Cirrhosis is associated with gut microbial dysbiosis, high readmissions and proton pump inhibitor (PPI) overuse, which could be inter-linked. Our aim was to determine the effect of PPI use, initiation and withdrawl on gut microbiota and readmissions in cirrhosis.


Four cohorts were enrolled. Readmissions study: Cirrhotic inpatients were followed throughout the hospitalization and 30/90-days post-discharge. PPI initiation, withdrawal/continuation patterns were analyzed between those with/without readmissions. Cross-sectional microbiota study: Cirrhotic outpatients and controls underwent stool microbiota analysis. Beneficial autochthonous and oral-origin taxa analysis vis-à-vis PPI use was performed. Longitudinal studies: Two cohorts of decompensated cirrhotic outpatients were enrolled. Patients on chronic unindicated PPI use were withdrawn for 14 days. Patients not on PPI were started on omeprazole for 14 days. Microbial analysis for oral-origin taxa was performed pre/post-intervention.


Readmissions study: 343 inpatients (151 on admission PPI) were enrolled. 21 were withdrawn and 45 were initiated on PPI resulting in a PPI use increase of 21%. PPIs were associated with higher 30 (p = 0.002) and 90-day readmissions (p = 0.008) independent of comorbidities, medications, MELD and age. Cross-sectional microbiota: 137 cirrhotics (59 on PPI) and 45 controls (17 on PPI) were included. PPI users regardless of cirrhosis had higher oral-origin microbiota while cirrhotics on PPI had lower autochthonous taxa compared to the rest. Longitudinal studies: Fifteen decompensated cirrhotics tolerated omeprazole initiation with an increase in oral-origin microbial taxa compared to baseline. PPIs were withdrawn from an additional 15 outpatients, which resulted in a significant reduction of oral-origin taxa compared to baseline.


PPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

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  1. 1.

    Johnson DA, Katz PO, Armstrong D, et al. The safety of appropriate use of over-the-counter proton pump inhibitors: an evidence-based review and Delphi consensus. Drugs. 2017;77:547–61.

  2. 2.

    Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28:235–42.

  3. 3.

    Dam G, Vilstrup H, Watson H, et al. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology. 2016;64:1265–72.

  4. 4.

    Cole HL, Pennycook S, Hayes PC. The impact of proton pump inhibitor therapy on patients with liver disease. Aliment Pharmacol Ther. 2016;44:1213–23.

  5. 5.

    Tsai CF, Chen MH, Wang YP, et al. Proton pump inhibitors increase risk for hepatic encephalopathy in patients with cirrhosis in a population study. Gastroenterology. 2017;152:134–41.

  6. 6.

    Bajaj JS, Ratliff SM, Heuman DM, et al. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther. 2012;36:866–74.

  7. 7.

    Bajaj JS, Zadvornova Y, Heuman DM, et al. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol. 2009;104:1130–4.

  8. 8.

    Bajaj JS, Cox IJ, Betrapally NS, et al. Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function. Am J Physiol Gastrointest Liver Physiol. 2014;307:G951–7.

  9. 9.

    Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28:26–42.

  10. 10.

    Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature. 2014;513:59–64.

  11. 11.

    O’Leary JG, Reddy KR, Wong F, et al. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13:753–9.

  12. 12.

    Bajaj JS, Reddy KR, Tandon P, et al. The 3-month readmission rate remains unacceptably high in a large North American cohort of patients with cirrhosis. Hepatology. 2016;64:200–8.

  13. 13.

    Nava GM, Stappenbeck TS. Diversity of the autochthonous colonic microbiota. Gut Microbes. 2011;2:99–104.

  14. 14.

    Patel VC, Shawcross DL. Salivary microbiota-immune profiling in cirrhosis: could this be the noninvasive strategy that will revolutionize prognostication in hepatology? Hepatology. 2015;62:1001–3.

  15. 15.

    Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol. 2014;60:940–7.

  16. 16.

  17. 17.

    Hamady M, Knight R. Microbial community profiling for human microbiome projects: tools, techniques, and challenges. Genome Res. 2009;19:1141–52.

  18. 18.

    Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30.

  19. 19.

    J Gregory Caporaso, Justin Kuczynski, Jesse Stombaugh, et al. Nature Methods, 2010;

  20. 20.

    Tapper EB. Challenge accepted: confronting readmissions for our patients with cirrhosis. Hepatology. 2016;64:26–8.

  21. 21.

    Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8.

  22. 22.

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

  23. 23.

    Naito Y, Kashiwagi K, Takagi T, et al. Intestinal dysbiosis secondary to proton-pump inhibitor use. Digestion. 2018;97:195–204.

  24. 24.

    Jackson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65:749–56.

  25. 25.

    Llorente C, Jepsen P, Inamine T, et al. Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. Nat Commun. 2017;8:837.

  26. 26.

    Chen Y, Yang F, Lu H, et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology. 2011;54:562–72.

  27. 27.

    Dultz G, Piiper A, Zeuzem S, et al. Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. Aliment Pharmacol Ther. 2015;41:459–66.

  28. 28.

    Bajaj JS, Heuman DM, Sanyal AJ, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS ONE. 2013;8:e60042.

  29. 29.

    Acharya C, Sahingur SE, Bajaj JS. Microbiota, cirrhosis, and the emerging oral-gut-liver axis. JCI Insight. 2017;5: pii: 94416.

  30. 30.

    Bajaj JS, Betrapally NS, Hylemon PB, et al. Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. Hepatology. 2015;62:1260–71.

  31. 31.

    Bert F, Valla D, Moreau R, et al. Viridans group streptococci causing spontaneous bacterial peritonitis and bacteremia in patients with end-stage liver disease. Liver Transpl. 2008;14:710–1.

  32. 32.

    Ahluwalia V, Betrapally NS, Hylemon PB, et al. Impaired gut-liver-brain axis in patients with cirrhosis. Sci Rep. 2016;6:26800.

  33. 33.

    Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302:G168–75.

  34. 34.

    Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Dig Dis Sci. 2009;54:2312–7.

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  1. Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA

    • Jasmohan S Bajaj MD
    • , Chathur Acharya MD
    • , Andrew Fagan BS
    • , Melanie B White RN
    • , Edith Gavis RN
    • , Douglas M Heuman MD
    • , Michael Fuchs MD
    • , Puneet Puri MD
    • , Mitchell L Schubert MD
    • , Arun J Sanyal MD
    • , Richard K Sterling MD
    • , R Todd Stravitz MD
    • , Mohammad S Siddiqui MD
    • , Velimir Luketic MD
    •  & Hannah Lee MD
  2. Microbiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA

    • Phillip B Hylemon PhD
  3. Microbiome Analysis Center, George Mason University, Manassas, VA, USA

    • Masoumeh Sikaroodi PhD
    •  & Patrick M Gillevet PhD


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Guarantor of the article

JSB is the guarantor.

Specific author contributions

JSB conceptualized the study, MS and PMG were involved in microbiota analysis, PBH was involved in the critical revisions, CA, MBW, AF, and EAG were involved in research coordination, Rest of the authors were involved in subject recruitment and follow-up.

Financial support

This work was partly supported from American College of Gastroenterology Clinical Research Award, VA Merit Review I0CX001076, McGuire Research Institute and an investigator-initiated grant by Grifols Pharmaceuticals, all to JSB. None of the study sponsors had any role in the study design, collection, analysis, and interpretation of the data and in the writing of the report.

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Corresponding author

Correspondence to Jasmohan S Bajaj MD.

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