Skip to main content

Advertisement

SpringerLink
Log in

Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth

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

Abstract

The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger’s test and Begg’s test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20–2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Corleto VD, Festa S, Di Giulio E, et al. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes. 2014;21(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  2. Bartholow M. Top 200 prescription drugs of 2009. Pharmacy Times. 2010. http://www.pharmacytimes.com/publications/issue/2010/may2010/rxfocustopdrugs-0510.

  3. Hollingworth S, Duncan EL, Martin JH. Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemiol Drug Saf. 2010;19(10):1019–24.

    Article  PubMed  Google Scholar 

  4. Batuwitage BT, Kingham JG, Morgan NE, et al. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J. 2007;83(975):66–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ramirez E, Lei SH, Borobia AM, et al. Overuse of PPIs in patients at admission, during treatment, and at discharge in a tertiary Spanish hospital. Curr Clin Pharmacol. 2010;5(4):288–97.

    Article  CAS  PubMed  Google Scholar 

  6. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336(7634):2–3.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Schnoll-Sussman F, Katz PO. Clinical implications of emerging data on the safety of proton pump inhibitors. Curr Treat Options Gastroenterol. 2017;15(1):1–9.

    Article  PubMed  Google Scholar 

  8. Posserud I, Stotzer PO, Bjornsson ES, et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56(6):802–8.

    Article  PubMed  Google Scholar 

  9. King T. Small intestinal bacterial overgrowth and irritable bowel syndrome. JAMA. 2004;292(18):2213 (author reply 2213–4).

    CAS  PubMed  Google Scholar 

  10. Laine L, Ahnen D, McClain C, et al. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2000;14(6):651–68.

    Article  CAS  PubMed  Google Scholar 

  11. Fried M, Siegrist H, Frei R, et al. Duodenal bacterial overgrowth during treatment in outpatients with omeprazole. Gut. 1994;35(1):23–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gough A, Andrews D, Bacon PA, et al. Evidence of omeprazole-induced small bowel bacterial overgrowth in patients with scleroderma. Br J Rheumatol. 1995;34(10):976–7.

    Article  CAS  PubMed  Google Scholar 

  13. Lewis SJ, Franco S, Young G, et al. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther. 1996;10(4):557–61.

    Article  CAS  PubMed  Google Scholar 

  14. Liang SF, Xu L, Zhang DS, et al. Effect of probiotics on small intestinal bacterial overgrowth in patients with gastric and colorectal cancer. Turk J Gastroenterol. 2016;27(3):227–32.

    Article  PubMed  Google Scholar 

  15. Giamarellos-Bourboulis EJ, Pyleris E, Barbatzas C, et al. Small intestinal bacterial overgrowth is associated with irritable bowel syndrome and is independent of proton pump inhibitor usage. BMC Gastroenterol. 2016;16(1):67–73

    Article  PubMed  PubMed Central  Google Scholar 

  16. Enko D, Kriegshauser G. Functional 13C-urea and glucose hydrogen/methane breath tests reveal significant association of small intestinal bacterial overgrowth in individuals with active Helicobacter pylori infection. Clin Biochem. 2016;50(1-2):46–9.

  17. Schatz RA, Zhang Q, Lodhia N, et al. Predisposing factors for positive d-Xylose breath test for evaluation of small intestinal bacterial overgrowth: a retrospective study of 932 patients. World J Gastroenterol. 2015;21(15):4574–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Franco DL, Disbrow MB, Kahn A, et al. Duodenal aspirates for small intestine bacterial overgrowth: yield, PPIs, and outcomes after treatment at a Tertiary Academic Medical Center. Gastroenterol Res Pract. 2015;2015:971582.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Senderovky M, Lasa J, Dima G, et al. Influence of proton pump inhibitors on intestinal fermentative profile: a case–control study. Acta Gastroenterol Latinoam. 2014;44(3):205–9.

    PubMed  Google Scholar 

  20. Jacobs C, Coss Adame E, Attaluri A, et al. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther. 2013;37(11):1103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ratuapli SK, Ellington TG, O’Neill MT, et al. Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am J Gastroenterol. 2012;107(5):730–5.

    Article  CAS  PubMed  Google Scholar 

  22. Compare D, Pica L, Rocco A, et al. Effects of long-term PPI treatment on producing bowel symptoms and SIBO. Eur J Clin Invest. 2011;41(4):380–6.

    Article  PubMed  Google Scholar 

  23. Choung RS, Ruff KC, Malhotra A, et al. Clinical predictors of small intestinal bacterial overgrowth by duodenal aspirate culture. Aliment Pharmacol Ther. 2011;33(9):1059–67.

    Article  CAS  PubMed  Google Scholar 

  24. Lombardo L, Foti M, Ruggia O, et al. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol. 2010;8(6):504–8.

    Article  PubMed  Google Scholar 

  25. Law D, Pimentel M. Proton pump inhibitor therapy does not affect hydrogen production on lactulose breath test in subjects with IBS. Dig Dis Sci. 2010;55(8):2302–8.

    Article  CAS  PubMed  Google Scholar 

  26. Majewski M, McCallum RW. Results of small intestinal bacterial overgrowth testing in irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med Sci. 2007;52:139–42.

    CAS  PubMed  Google Scholar 

  27. Pereira SP, Gainsborough N, Dowling RH. Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly. Aliment Pharmacol Ther. 1998;12(1):99–104.

    Article  CAS  PubMed  Google Scholar 

  28. Hutchinson S, Logan R. The effect of long-term omeprazole on the glucose-hydrogen breath test in elderly patients. Age Ageing. 1997;26(2):87–9.

    Article  CAS  PubMed  Google Scholar 

  29. Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996;39(1):54–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11(5):483–90.

    Article  CAS  PubMed  Google Scholar 

  31. Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement. JAMA. 2015;313(16):1657–65.

    Article  PubMed  Google Scholar 

  32. Wells GA, Shea B, O’Connell D et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute, Ottawa

  33. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.

    Article  PubMed  Google Scholar 

  34. Tsuda A, Suda W, Morita H, et al. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin Transl Gastroenterol. 2015;6:e89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Freedberg DE, Toussaint NC, Chen SP, et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 2015;149(4):883–5.e9.

    PubMed  Google Scholar 

  36. Ardatskaia MD, Loginov VA, Minushkin ON. Syndrome of bacterial overgrowth in patients with the reduced stomach acid secretion: some aspects of the diagnosis. Eksp Klin Gastroenterol. 2014;12:30–6.

    Google Scholar 

  37. Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, et al. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012;57(5):1321–9.

    Article  PubMed  Google Scholar 

  38. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53(11):1119–29.

    Article  CAS  PubMed  Google Scholar 

  39. Egger M, Juni P, Bartlett C, et al. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technol Assess. 2003;7(1):1–76.

    CAS  PubMed  Google Scholar 

  40. Terrin N, Schmid CH, Lau J, et al. Adjusting for publication bias in the presence of heterogeneity. Stat Med. 2003;22(13):2113–26.

    Article  PubMed  Google Scholar 

  41. Peters JL, Sutton AJ, Jones DR, et al. Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med. 2007;26(25):4544–62.

    Article  PubMed  Google Scholar 

  42. Nelis GF, Engelage AH, Samson G. Does long-term inhibition of gastric acid secretion with omeprazole lead to small intestinal bacterial overgrowth? Neth J Med. 1994;45(3):93–100.

    CAS  PubMed  Google Scholar 

  43. Hawkey CJ, Richter JE, et al., editors. Textbook of clinical gastroenterology and Hepatology. Hoboken: Wiley; 2012.

    Google Scholar 

  44. Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome consensus conference. Aliment Pharmacol Ther. 2009;29(Suppl 1):1–49.

    PubMed  Google Scholar 

  45. Rana SV, Sharma S, Kaur J, et al. Comparison of lactulose and glucose breath test for diagnosis of small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Digestion. 2012;85(3):243–7.

    Article  CAS  PubMed  Google Scholar 

  46. Yu D, Cheeseman F, Vanner S. Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS. Gut. 2011;60(3):334–40.

    Article  PubMed  Google Scholar 

  47. Chu H, Fox M, Zheng X, et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome: clinical characteristics, psychological factors, and peripheral cytokines. Gastroenterol Res Pract. 2016;2016:3230859.

    PubMed  PubMed Central  Google Scholar 

  48. Abbasi MH, Zahedi M, Moghadam SD, et al. Small bowel bacterial overgrowth in patients with irritable bowel syndrome: the first study in iran. Middle East. J Dig Dis. 2015;7(1):36–40.

    Google Scholar 

  49. Moraru IG, Moraru AG, Andrei M, et al. Small intestinal bacterial overgrowth is associated to symptoms in irritable bowel syndrome. Evidence from a multicentre study in Romania. Rom J Intern Med. 2014;52(3):143–50.

    PubMed  Google Scholar 

  50. Spiegel BM, Chey WD, Chang L. Bacterial overgrowth and irritable bowel syndrome: unifying hypothesis or a spurious consequence of proton pump inhibitors? Am J Gastroenterol. 2008;103(12):2972–6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Talley NJ, Dennis EH, Schettler-Duncan VA, et al. Overlapping upper and lower gastrointestinal symptoms in irritable bowel syndrome patients with constipation or diarrhea. Am J Gastroenterol. 2003;98(11):2454–9.

    Article  PubMed  Google Scholar 

  52. Locke GR 3rd, Zinsmeister AR, Fett SL, et al. Overlap of gastrointestinal symptom complexes in a US community. Neurogastroenterol Motil. 2005;17(1):29–34.

    Article  PubMed  Google Scholar 

  53. Ford AC, Spiegel BM, Talley NJ, et al. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009;7(12):1279–86.

    Article  PubMed  Google Scholar 

  54. Nucera G, Gabrielli M, Lupascu A, et al. Abnormal breath tests to lactose, fructose and sorbitol in irritable bowel syndrome may be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2005;21(11):1391–5.

    Article  CAS  PubMed  Google Scholar 

  55. Yakoob J, Abbas Z, Khan R, et al. Small intestinal bacterial overgrowth and lactose intolerance contribute to irritable bowel syndrome symptomatology in Pakistan. Saudi J Gastroenterol. 2011;17(6):371–5.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sachdeva S, Rawat AK, Reddy RS, et al. Small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome: frequency and predictors. J Gastroenterol Hepatol. 2011;26[Suppl 3]:135–8.

    Article  PubMed  Google Scholar 

  57. Ghoshal UC, Kumar S, Mehrotra M, et al. Frequency of small intestinal bacterial overgrowth in patients with irritable bowel syndrome and chronic non-specific diarrhea. J Neurogastroenterol Motil. 2010;16(1):40–6.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Washio E, Esaki M, Maehata Y, et al. Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: a randomized placebo-controlled trial. Clin Gastroenterol Hepatol. 2016;14(6):809–15.

    Article  CAS  PubMed  Google Scholar 

  59. Watanabe T, Tanigawa T, Nadatani Y, et al. Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damage. Dig Liver Dis. 2013;45(5):390–5.

    Article  CAS  PubMed  Google Scholar 

  60. Juillerat P, Schneeweiss S, Cook EF, et al. Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36(3):239–47.

    Article  CAS  PubMed  Google Scholar 

  61. Shah R, Richardson P, Yu H, et al. Gastric acid suppression is associated with an increased risk of adverse outcomes in inflammatory bowel disease. Digestion. 2017;95(3):188–93.

    Article  CAS  PubMed  Google Scholar 

  62. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017;95(1):22–8.

    Article  CAS  PubMed  Google Scholar 

  63. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141(4):1314–22, 1322 e1–5.

    PubMed  Google Scholar 

  64. Muraki M, Fujiwara Y, Machida H, et al. Role of small intestinal bacterial overgrowth in severe small intestinal damage in chronic non-steroidal anti-inflammatory drug users. Scand J Gastroenterol. 2014;49(3):267–73.

    Article  CAS  PubMed  Google Scholar 

  65. Castiglione F, Del Blanco GDV, Rispo A, et al. Orocecal transit time and bacterial overgrowth in patients with Crohn’s disease. J Clin Gastroenterol. 2000;31(1):63–6.

    Article  CAS  PubMed  Google Scholar 

  66. Rana SV, Sharma S, Malik A, et al. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci. 2013;58(9):2594–8.

    Article  CAS  PubMed  Google Scholar 

  67. Greco A, Caviglia GP, Brignolo P, et al. Glucose breath test and Crohn’s disease: diagnosis of small intestinal bacterial overgrowth and evaluation of therapeutic response. Scand J Gastroenterol. 2015;50(11):1376–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Zhejiang Province Key Science and Technology Innovation Team (2013TD13), the National Natural Science Foundation of China (81472214), and the Zhejiang Provincial Medical and Health Research Plan (2015126452).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China

    Tingting Su, Sanchuan Lai, Xingkang He & Shujie Chen

  2. Institute of Gastroenterology, Zhejiang University, Hangzhou, 310016, Zhejiang, China

    Tingting Su, Sanchuan Lai, Xingkang He & Shujie Chen

  3. Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Hospital, Ann Arbor, MI, USA

    Allen Lee

Authors
  1. Tingting Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanchuan Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Allen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingkang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shujie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Allen Lee or Shujie Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 805 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, T., Lai, S., Lee, A. et al. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol 53, 27–36 (2018). https://doi.org/10.1007/s00535-017-1371-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-017-1371-9

Keywords

Search

Navigation