Skip to main content

Associations among gut permeability, inflammatory markers, and symptoms in patients with irritable bowel syndrome

Abstract

Background

Alterations in gastrointestinal (GI) permeability and immune measures are present in some patients with irritable bowel syndrome (IBS) but the relationship to symptoms is poorly defined. In adults with IBS, we compared permeability, unstimulated peripheral blood monocyte (PBMC) interleukin-10 (IL-10) levels, IBS life interference, and GI and psychological distress symptoms.

Methods

In 88 women and 18 men with IBS, GI permeability was quantitated as percent recovery of urinary sucrose and the lactulose/mannitol (L/M) ratio. IL-10 was measured in supernatants from 72-h incubated, unstimulated PBMCs. Participants completed a 4-week daily diary recording IBS life interference on daily activities and work, IBS symptoms, and psychological distress symptoms. They also completed the Brief Symptom Inventory.

Results

The L/M ratio but not percent sucrose recovery was significantly correlated with IBS interference with activities and work and retrospectively measured anxiety and depression. Unstimulated PBMC production of IL-10 correlated significantly with IBS interference with daily work, IBS symptom score, and abdominal pain. We identified a subgroup of IBS subjects with higher IL-10 and/or higher L/M ratio who had substantially higher IBS interference and IBS symptom scores.

Conclusions

Our findings suggest a distinct subgroup of IBS patients with alterations in gut barrier function. This subgroup is characterized by increased GI permeability and/or increased PBMC production of IL-10. These physiologic alterations reflect more severe IBS as measured by interference of IBS with daily activities and daily IBS symptoms.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. Maxion-Bergemann S, Thielecke F, Abel F, Bergemann R. Costs of irritable bowel syndrome in the UK and US. Pharmacoeconomics. 2006;24(1):21–37.

    Article  PubMed  Google Scholar 

  2. Agarwal N, Spiegel BM. The effect of irritable bowel syndrome on health-related quality of life and health care expenditures. Gastroenterol Clin North Am. 2011;40(1):11–9.

    Article  PubMed  Google Scholar 

  3. Graham DP, Savas L, White D, El-Serag R, Laday-Smith S, Tan G, et al. Irritable bowel syndrome symptoms and health related quality of life in female veterans. Aliment Pharmacol Ther. 2010;31(2):261–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Drossman D, Corazziari E, Delvaux M, Spiller R, Talley N, Thompson W, et al. Rome III: the functional gastrointestinal disorders. 3rd ed. McLean: Degnon Associates; 2006.

    Google Scholar 

  5. Qin HY, Wu JC, Tong XD, Sung JJ, Xu HX, Bian ZX. Systematic review of animal models of post-infectious/post-inflammatory irritable bowel syndrome. J Gastroenterol. 2011;46(2):164–74.

    Article  PubMed  Google Scholar 

  6. Stasi C, Rosselli M, Bellini M, Laffi G, Milani S. Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. J Gastroenterol. 2012;47(11):1177–85.

    Article  CAS  PubMed  Google Scholar 

  7. Adam B, Tsopelas C, Liebregts T, Bartholomeusz FD, Holtmann G. Host immune response determines visceral hyperalgesia in a rat model of post-inflammatory irritable bowel syndrome. J Gastroenterol. 2013;48(10):1119–27.

    Article  CAS  PubMed  Google Scholar 

  8. Ford AC, Talley NJ. Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review. J Gastroenterol. 2011;46(4):421–31.

    Article  PubMed  Google Scholar 

  9. Matricon J, Meleine M, Gelot A, Piche T, Dapoigny M, Muller E, et al. Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment Pharmacol Ther. 2012;36(11–12):1009–31.

    Article  CAS  PubMed  Google Scholar 

  10. Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303(7):G775–85.

    Article  CAS  PubMed  Google Scholar 

  11. Scully P, McKernan DP, Keohane J, Groeger D, Shanahan F, Dinan TG, et al. Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity. Am J Gastroenterol. 2010;105(10):2235–43.

    Article  CAS  PubMed  Google Scholar 

  12. Ortiz-Lucas M, Saz-Peiro P, Sebastian-Domingo JJ. Irritable bowel syndrome immune hypothesis. Part one: the role of lymphocytes and mast cells. Rev Esp Enferm Dig. 2010;102(11):637–47.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu H, Lei X, Liu Q, Wang Y. Interleukin-10-1082A/G polymorphism and inflammatory bowel disease susceptibility: a meta-analysis based on 17,585 subjects. Cytokine. 2013;61(1):146–53.

    Article  CAS  PubMed  Google Scholar 

  14. Banchereau J, Pascual V, O’Garra A. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol. 2012;13(10):925–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13(8):722–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Barreau F, Ferrier L, Fioramonti J, Bueno L. New insights in the etiology and pathophysiology of irritable bowel syndrome: contribution of neonatal stress models. Pediatr Res. 2007;62(3):240–5.

    Article  PubMed  Google Scholar 

  17. Li X, Kan EM, Lu J, Cao Y, Wong RK, Keshavarzian A, et al. Combat-training increases intestinal permeability, immune activation and gastrointestinal symptoms in soldiers. Aliment Pharmacol Ther. 2013;37(8):799–809.

    Article  CAS  PubMed  Google Scholar 

  18. Catassi C, Pierani P, Natalini G, Gabrielli O, Coppa GV, Giorgi PL. Clinical application of a simple HPLC method for the sugar intestinal permeability test. J Pediatr Gastroenterol Nutr. 1991;12(2):209–12.

    Article  CAS  PubMed  Google Scholar 

  19. Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou CN, Smith EO. Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants. Pediatr Res. 1998;44:519–23.

    Article  CAS  PubMed  Google Scholar 

  20. McOmber ME, Ou CN, Shulman RJ. Effects of timing, sex, and age on site-specific gastrointestinal permeability testing in children and adults. J Pediatr Gastroenterol Nutr. 2010;50(3):269–75.

    Article  PubMed Central  PubMed  Google Scholar 

  21. O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology. 2005;128(3):541–51.

    Article  PubMed  Google Scholar 

  22. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353–65.

    Article  CAS  PubMed  Google Scholar 

  23. Jarrett ME, Cain KC, Burr RL, Hertig VL, Rosen SN, Heitkemper MM. Comprehensive self-management for irritable bowel syndrome: randomized trial of in-person vs. combined in-person and telephone sessions. Am J Gastroenterol. 2009;104(12):3004–14.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Derogatis L. BSI: Brief Symptom Inventory; administration, scoring and procedures manual. 4th ed. Minneapolis: National Computer Systems; 1993.

    Google Scholar 

  25. Camilleri M, Lasch K, Zhou W. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303:G775–85.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou Q, Zhang B, Verne GN. Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome. Pain. 2009;146(1–2):41–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther. 2004;20(11–12):1317–22.

    Article  CAS  PubMed  Google Scholar 

  28. Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. AmJ Gastroenterol. 2006;101(6):1288–94.

    Article  Google Scholar 

  29. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.

    Article  CAS  PubMed  Google Scholar 

  30. Kaji I, Yasuoka Y, Karaki S, Kuwahara A. Activation of TRPA1 by luminal stimuli induces EP4-mediated anion secretion in human and rat colon. Am J Physiol Gastrointest Liver Physiol. 2012;302(7):G690–701.

    Article  CAS  PubMed  Google Scholar 

  31. Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1782–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Langhorst J, Junge A, Rueffer A, Wehkamp J, Foell D, Michalsen A, et al. Elevated human beta-defensin-2 levels indicate an activation of the innate immune system in patients with irritable bowel syndrome. Am J Gastroenterol. 2009;104(2):404–10.

    Article  CAS  PubMed  Google Scholar 

  33. Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cellular and molecular life sciences. CMLS. 2013;70(4):631–59.

    Article  CAS  PubMed  Google Scholar 

  34. Chang L, Adeyemo M, Karagiannides I, Videlock EJ, Bowe C, Shih W, et al. Serum and colonic mucosal immune markers in irritable bowel syndrome. Am J Gastroenterol. 2012;107(2):262–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Schmulson M, Pulido-London D, Rodriguez O, Morales-Rochlin N, Martinez-Garcia R, Gutierrez-Ruiz MC, et al. Lower serum IL-10 is an independent predictor of IBS among volunteers in Mexico. Am J Gastroenterol. 2012;107(5):747–53.

    Article  CAS  PubMed  Google Scholar 

  36. Kindt S, Van Oudenhove L, Broekaert D, Kasran A, Ceuppens JL, Bossuyt X, et al. Immune dysfunction in patients with functional gastrointestinal disorders. Neurogastroenterol Motil. 2009;21(4):389–98.

    Article  CAS  PubMed  Google Scholar 

  37. Hughes PA, Harrington AM, Castro J, Liebregts T, Adam B, Grasby DJ, et al. Sensory neuro-immune interactions differ between irritable bowel syndrome subtypes. Gut. 2012;62:1456–65.

    Article  PubMed  Google Scholar 

  38. Liebregts T, Adam B, Bredack C, Roth A, Heinzel S, Lester S, et al. Immune activation in patients with irritable bowel syndrome. Gastroenterology. 2007;132(3):913–20.

    Article  CAS  PubMed  Google Scholar 

  39. Hua MC, Lai MW, Kuo ML, Yao TC, Huang JL, Chen SM. Decreased interleukin-10 secretion by peripheral blood mononuclear cells in children with irritable bowel syndrome. J Pediatr Gastroenterol Nutr. 2011;52(4):376–81.

    Article  CAS  PubMed  Google Scholar 

  40. Chogle A, Sztainberg M, Bass L, Youssef NN, Miranda A, Nurko S, et al. Accuracy of pain recall in children. J Pediatr Gastroenterol Nutr. 2012;55(3):288–91.

    Article  PubMed  Google Scholar 

  41. Engsbro AL, Simren M, Bytzer P. The Rome II and Rome III criteria identify the same subtype-populations in irritable bowel syndrome: agreement depends on the method used for symptom report. Neurogastroenterol Motil. 2012;24(7):604–11, e266.

    Google Scholar 

  42. Weinland SR, Morris CB, Hu Y, Leserman J, Bangdiwala SI, Drossman DA. Characterization of episodes of irritable bowel syndrome using ecological momentary assessment. Am J Gastroenterol. 2011;106(10):1813–20.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by R01 NR004142 and R01 NR05337 from the National Institutes of Health, the Daffy’s Foundation, the US Department of Agriculture/Agricultural Research Service (USDA/ARS) under Cooperative Agreement No. 6250-51000-043, and P30 DK56338 which funds the Texas Medical Center Digestive Disease Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work is a publication of the University of Washington and the USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital. The contents do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert J. Shulman.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 30 kb)

Supplementary material 2 (DOCX 30 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shulman, R.J., Jarrett, M.E., Cain, K.C. et al. Associations among gut permeability, inflammatory markers, and symptoms in patients with irritable bowel syndrome. J Gastroenterol 49, 1467–1476 (2014). https://doi.org/10.1007/s00535-013-0919-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-013-0919-6

Keywords

  • Permeability
  • Cytokine
  • Symptoms
  • Irritable bowel syndrome