Advertisement

The Altered Mucosal Barrier Function in the Duodenum Plays a Role in the Pathogenesis of Functional Dyspepsia

  • Keishi Komori
  • Eikichi IharaEmail author
  • Yosuke Minoda
  • Haruei Ogino
  • Taisuke Sasaki
  • Minako Fujiwara
  • Yoshinao Oda
  • Yoshihiro Ogawa
Original Article
  • 12 Downloads

Abstract

Background

An altered gastrointestinal barrier function is reportedly associated with the pathogenesis of functional dyspepsia (FD); however, the pathogenesis of FD has not yet been fully elucidated.

Aims

The objective of the present study was to determine whether the mucosal barrier function is impaired in patients with FD and to investigate the mechanisms underlying FD.

Methods

The present study included patients with FD (FD group, n = 24), non-FD patients with abdominal symptoms (symptomatic control group, n = 14), and patients with no abdominal symptoms (asymptomatic control group, n = 20). The groups were compared regarding the mucosal electrical impedance (MI) values of the stomach and duodenum, which were measured using a tissue conductance meter during esophagogastroduodenoscopy.

Results

There were no significant differences between the three groups in the MI of the stomach. In contrast, the duodenal MI of the FD group (17.8 ± 4.3 Ω) was significantly lower than those of the symptomatic control group (27.2 ± 6.4 Ω, p < 0.0001) and asymptomatic control group (23.0 ± 7.4 Ω, p = 0.016). The expression of zonula occludens-1 (ZO-1) was significantly lower in the FD group than in the symptomatic control group (p = 0.011), where ZO-1 was positively correlated with the duodenal MI (β = 0.513, p = 0.017). The interleukin (IL)-1β expression was significantly higher in the FD group than in the symptomatic control group (p = 0.041), where IL-1β was inversely correlated with the duodenal MI (β = − 0.600, p = 0.004).

Conclusions

The mucosal barrier function of the duodenum was altered in patients with FD. Both a decreased ZO-1 and increased IL-1β may play a role in the pathogenesis of FD.

Keywords

Functional dyspepsia Tight junction Mucosal barrier function Impedance IL-1β ZO-1 

Notes

Acknowledgment

We appreciate the technical assistance we received from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. We thank Kelly Zammit, BVSc, from Edanz Editing (www.edanzediting.com/ac), for editing a draft of this manuscript.

Author’s contribution

KK and HO proposed the study. KK, EI, and YM performed the research. KK and YM collected and analyzed the data. TS, MF, and YO performed the histological diagnosis. KK and EI wrote the manuscript. YO supervised the study. All authors contributed to the interpretation of the study.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10620_2019_5470_MOESM1_ESM.jpg (174 kb)
Supplemental Figure 1. Correlation between the esophageal mucosal electrical impedance (MI) measured using the 24-h multichannel intraluminal pH/impedance test (MII-pH) versus the tissue conductance meter. The esophageal MI was measured in 14 patients (from either the functional dyspepsia group or the symptomatic control group) using both the MII-pH and the tissue conductance meter. The correlation between the MI values obtained using the different devices was calculated by performing Pearson’s correlation analysis. (JPEG 173 kb)

References

  1. 1.
    Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;130:1466–1479.CrossRefGoogle Scholar
  2. 2.
    El-Serag HB, Talley NJ. The prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther. 2004;19:643–654.CrossRefGoogle Scholar
  3. 3.
    Suzuki H. The application of the Rome IV criteria to functional esophagogastroduodenal disorders in Asia. J Neurogastroenterol Motil. 2017;23:325–333.CrossRefGoogle Scholar
  4. 4.
    Halling K, Kulich K, Carlsson J, Wiklund I. An international comparison of the burden of illness in patients with dyspepsia. Dig Dis. 2008;26:264–273.CrossRefGoogle Scholar
  5. 5.
    Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology. 1998;115:1346–1352.CrossRefGoogle Scholar
  6. 6.
    Lunding JA, Tefera S, Gilja OH, et al. Rapid initial gastric emptying and hypersensitivity to gastric filling in functional dyspepsia: effects of duodenal lipids. Scand J Gastroenterol. 2006;41:1028–1036.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    Boeckxstaens GE, Hirsch DP, Kuiken SD, Heisterkamp SH, Tytgat GN. The proximal stomach and postprandial symptoms in functional dyspeptics. Am J Gastroenterol. 2002;97:40–48.CrossRefGoogle Scholar
  9. 9.
    Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology. 2001;121:526–535.CrossRefGoogle Scholar
  10. 10.
    Bratten J, Jones MP. Prolonged recording of duodenal acid exposure in patients with functional dyspepsia and controls using a radiotelemetry pH monitoring system. J Clin Gastroenterol. 2009;43:527–533.CrossRefGoogle Scholar
  11. 11.
    Feinle C, Meier O, Otto B, D’Amato M, Fried M. Role of duodenal lipid and cholecystokinin A receptors in the pathophysiology of functional dyspepsia. Gut. 2001;48:347–355.CrossRefGoogle Scholar
  12. 12.
    Hammer J, Fuhrer M. Clinical characteristics of functional dyspepsia depending on chemosensitivity to capsaicin. Neurogastroenterol Motil. 2017;29:1–12.CrossRefGoogle Scholar
  13. 13.
    Kindt S, Tertychnyy A, de Hertogh G, Geboes K, Tack J. Intestinal immune activation in presumed post-infectious functional dyspepsia. Neurogastroenterol Motil. 2009;21:832–856.CrossRefGoogle Scholar
  14. 14.
    Talley NJ, Walker MM, Aro P, et al. Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case–control study. Clin Gastroenterol Hepatol. 2007;5:1175–1183.CrossRefGoogle Scholar
  15. 15.
    Vanheel H, Vicario M, Vanuytsel T, et al. Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut. 2014;63:262–271.CrossRefGoogle Scholar
  16. 16.
    Ishigami H, Matsumura T, Kasamatsu S, et al. Endoscopy-guided evaluation of duodenal mucosal permeability in functional dyspepsia. Clin Transl Gastroenterol. 2017;8:e83.CrossRefGoogle Scholar
  17. 17.
    Koizumi H, Suzuki H, Ohbuchi T, Kitamura T, Hashida K, Nakamura M. Increased permeability of the epithelium of middle ear cholesteatoma. Clin Otolaryngol. 2015;40:106–114.CrossRefGoogle Scholar
  18. 18.
    Yamamoto T, Yamamoto Y. Electrical properties of the epidermal stratum corneum. Med Biol Eng. 1976;14:151–158.CrossRefGoogle Scholar
  19. 19.
    Lawrence JN. Electrical resistance and tritiated water permeability as indicators of barrier integrity of in vitro human skin. Toxicol In Vitro. 1997;11:241–249.CrossRefGoogle Scholar
  20. 20.
    Martinsen OG, Grimnes S, Nilsen SH. Water sorption and electrical properties of a human nail. Skin Res Technol. 2008;14:142–146.CrossRefGoogle Scholar
  21. 21.
    Suzuki H, Koizumi H, Ikezaki S, et al. Electrical impedance and expression of tight junction components of the nasal turbinate and polyp. ORL J Otorhinolaryngol Relat Spec. 2016;78:16–25.CrossRefGoogle Scholar
  22. 22.
    Farre R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut. 2011;60:885–892.CrossRefGoogle Scholar
  23. 23.
    Iboshi Y, Nakamura K, Ihara E, et al. Multigene analysis unveils distinctive expression profiles of helper T-cell-related genes in the intestinal mucosa that discriminate between ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2014;20:967–977.PubMedGoogle Scholar
  24. 24.
    Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17:564–580.CrossRefGoogle Scholar
  25. 25.
    Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55–60.CrossRefGoogle Scholar
  26. 26.
    Thaiss CA, Levy M, Grosheva I, et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science. 2018;359:1376–1383.CrossRefGoogle Scholar
  27. 27.
    Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol. 1986;103:755–766.CrossRefGoogle Scholar
  28. 28.
    Umeda K, Ikenouchi J, Katahira-Tayama S, et al. ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation. Cell. 2006;126:741–754.CrossRefGoogle Scholar
  29. 29.
    Montalto M, Cuoco L, Ricci R, Maggiano N, Vecchio FM, Gasbarrini G. Immunohistochemical analysis of ZO-1 in the duodenal mucosa of patients with untreated and treated celiac disease. Digestion. 2002;65:227–233.CrossRefGoogle Scholar
  30. 30.
    Pizzuti D, Bortolami M, Mazzon E, et al. Transcriptional downregulation of tight junction protein ZO-1 in active coeliac disease is reversed after a gluten-free diet. Dig Liver Dis. 2004;36:337–341.CrossRefGoogle Scholar
  31. 31.
    Bueno L, Fioramonti J. Protease-activated receptor 2 and gut permeability: a review. Neurogastroenterol Motil. 2008;20:580–587.CrossRefGoogle Scholar
  32. 32.
    Jacob C, Yang PC, Darmoul D, et al. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem. 2005;280:31936–31948.CrossRefGoogle Scholar
  33. 33.
    Hirano M, Hirano K. Myosin di-phosphorylation and peripheral actin bundle formation as initial events during endothelial barrier disruption. Sci Rep. 2016;6:20989.CrossRefGoogle Scholar
  34. 34.
    Liebregts T, Adam B, Bredack C, et al. Small bowel homing T cells are associated with symptoms and delayed gastric emptying in functional dyspepsia. Am J Gastroenterol. 2011;106:1089–1098.CrossRefGoogle Scholar
  35. 35.
    Al-Sadi RM, Ma TY. IL-1β causes an increase in intestinal epithelial tight junction permeability. J Immunol. 2007;178:4641–4649.CrossRefGoogle Scholar
  36. 36.
    Cui HS, Hayasaka S, Zhang XY, Hayasaka Y, Chi ZL, Zheng LS. Effect of berberine on barrier function in a human retinal pigment epithelial cell line. Jpn J Ophthalmol. 2007;51:64–67.CrossRefGoogle Scholar
  37. 37.
    Kimura K, Teranishi S, Nishida T. Interleukin-1β-induced disruption of barrier function in cultured human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2009;50:597–603.CrossRefGoogle Scholar
  38. 38.
    Tanaka H, Fukuda K, Ishida W, Harada Y, Sumi T, Fukushima A. Rebamipide increases barrier function and attenuates TNFα-induced barrier disruption and cytokine expression in human corneal epithelial cells. Br J Ophthalmol. 2013;97:912–916.CrossRefGoogle Scholar
  39. 39.
    Esnault S, Kelly EA, Nettenstrom LM, Cook EB, Seroogy CM, Jarjour NN. Human eosinophils release IL-1β and increase expression of IL-17A in activated CD4+ T lymphocytes. Clin Exp Allergy. 2012;42:1756–1764.CrossRefGoogle Scholar
  40. 40.
    Futagami S, Shindo T, Kawagoe T, et al. Migration of eosinophils and CCR2-/CD68-double positive cells into the duodenal mucosa of patients with postinfectious functional dyspepsia. Am J Gastroenterol. 2010;105:1835–1842.CrossRefGoogle Scholar
  41. 41.
    Walker MM, Salehian SS, Murray CE, et al. Implications of eosinophilia in the normal duodenal biopsy—an association with allergy and functional dyspepsia. Aliment Pharmacol Ther. 2010;31:1229–1236.CrossRefGoogle Scholar
  42. 42.
    Saritas Yuksel E, Higginbotham T, Slaughter JC, et al. Use of direct, endoscopic-guided measurements of mucosal impedance in diagnosis of gastroesophageal reflux disease. Clin Gastroenterol Hepatol. 2012;10:1110–1116.CrossRefGoogle Scholar
  43. 43.
    van Rhijn BD, Weijenborg PW, Verheij J, et al. Proton pump inhibitors partially restore mucosal integrity in patients with proton pump inhibitor-responsive esophageal eosinophilia but not eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2014;12:1815–1823.CrossRefGoogle Scholar
  44. 44.
    Li X, Chen H, Lu H, et al. The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand J Gastroenterol. 2010;45:573–581.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Keishi Komori
    • 1
  • Eikichi Ihara
    • 1
    Email author
  • Yosuke Minoda
    • 1
  • Haruei Ogino
    • 1
  • Taisuke Sasaki
    • 2
  • Minako Fujiwara
    • 2
  • Yoshinao Oda
    • 2
  • Yoshihiro Ogawa
    • 1
  1. 1.Department of Medicine and Bioregulatory Science, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

Personalised recommendations