Korean J Gastroenterol.  2016 Sep;68(3):132-137. 10.4166/kjg.2016.68.3.132.

Current Status of Translational Research on Functional Dyspepsia

• Park JH
• Kim JW
• Park JK
• Shin CM
• Jung KW

• KMID: 2358714
• DOI: http://doi.org/10.4166/kjg.2016.68.3.132

Abstract

Functional dyspepsia (FD) has a diverse pathophysiology and treatment is difficult. Translational research to understand its pathophysiology is underway. Hormonal factors, including ghrelin, seem promising, offering an understanding of appetite and eating. Functional MRI brain study can expand our knowledge of the brain-gut axis. Finally, immune systems research, including mast cells, can help with comprehensive understanding of FD. The clinical approaches based on these translational research projects are necessary to improve understanding of FD, leading to more effective treatment.

Keyword

Functional dyspepsia; Translational medical research

MeSH Terms

Appetite
Brain
Dyspepsia*
Eating
Ghrelin
Immune System
Magnetic Resonance Imaging
Mast Cells
Translational Medical Research*
Ghrelin

Reference

References

1. El-Serag HB, Talley NJ. Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther. 2003; 18:387–393.

2. Agréus L, Borgquist L. The cost of gastro-oesophageal reflux disease, dyspepsia and peptic ulcer disease in Sweden. Pharmacoeconomics. 2002; 20:347–355.

3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999; 402:656–660.

4. Date Y, Kojima M, Hosoda H, 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. 2000; 141:4255–4261.

5. Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-ac-yl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun. 2000; 279:909–913.

6. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001; 50:1714–1719.

7. Foster-Schubert KE, Overduin J, Prudom CE, et al. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab. 2008; 93:1971–1979.

8. Janssen S, Depoortere I. Nutrient sensing in the gut: new roads to therapeutics? Trends Endocrinol Metab. 2013; 24:92–100.

9. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001; 409:194–198.

10. Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 2008; 7:400–409.

11. Avau B, Carbone F, Tack J, Depoortere I. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil. 2013; 25:720–732.

12. Levin F, Edholm T, Schmidt PT, et al. Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J Clin Endocrinol Metab. 2006; 91:3296–3302.

13. Falkén Y, Hellström PM, Sanger GJ, et al. Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans. Neurogastroenterol Motil. 2010; 22:e192–e200.

14. Shindo T, Futagami S, Hiratsuka T, et al. Comparison of gastric emptying and plasma ghrelin levels in patients with functional dyspepsia and non-erosive reflux disease. Digestion. 2009; 79:65–72.

15. Shinomiya T, Fukunaga M, Akamizu T, et al. Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol. 2005; 40:648–653.

16. Akamizu T, Iwakura H, Ariyasu H, et al. Repeated administration of ghrelin to patients with functional dyspepsia: its effects on food intake and appetite. Eur J Endocrinol. 2008; 158:491–498.

17. Takamori K, Mizuta Y, Takeshima F, et al. Relation among plasma ghrelin level, gastric emptying, and psychologic condition in patients with functional dyspepsia. J Clin Gastroenterol. 2007; 41:477–483.

18. Lee KJ, Cha DY, Cheon SJ, Yeo M, Cho SW. Plasma ghrelin levels and their relationship with gastric emptying in patients with dys-motility-like functional dyspepsia. Digestion. 2009; 80:58–63.

19. Arai M, Matsumura T, Tsuchiya N, et al. Rikkunshito improves the symptoms in patients with functional dyspepsia, accompanied by an increase in the level of plasma ghrelin. Hepatogastroenterology. 2012; 59:62–66.

20. Ejskjaer N, Dimcevski G, Wo J, et al. Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. Neurogastroenterol Motil. 2010; 22:1069–e281.

21. Ejskjaer N, Vestergaard ET, Hellström PM, et al. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther. 2009; 29:1179–1187.

22. Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ. The Ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial. Dis Colon Rectum. 2010; 53:126–134.

23. Bochicchio G, Charlton P, Pezzullo JC, Kosutic G, Senagore A. Ghrelin agonist TZP-101/ulimorelin accelerates gastrointestinal recovery independently of opioid use and surgery type: co-variate analysis of phase 2 data. World J Surg. 2012; 36:39–45.

24. Ejskjaer N, Wo JM, Esfandyari T, et al. A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterol Motil. 2013; 25:e140–e150.

25. Jaradeh SS, Prieto TE. Evaluation of the autonomic nervous system. Phys Med Rehabil Clin N Am. 2003; 14:287–305.

26. Mearin F, Cucala M, Azpiroz F, Malagelada JR. The origin of symptoms on the brain-gut axis in functional dyspepsia. Gastroenterology. 1991; 101:999–1006.

27. Aziz Q, Schnitzler A, Enck P. Functional neuroimaging of visceral sensation. J Clin Neurophysiol. 2000; 17:604–612.

28. Moisset X, Bouhassira D, Denis D, Dominique G, Benoit C, Sabaté JM. Anatomical connections between brain areas activated during rectal distension in healthy volunteers: a visceral pain network. Eur J Pain. 2010; 14:142–148.

29. McMahon SB. Are there fundamental differences in the peripheral mechanisms of visceral and somatic pain? Behav Brain Sci. 1997; 20:381–391. discussion 435–513.

30. Dunckley P, Wise RG, Aziz Q, et al. Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness. Neuroscience. 2005; 133:533–542.

31. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002; 3:655–666.

32. Menon V, Uddin LQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct. 2010; 214:655–667.

33. Zubieta JK, Smith YR, Bueller JA, et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science. 2001; 293:311–315.

34. Lee IS, Wang H, Chae Y, Preissl H, Enck P. Functional neuroimaging studies in functional dyspepsia patients: a systematic review. Neurogastroenterol Motil. 2016; 28:793–805.

35. Zeng F, Song WZ, Liu XG, et al. Brain areas involved in acupuncture treatment on functional dyspepsia patients: a PET-CT study. Neurosci Lett. 2009; 456:6–10.

36. Zeng F, Qin W, Liang F, et al. Abnormal resting brain activity in patients with functional dyspepsia is related to symptom severity. Gastroenterology. 2011; 141:499–506.

37. Zhou G, Liu P, Zeng F, et al. Increased interhemispheric resting-state functional connectivity in functional dyspepsia: a pilot study. NMR Biomed. 2013; 26:410–415.

38. Liu P, Zeng F, Zhou G, et al. Alterations of the default mode network in functional dyspepsia patients: a resting-state fmri study. Neurogastroenterol Motil. 2013; 25:e382–e388.

39. Liu P, Qin W, Wang J, et al. Identifying neural patterns of functional dyspepsia using multivariate pattern analysis: a resting-state FMRI study. PLoS One. 2013; 8:e68205.

40. Nan J, Liu J, Zhang D, et al. Altered intrinsic regional activity and corresponding brain pathways reflect the symptom severity of functional dyspepsia. Neurogastroenterol Motil. 2014; 26:660–669.

41. Nan J, Liu J, Mu J, et al. Brain-based correlations between psychological factors and functional dyspepsia. J Neurogastroenterol Motil. 2015; 21:103–110.

42. Zhou G, Liu P, Wang J, et al. Fractional amplitude of low-frequency fluctuation changes in functional dyspepsia: a resting-state fMRI study. Magn Reson Imaging. 2013; 31:996–1000.

43. Nan J, Liu J, Li G, et al. Whole-brain functional connectivity identification of functional dyspepsia. PLoS One. 2013; 8:e65870.

44. Vandenberghe J, Dupont P, Van Oudenhove L, et al. Regional cerebral blood flow during gastric balloon distention in functional dyspepsia. Gastroenterology. 2007; 132:1684–1693.

45. Van Oudenhove L, Vandenberghe J, Dupont P, et al. Abnormal regional brain activity during rest and (anticipated) gastric distension in functional dyspepsia and the role of anxiety: a H(2)(15)O-PET study. Am J Gastroenterol. 2010; 105:913–924.

46. Van Oudenhove L, Vandenberghe J, Dupont P, et al. Regional brain activity in functional dyspepsia: a H(2)(15)O-PET study on the role of gastric sensitivity and abuse history. Gastroenterology. 2010; 139:36–47.

47. Zeng F, Qin W, Ma T, et al. Influence of acupuncture treatment on cerebral activity in functional dyspepsia patients and its relationship with efficacy. Am J Gastroenterol. 2012; 107:1236–1247.

48. Li Z, Zeng F, Yang Y, et al. Different cerebral responses to puncturing at ST36 among patients with functional dyspepsia and healthy subjects. Forsch Komplementmed. 2014; 21:99–104.

49. Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders. Gut. 2016; 65:155–168.

50. Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol. 2007; 7:93–104.

51. Vanheel H, Vicario M, Vanuytsel T, et al. Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut. 2014; 63:262–271.

52. Wang X, Li X, Ge W, et al. Quantitative evaluation of duodenal eosinophils and mast cells in adult patients with functional dyspepsia. Ann Diagn Pathol. 2015; 19:50–56.

53. Neilan NA, Garg UC, Schurman JV, Friesen CA. Intestinal permeability in children/adolescents with functional dyspepsia. BMC Res Notes. 2014; 7:275.

54. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014; 63:1293–1299.

55. Friesen CA, Sandridge L, Andre L, Roberts CC, Abdel-Rahman SM. Mucosal eosinophilia and response to H1/H2 antagonist and cromolyn therapy in pediatric dyspepsia. Clin Pediatr (Phila). 2006; 45:143–147.