Crural diaphragm

The lower oesophageal sphincter is anchored by ligaments to the skeletal muscle of the crural diaphragm.

Intrinsic primary afferent neurons

Specialized nerves within the enteric nervous system that act as enteric sensory neurons, that are characterized by morphology, location, electrophysiological properties and sensitivity to luminal chemicals or mechanical distortion.

Vago–vagal reflexes

Reflexes that use both vagal afferent nerves (to signal a response) and vagal efferent nerves (to effect a response). Includes, for example, the transient lower oesophageal sphincter relaxations evoked by gastric fundus distension.

Gastric accommodation

Relaxation of the upper regions of the stomach during eating to make room for the ingested food. Impairment of accommodation can, for example, lead to early satiety.


Increasing or stimulating appetite.

Arcuate nucleus

The hypothalamic nucleus associated with feeding behaviours.


This pungent chemical is contained within chillies and is now known to activate vanilloid receptors.

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Sanger, G., Lee, K. Hormones of the gut–brain axis as targets for the treatment of upper gastrointestinal disorders. Nat Rev Drug Discov 7, 241–254 (2008).

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