Skip to main content

Advertisement

Log in

NSAID enteropathy: could probiotics prevent it?

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world; nevertheless, about 50–70 % of patients on long-term NSAIDs develop small intestine injury, namely NSAID enteropathy, sometimes with serious outcomes. No medications with proven efficacy are yet available to prevent NSAID enteropathy. A series of therapeutic strategies targeting the different mechanisms involved in small bowel injury have been investigated, but without definitive results. Intestinal bacteria and their degradation products are essential for the development of NSAID-induced small bowel lesions, because “germ-free” animals were found to be resistant to indomethacin injuries. Therefore, it has been suggested that modulating the intestinal flora, for example by using probiotics, could protect against NSAID enteropathy. In this work, we reviewed the main therapeutic strategies for NSAID enteropathy, in particular analyzing the available studies relating to the eventual protective role of probiotics. We found that results are not all concordant; nevertheless, the more recent studies provide better understanding about pathogenetic mechanisms involved in small intestinal injury and the role of probiotics, and show encouraging results. Larger and well-designed studies should be performed to evaluate the actual role of probiotics in NSAID enteropathy, the eventual differences among probiotic strains, dose-responses, and optimal duration of therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010;24:121–32.

    Article  PubMed  CAS  Google Scholar 

  2. Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, et al. Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol. 2009;44:879–88.

    Article  PubMed  Google Scholar 

  3. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol. 2005;3:133–41.

    Article  PubMed  Google Scholar 

  4. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol. 2005;3:55–9.

    Article  PubMed  Google Scholar 

  5. Maiden L. Capsule endoscopic diagnosis of nonsteroidal antiinflammatory drug-induced enteropathy. J Gastroenterol. 2009;19:64–71.

    Article  Google Scholar 

  6. Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology. 2005;128:1172–8.

    Article  PubMed  Google Scholar 

  7. Zeino Z, Sisson G, Bjarnason I. Adverse effects of drugs on small intestine and colon. Best Pract Res Clin Gastroenterol. 2010;24:133–41.

    Article  PubMed  CAS  Google Scholar 

  8. Whittle BJ. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology. 1981;80:94–8.

    PubMed  CAS  Google Scholar 

  9. Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small intestine in humans. Gastroenterology. 1993;104:1832–47.

    PubMed  CAS  Google Scholar 

  10. Sigthorsson G, Simpson RJ, Walley M, et al. COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice. Gastroenterology. 2002;122:1913–23.

    Article  PubMed  CAS  Google Scholar 

  11. Silverstein FE, Faich G, Goldstein JL, Anthony A, Foster R, Hotz-Behoftsitz C, et al. Gastrointestinal toxicity with celecoxib as NSAIDs for osteoarthritis and rheumatoid arthritis in the CLASS study. JAMA. 2000;284:1247–55.

    Article  PubMed  CAS  Google Scholar 

  12. Laine L, Connors LG, Reicin A, Hawkey CJ, Burgos-Vargas R, Schnitzer TJ, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology. 2003;124:288–92.

    Article  PubMed  CAS  Google Scholar 

  13. Bjarnason I, Takeuchi K. Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. J Gastroenterol. 2009;44:23–9.

    Article  PubMed  CAS  Google Scholar 

  14. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092–102.

    Article  PubMed  CAS  Google Scholar 

  15. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520–8.

    Article  PubMed  CAS  Google Scholar 

  16. Somasundaram S, Hayllar H, Rafi S, Wrigglesworth JM, Macpherson AJ, Bjarnason I. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol. 1995;30:289–99.

    Article  PubMed  CAS  Google Scholar 

  17. Robert A. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins. 1977;14:333–41.

    PubMed  CAS  Google Scholar 

  18. Dietzel K, Beck WS, Schneider HT, Geisslinger G, Brune K. The biliary elimination and enterohepatic circulation of ibuprofen in rats. Pharm Res. 1990;7:87–90.

    Article  PubMed  CAS  Google Scholar 

  19. Petruzzelli M, Vacca M, Moschetta A, Cinzia Sasso R, Palasciano G, van Erpecum KJ, et al. Intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs: role of bile salts. Clin Biochem. 2007;40:503–10.

    Article  PubMed  CAS  Google Scholar 

  20. Qin Y, Naito Y, Handa O, Hayashi N, Kuki A, Mizushima K, et al. Heat shock protein 70-dependent protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells. J Clin Biochem Nutr. 2011;49:174–81.

    Article  PubMed  CAS  Google Scholar 

  21. Hayashi Y, Yamamoto H, Takauchi H, Sunada K, Miyata T, Yano T, et al. Nonsteroidal anti-inflammatory drug-induced small-bowel lesions indentified by double-balloon endoscopy: endoscopic features of the lesions and endoscopic treatments for diaphragm disease. J Gastroenterol. 2009;44:57–63.

    Article  PubMed  Google Scholar 

  22. Adebayo D, Bjarnason I. Is non-steroidal anti-inflammatory drug (NSAID) enteropathy clinically more important than NSAID gastropathy? Postgrad Med J. 2006;82:186–91.

    Article  PubMed  CAS  Google Scholar 

  23. Bjarnason I, Smethurst P, Clark P, Menzies I, Levi J, Peters T. Effect of prostaglandins on indomethacin induced increased intestinal permeability in man. Scand J Gastroenterol. 1989;29:97–103.

    Article  Google Scholar 

  24. Bjarnason I, Smethurst P, Fenn GC, Lee CE, Menzies IS, Levi AJ. Misoprostol reduces indomethacin induced changes in human small intestinal permeability. Dig Dis Sci. 1989;34:407–11.

    Article  PubMed  CAS  Google Scholar 

  25. Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci. 1993;38:417–25.

    Article  PubMed  CAS  Google Scholar 

  26. Watanabe T, Sugimori S, Kameda N, Machida H, Okazaki H, Tanigawa T, et al. Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study. Clin Gastroenterol Hepatol. 2008;6:1279–82.

    Article  PubMed  Google Scholar 

  27. Fujimori S, Seo T, Gudis K, Ehara A, Kobayashi T, Mitsui K, et al. Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc. 2009;69:1339–46.

    Article  PubMed  Google Scholar 

  28. Yoshida N, Yoshikawa T, Tanaka Y, Fujita N, Kassai K, Naito Y, et al. A new mechanism for anti-inflammatory actions of proton pump inhibitors—inhibitory effects on neutrophil–endothelial cell interactions. Aliment Pharmacol Ther. 2000;14:74–81.

    Article  PubMed  CAS  Google Scholar 

  29. Yoda Y, Amagase K, Kato S, Tokioka S, Murano M, Kakimoto K, et al. Prevention by lansoprazole, a proton pump inhibitor, of indomethacin-induced small intestinal ulceration in rats through induction of heme oxygenase-1. J Physiol Pharmacol. 2010;61:287–94.

    PubMed  CAS  Google Scholar 

  30. Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141:1314–22.

    Article  PubMed  CAS  Google Scholar 

  31. Niwa Y, Nakamura M, Ohmiya N, Maeda O, Ando T, Itoh A, et al. Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study. J Gastroenterol. 2008;43:270–6.

    Article  PubMed  CAS  Google Scholar 

  32. Fujimori S, Takahashi Y, Gudis K, Seo T, Ehara A, Kobayashi T, et al. Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy. J Gastroenterol. 2011;46:57–64.

    Article  PubMed  CAS  Google Scholar 

  33. Mizukami K, Murakami K, Abe T, Inoue K, Uchida M, Okimoto T, et al. Aspirin-induced small bowel injuries and the preventive effect of rebamipide. World J Gastroenterol. 2011;14(17):5117–22.

    Article  Google Scholar 

  34. Lanas A, Scarpignato C. Microbial flora in NSAID-induced intestinal damage: a role for antibiotics? Digestion. 2006;73:136–50.

    Article  PubMed  CAS  Google Scholar 

  35. Bjarnason I, Hayllar J, Smethurst P, Price A, Gumpel MJ. Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enteropathy. Gut. 1992;33:1204–8.

    Article  PubMed  CAS  Google Scholar 

  36. Scarpignato C. NSAID-induced intestinal damage: are luminal bacteria the therapeutic target? Gut. 2008;57:145–8.

    Article  PubMed  CAS  Google Scholar 

  37. Reuter BK, Davles NM, Wallace JL. Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Gastroenterology. 1997;112:109–17.

    Article  PubMed  CAS  Google Scholar 

  38. Hagiwara M, Kataoka K, Arimochi H, Kuwahara T, Ohnishi Y. Role of unbalanced growth of gram-negative bacteria in ileal ulcer formation in rats treated with a nonsteroidal anti-inflammatory drug. J Med Invest. 2004;51:43–51.

    Article  PubMed  Google Scholar 

  39. Watanabe T, Higuchi K, Kobata A, Nishio H, Tanigawa T, Shiba M, et al. Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent. Gut. 2008;57:181–7.

    Article  PubMed  CAS  Google Scholar 

  40. Fuller R. Probiotics in human medicine. Gut. 1991;32:439–42.

    Article  PubMed  CAS  Google Scholar 

  41. Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology. 2001;121:580–91.

    Article  PubMed  CAS  Google Scholar 

  42. Ohland C, MacNaughton W. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol. 2010;298:G807–19.

    Article  PubMed  CAS  Google Scholar 

  43. Eun CS, Kim YS, Han DS, Choi JH, Lee AR, Park YK. Lactobacillus casei prevents impaired barrier function in intestinal epithelial cells. APMIS. 2011;119:49–56.

    Article  PubMed  CAS  Google Scholar 

  44. Ng SC, Hart AL, Kamm MA, Stagg AJ, Knight SC. Mechanisms of action of probiotics: recent advances. Inflamm Bowel Dis. 2009;15:300–10.

    Article  PubMed  CAS  Google Scholar 

  45. Otte JM, Podolsky DK. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms. Am J Physiol Gastrointest Liver Physiol. 2004;286:G613–26.

    Article  PubMed  CAS  Google Scholar 

  46. Sherman PM, Johnson-Henry KC, Yeung HP, Ngo PS, Goulet J, Tompkins TA. Probiotics reduce enterohemorrhagic Escherichia coli O157:H7- and enteropathogenic E. coli O127:H6-induced changes in polarized T84 epithelial cell monolayers by reducing bacterial adhesion and cytoskeletal rearrangements. Infect Immun. 2005;73:5183–8.

    Article  PubMed  CAS  Google Scholar 

  47. Lammers KM, Helwig U, Swennen E, Rizzello F, Venturi A, Caramelli E, et al. Effect of probiotic strains on interleukin 8 production by HT29/19A cells. Am J Gastroenterol. 2002;97:1182–6.

    Article  PubMed  CAS  Google Scholar 

  48. Hooper LV, Gordon JI. Commensal host–bacterial relationships in the gut. Science. 2001;292:1115–8.

    Article  PubMed  CAS  Google Scholar 

  49. Neish AS, Gewirtz AT, Zeng H, Young AN, Hobert ME, Karmali V, et al. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science. 2000;289:1560–3.

    Article  PubMed  CAS  Google Scholar 

  50. Venturi A, Gionchetti P, Rizzello F, Johansson R, Zucconi E, Brigidi P, et al. Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther. 1999;13:1103–8.

    Article  PubMed  CAS  Google Scholar 

  51. Watanabe T, Nishio H, Tanigawa T, Yamagami H, Okazaki H, Watanabe K, et al. Probiotic Lactobacillus casei strain Shirota prevents indomethacin-induced small intestinal injury: involvement of lactic acid. Am J Physiol Gastrointest Liver Physiol. 2009;297:G506–13.

    Article  PubMed  CAS  Google Scholar 

  52. Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomized trial. Lancet. 1999;354:635–9.

    Article  PubMed  CAS  Google Scholar 

  53. Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, et al. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005;100:1539–46.

    Article  PubMed  Google Scholar 

  54. Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104:437–43.

    Article  PubMed  CAS  Google Scholar 

  55. Sood A, Midha V, Makharia GK, Ahuja V, Singal D, Goswami P, et al. The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7:1202–9.

    Article  PubMed  Google Scholar 

  56. 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;128:541–51.

    Article  PubMed  Google Scholar 

  57. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet. 1987;2:1519.

    Article  PubMed  CAS  Google Scholar 

  58. McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, et al. Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with placebo. Am J Gastroenterol. 1995;90:439–48.

    PubMed  CAS  Google Scholar 

  59. Montalto M, Maggiano N, Ricci R, Curigliano V, Santoro L, Di Nicuolo F, et al. Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells. Digestion. 2004;69:225–8.

    Article  PubMed  CAS  Google Scholar 

  60. Kamil R, Geier MS, Butler RN, Howarth GS. Lactobacillus rhamnosus GG exacerbates intestinal ulceration in a model of indomethacin-induced enteropathy. Dig Dis Sci. 2007;52:1247–52.

    Article  PubMed  CAS  Google Scholar 

  61. Gotteland M, Cruchet S, Verbeke S. Effect of Lactobacillus ingestion on the gastrointestinal mucosal barrier alterations induced by indometacin in humans. Aliment Pharmacol Ther. 2001;15:11–7.

    Article  PubMed  CAS  Google Scholar 

  62. Montalto M, Gallo A, Curigliano V, D’Onofrio F, Santoro L, Covino M, et al. Clinical trial: the effects of a probiotic mixture on non-steroidal anti-inflammatory drug enteropathy—a randomized, double-blind, cross-over, placebo-controlled study. Aliment Pharmacol Ther. 2010;32:209–14.

    Article  PubMed  CAS  Google Scholar 

  63. Endo H, Higurashi T, Hosono K, Sakai E, Sekino Y, Iida H, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol. 2011;46:894–905.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Maria Elena Riccioni for providing the endoscopy image.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Massimo Montalto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Montalto, M., Gallo, A., Gasbarrini, A. et al. NSAID enteropathy: could probiotics prevent it?. J Gastroenterol 48, 689–697 (2013). https://doi.org/10.1007/s00535-012-0648-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0648-2

Keywords

Navigation