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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Does Long-Term Proton Pump Inhibitor Therapy Affect the Health of Gut Microbiota?

Chansu Lee1, and Sung Noh Hong2

1Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea, 2Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Sung Noh Hong, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea, Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail: gisnhong@gmail.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut and Liver 2016; 10(6): 865-866

Published online November 15, 2016 https://doi.org/10.5009/gnl16438

Copyright © Gut and Liver.

Proton pump inhibitors (PPIs) are among the most widely sold medications in the world and are generally considered safe. PPIs are frequently prescribed or taken for long periods without evidence-based indication.1 However, long-term use of PPIs has not been studied in depth, and several side effects have recently been identified, including an increased risk of enteric infections such as small intestinal bacterial overgrowth and Clostridium difficile infections.2,3 The increased risk of enteric infections can be caused by the changes in the PPI-user’s gut microbiome, which result from the reduced acidity of the stomach and the subsequent survival of more bacteria that are ingested with food and oral mucus. Gut microbiota can resist or promote the colonization of C. difficile and other enteric infections through mechanisms that directly inhibit bacterial growth or enhance the immune system.4

Through the fecal microbiome analysis of 1,815 individuals spanning three cohorts, PPI use was associated with decreased bacterial richness and profound changes in the gut microbiome.5 Oral bacteria and potential pathogenic bacteria were increased in the feces of PPI users. In addition, the alterations of fecal microbiota in PPI users were more prominent than individuals who had used antibiotics or other drugs.5 A recently published, large, healthy twin cohort study identified significant associations between the composition of gut microbiota in feces and PPI use.6

The best way to confirm that long-term PPI use altered gut microbiota composition is to conduct double-blinded, randomized, placebo-controlled trials; however, this study may not be feasible due to ethical concerns. Animal models should be investigated to determine the impact of long-term PPI therapy on gut microbiota and to set up preclinical trials to resolve the problem associated with long-term PPI therapy.

Until recently, few studies have confirmed the effects of long-term PPI treatment on the gut microbiota in animal models.7 In this issue of Gut and Liver, the article “Impact of long-term proton pump inhibitor therapy on gut microbiota in F344 rats: pilot study” by Shin et al.8 investigated compositional changes in gut microbiota due to long-term PPI use in F344 rats treated with lansoprazole for 50 weeks. The gut microbiota in rats’ terminal ileum was profiled using 16S rRNA sequencing. Shin et al.8 found that the profile of gut microbiota in the terminal ileum of F344 rats treated with lansoprazole for 50 weeks was quite different than that of the control group. Terminal ileal microbiota profiles showed a predominance of Proteobacteria (93.9%) due to the abundance of Escherichia or Pasteurella genera in control rats, whereas lansoprazole-treated rats showed an increased population of Firmicutes (66.9%) due to an increased ratio of Clostridium g4 or Lactobacillus genera. This study was performed underregulated conditions to define the effect of long-term PPI use on gut microbiota, which suggests the results of this study may be more reproducible than those of previous studies. This study provided good additional evidence to support the alteration of gut microbiota induced by long-term PPI use.

In addition, this study suggested a new correlation between the alteration of small intestinal microbiota and changes in body weight in long-term PPI-treated animal models. PPIs induce strong acid suppression in the stomach to treat upper gastrointestinal ulcerative lesions, including reflux esophagitis, which results in symptom-related food abstinence. PPI therapy promotes patients’ weight gain. However, it was reported that PPI treatment induced weight loss in patients who had already had bariatric surgery.9 Previous mouse and human studies have associated Firmicutes with obesity and Bacteroidetes with weight loss.10 PPI may have another regulatory mechanism responsible for the regulation of body weight and the alteration of gut microbiome; this requires further study.

Although the animal models are a different size and have different physiologies compared to humans, the role of animal models is to gain preclinical data of the responses and safety of interventions. Alteration of gut microbiome may be controlled using probiotics and/or prebiotics in the near future. The changes in gut microbiome due to PPI depend on the species and intestinal sampling site. Shin and colleagues established the rodent model for long-term PPI use and this model is thought be applicable to further preclinical trials to alleviate the adverse effects of long-term PPI use. Fecal microbiota transplantation may be another promising therapy for controlling gut microbiota.

To date, microbiota changes in terminal ileum due to PPI administration may be summarized as an increase in Firmicutes and/or a decrease in Bacteroidetes. Given the widespread use of PPI, adverse effects, including enteric infections, should not be overlooked. The studies investigating the impact of PPIs on the gut microbiome consistently indicate that PPI use affects the alteration of gut microbiome. Therefore, healthcare practitioners should consider the influence of PPI on gut microbiome.

No potential conflict of interest relevant to this article was reported.

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (number: 2014R1A2A11052136).

  1. Kelly, OB, Dillane, C, Patchett, SE, Harewood, GC, and Murray, FE (2015). The inappropriate prescription of oral proton pump inhibitors in the hospital setting: a prospective cross-sectional study. Dig Dis Sci. 60, 2280-2286.
    Pubmed CrossRef
  2. Kwok, CS, Arthur, AK, Anibueze, CI, Singh, S, Cavallazzi, R, and Loke, YK (2012). Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 107, 1011-1019.
    Pubmed CrossRef
  3. Ratuapli, SK, Ellington, TG, and O’Neill, MT (2012). Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am J Gastroenterol. 107, 730-735.
    Pubmed CrossRef
  4. Freedberg, DE, Toussaint, NC, and Chen, SP (2015). Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 149, 883-885.
    Pubmed KoreaMed CrossRef
  5. Imhann, F, Bonder, MJ, and Vich Vila, A (2016). Proton pump inhibitors affect the gut microbiome. Gut. 65, 740-748.
    KoreaMed CrossRef
  6. Jackson, MA, Goodrich, JK, and Maxan, ME (2016). Proton pump inhibitors alter the composition of the gut microbiota. Gut. 65, 749-756.
    Pubmed KoreaMed CrossRef
  7. Kanno, T, Matsuki, T, and Oka, M (2009). Gastric acid reduction leads to an alteration in lower intestinal microflora. Biochem Biophys Res Commun. 381, 666-670.
    Pubmed CrossRef
  8. Shin, CM, Kim, N, and Kim, YS (2016). Impact of long-term proton pump inhibitor therapy on gut microbiota in F344 rats: pilot study. Gut Liver. 10, 896-901.
    Pubmed CrossRef
  9. Ward, EK, Schuster, DP, and Stowers, KH (2014). The effect of PPI use on human gut microbiota and weight loss in patients undergoing laparoscopic Roux-en-Y gastric bypass. Obes Surg. 24, 1567-1571.
    Pubmed CrossRef
  10. Ley, RE, Turnbaugh, PJ, Klein, S, and Gordon, JI (2006). Microbial ecology: human gut microbes associated with obesity. Nature. 444, 1022-1023.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2016; 10(6): 865-866

Published online November 15, 2016 https://doi.org/10.5009/gnl16438

Copyright © Gut and Liver.

Does Long-Term Proton Pump Inhibitor Therapy Affect the Health of Gut Microbiota?

Chansu Lee1, and Sung Noh Hong2

1Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea, 2Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Sung Noh Hong, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea, Tel: +82-2-3410-3409, Fax: +82-2-3410-6983, E-mail: gisnhong@gmail.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

BODY

Proton pump inhibitors (PPIs) are among the most widely sold medications in the world and are generally considered safe. PPIs are frequently prescribed or taken for long periods without evidence-based indication.1 However, long-term use of PPIs has not been studied in depth, and several side effects have recently been identified, including an increased risk of enteric infections such as small intestinal bacterial overgrowth and Clostridium difficile infections.2,3 The increased risk of enteric infections can be caused by the changes in the PPI-user’s gut microbiome, which result from the reduced acidity of the stomach and the subsequent survival of more bacteria that are ingested with food and oral mucus. Gut microbiota can resist or promote the colonization of C. difficile and other enteric infections through mechanisms that directly inhibit bacterial growth or enhance the immune system.4

Through the fecal microbiome analysis of 1,815 individuals spanning three cohorts, PPI use was associated with decreased bacterial richness and profound changes in the gut microbiome.5 Oral bacteria and potential pathogenic bacteria were increased in the feces of PPI users. In addition, the alterations of fecal microbiota in PPI users were more prominent than individuals who had used antibiotics or other drugs.5 A recently published, large, healthy twin cohort study identified significant associations between the composition of gut microbiota in feces and PPI use.6

The best way to confirm that long-term PPI use altered gut microbiota composition is to conduct double-blinded, randomized, placebo-controlled trials; however, this study may not be feasible due to ethical concerns. Animal models should be investigated to determine the impact of long-term PPI therapy on gut microbiota and to set up preclinical trials to resolve the problem associated with long-term PPI therapy.

Until recently, few studies have confirmed the effects of long-term PPI treatment on the gut microbiota in animal models.7 In this issue of Gut and Liver, the article “Impact of long-term proton pump inhibitor therapy on gut microbiota in F344 rats: pilot study” by Shin et al.8 investigated compositional changes in gut microbiota due to long-term PPI use in F344 rats treated with lansoprazole for 50 weeks. The gut microbiota in rats’ terminal ileum was profiled using 16S rRNA sequencing. Shin et al.8 found that the profile of gut microbiota in the terminal ileum of F344 rats treated with lansoprazole for 50 weeks was quite different than that of the control group. Terminal ileal microbiota profiles showed a predominance of Proteobacteria (93.9%) due to the abundance of Escherichia or Pasteurella genera in control rats, whereas lansoprazole-treated rats showed an increased population of Firmicutes (66.9%) due to an increased ratio of Clostridium g4 or Lactobacillus genera. This study was performed underregulated conditions to define the effect of long-term PPI use on gut microbiota, which suggests the results of this study may be more reproducible than those of previous studies. This study provided good additional evidence to support the alteration of gut microbiota induced by long-term PPI use.

In addition, this study suggested a new correlation between the alteration of small intestinal microbiota and changes in body weight in long-term PPI-treated animal models. PPIs induce strong acid suppression in the stomach to treat upper gastrointestinal ulcerative lesions, including reflux esophagitis, which results in symptom-related food abstinence. PPI therapy promotes patients’ weight gain. However, it was reported that PPI treatment induced weight loss in patients who had already had bariatric surgery.9 Previous mouse and human studies have associated Firmicutes with obesity and Bacteroidetes with weight loss.10 PPI may have another regulatory mechanism responsible for the regulation of body weight and the alteration of gut microbiome; this requires further study.

Although the animal models are a different size and have different physiologies compared to humans, the role of animal models is to gain preclinical data of the responses and safety of interventions. Alteration of gut microbiome may be controlled using probiotics and/or prebiotics in the near future. The changes in gut microbiome due to PPI depend on the species and intestinal sampling site. Shin and colleagues established the rodent model for long-term PPI use and this model is thought be applicable to further preclinical trials to alleviate the adverse effects of long-term PPI use. Fecal microbiota transplantation may be another promising therapy for controlling gut microbiota.

To date, microbiota changes in terminal ileum due to PPI administration may be summarized as an increase in Firmicutes and/or a decrease in Bacteroidetes. Given the widespread use of PPI, adverse effects, including enteric infections, should not be overlooked. The studies investigating the impact of PPIs on the gut microbiome consistently indicate that PPI use affects the alteration of gut microbiome. Therefore, healthcare practitioners should consider the influence of PPI on gut microbiome.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGEMENTS

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (number: 2014R1A2A11052136).

References

  1. Kelly, OB, Dillane, C, Patchett, SE, Harewood, GC, and Murray, FE (2015). The inappropriate prescription of oral proton pump inhibitors in the hospital setting: a prospective cross-sectional study. Dig Dis Sci. 60, 2280-2286.
    Pubmed CrossRef
  2. Kwok, CS, Arthur, AK, Anibueze, CI, Singh, S, Cavallazzi, R, and Loke, YK (2012). Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 107, 1011-1019.
    Pubmed CrossRef
  3. Ratuapli, SK, Ellington, TG, and O’Neill, MT (2012). Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am J Gastroenterol. 107, 730-735.
    Pubmed CrossRef
  4. Freedberg, DE, Toussaint, NC, and Chen, SP (2015). Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 149, 883-885.
    Pubmed KoreaMed CrossRef
  5. Imhann, F, Bonder, MJ, and Vich Vila, A (2016). Proton pump inhibitors affect the gut microbiome. Gut. 65, 740-748.
    KoreaMed CrossRef
  6. Jackson, MA, Goodrich, JK, and Maxan, ME (2016). Proton pump inhibitors alter the composition of the gut microbiota. Gut. 65, 749-756.
    Pubmed KoreaMed CrossRef
  7. Kanno, T, Matsuki, T, and Oka, M (2009). Gastric acid reduction leads to an alteration in lower intestinal microflora. Biochem Biophys Res Commun. 381, 666-670.
    Pubmed CrossRef
  8. Shin, CM, Kim, N, and Kim, YS (2016). Impact of long-term proton pump inhibitor therapy on gut microbiota in F344 rats: pilot study. Gut Liver. 10, 896-901.
    Pubmed CrossRef
  9. Ward, EK, Schuster, DP, and Stowers, KH (2014). The effect of PPI use on human gut microbiota and weight loss in patients undergoing laparoscopic Roux-en-Y gastric bypass. Obes Surg. 24, 1567-1571.
    Pubmed CrossRef
  10. Ley, RE, Turnbaugh, PJ, Klein, S, and Gordon, JI (2006). Microbial ecology: human gut microbes associated with obesity. Nature. 444, 1022-1023.
    Pubmed CrossRef
Gut and Liver

Vol.15 No.4
July, 2021

pISSN 1976-2283
eISSN 2005-1212

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