Effects of Proton Pump Inhibitors on the Gastrointestinal Microbiota in Gastroesophageal Reflux Disease

Proton pump inhibitors (PPIs) are commonly used to lessen symptoms in patients with gastroesophageal reflux disease (GERD). However, the effects of PPI therapy on the gastrointestinal microbiota in GERD patients remain unclear. We examined the association between the PPI usage and the microbiota present in gastric mucosal and fecal samples from GERD patients and healthy controls (HCs) using 16S rRNA gene sequencing. GERD patients taking PPIs were further divided into short-term and long-term PPI user groups. We showed that PPI administration lowered the relative bacterial diversity of the gastric microbiota in GERD patients. Compared to the non-PPI-user and HC groups, higher abundances of Planococcaceae, Oxalobacteraceae, and Sphingomonadaceae were found in the gastric microbiota from the PPI-user group. In addition, the Methylophilus genus was more highly abundant in the long-term PPI user group than in the short-term PPI-user group. Despite the absence of differences in alpha diversity, there were significant differences in the fecal bacterial composition of between GERD patients taking PPIs and those not taking PPIs. There was a higher abundance of Streptococcaceae, Veillonellaceae, Acidaminococcaceae, Micrococcaceae, and Flavobacteriaceae present in the fecal microbiota from the PPI-user group than those from the non-PPI-user and HC groups. Additionally, a significantly higher abundance of Ruminococcus was found in GERD patients on long-term PPI medication than that on short-term PPI medication. Our study indicates that PPI administration in patients with GERD has a significant effect on the abundance and structure of the gastric mucosal microbiota but only on the composition of the fecal microbiota.

[1]  J. Torres,et al.  Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[2]  M Weda,et al.  Potential association between the recent increase in campylobacteriosis incidence in the Netherlands and proton-pump inhibitor use - an ecological study. , 2014, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[3]  Uri Gophna,et al.  Gastric microbiota is altered in oesophagitis and Barrett's oesophagus and further modified by proton pump inhibitors. , 2014, Environmental microbiology.

[4]  Hye-Kyung Jung,et al.  Epidemiology of Gastroesophageal Reflux Disease in Asia: A Systematic Review , 2011, Journal of neurogastroenterology and motility.

[5]  D. Scott,et al.  The Gastric and Intestinal Microbiome: Role of Proton Pump Inhibitors , 2017, Current Gastroenterology Reports.

[6]  K. Bergh,et al.  Gastric juice: a barrier against infectious diseases. , 2005, Basic & clinical pharmacology & toxicology.

[7]  Anders F. Andersson,et al.  Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing , 2008, PloS one.

[8]  Vincent Wai-Sun Wong,et al.  Bacterial Microbiota Profiling in Gastritis without Helicobacter pylori Infection or Non-Steroidal Anti-Inflammatory Drug Use , 2009, PloS one.

[9]  Philip Abraham,et al.  Gastric microbiome of Indian patients with Helicobacter pylori infection, and their interaction networks , 2017, Scientific Reports.

[10]  Masahira Hattori,et al.  Influence of Proton-Pump Inhibitors on the Luminal Microbiota in the Gastrointestinal Tract , 2015, Clinical and Translational Gastroenterology.

[11]  John K Marshall,et al.  Systematic Review of the Risk of Enteric Infection in Patients Taking Acid Suppression , 2007, The American Journal of Gastroenterology.

[12]  S. Travis,et al.  'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? , 2015, Intestinal research.

[13]  Young Sook Park,et al.  A Proton Pump Inhibitor’s Effect on Bone Metabolism Mediated by Osteoclast Action in Old Age: A Prospective Randomized Study , 2014, Gut and liver.

[14]  Tim D Spector,et al.  Proton pump inhibitors alter the composition of the gut microbiota , 2015, Gut.

[15]  K. Altman,et al.  The effect of proton pump inhibitors on the human microbiota. , 2009, Current drug metabolism.

[16]  Se Jin Song,et al.  Tracking down the sources of experimental contamination in microbiome studies , 2014, Genome Biology.

[17]  D. Jonkers,et al.  Non‐Helicobacter pylori bacterial flora during acid‐suppressive therapy: differential findings in gastric juice and gastric mucosa , 2001, Alimentary pharmacology & therapeutics.

[18]  Nora C. Toussaint,et al.  Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. , 2015, Gastroenterology.

[19]  Elisabeth M Bik,et al.  Molecular analysis of the bacterial microbiota in the human stomach. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Robert C. Edgar,et al.  UPARSE: highly accurate OTU sequences from microbial amplicon reads , 2013, Nature Methods.

[21]  Carol Friedman,et al.  Proton Pump Inhibitors and Risk for Recurrent Clostridium difficile Infection Among Inpatients , 2013, The American Journal of Gastroenterology.

[22]  R. Valuck,et al.  A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. , 2004, Journal of clinical epidemiology.

[23]  Jingyuan Fu,et al.  Proton pump inhibitors affect the gut microbiome , 2015, Gut.

[24]  H B Xu,et al.  Proton pump inhibitor use and risk of spontaneous bacterial peritonitis in cirrhotic patients: a systematic review and meta-analysis. , 2015, Genetics and molecular research : GMR.

[25]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.

[26]  Paul Turner,et al.  Reagent and laboratory contamination can critically impact sequence-based microbiome analyses , 2014, BMC Biology.

[27]  C. Frenette,et al.  Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. , 2015, JAMA internal medicine.

[28]  C. Reimer,et al.  Safety of long-term PPI therapy. , 2013, Best practice & research. Clinical gastroenterology.

[29]  Scot E. Dowd,et al.  Inherent bacterial DNA contamination of extraction and sequencing reagents may affect interpretation of microbiota in low bacterial biomass samples , 2016, Gut Pathogens.

[30]  Karl Kashofer,et al.  The Influence of Proton Pump Inhibitors on the Fecal Microbiome of Infants with Gastroesophageal Reflux—A Prospective Longitudinal Interventional Study , 2017, Front. Cell. Infect. Microbiol..

[31]  R. Fass.  CLINICAL IMPLICATIONS OF CHRONIC THERAPY FOR GERD , 2009 .

[32]  Scot E Dowd,et al.  Effect of the proton pump inhibitor omeprazole on the gastrointestinal bacterial microbiota of healthy dogs. , 2012, FEMS microbiology ecology.

[33]  D. Adler,et al.  Clostridium difficile-Associated Diarrhea and Proton Pump Inhibitor Therapy: A Meta-Analysis , 2012, The American Journal of Gastroenterology.

[34]  Jesse R. Zaneveld,et al.  Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences , 2013, Nature Biotechnology.

[35]  Walter Ricciardi,et al.  Effects of Proton Pump Inhibitors on the Gastric Mucosa-Associated Microbiota in Dyspeptic Patients , 2016, Applied and Environmental Microbiology.

[36]  Miriam C J M Sturkenboom,et al.  Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. , 2004, JAMA.

[37]  Amy Linsky,et al.  Proton pump inhibitors and risk for recurrent Clostridium difficile infection. , 2010, Archives of internal medicine.

[38]  William A. Walters,et al.  QIIME allows analysis of high-throughput community sequencing data , 2010, Nature Methods.

[39]  W. Leslie,et al.  A comparison of the gut microbiome between long‐term users and non‐users of proton pump inhibitors , 2016, Alimentary pharmacology & therapeutics.

[40]  Jacobo de la Cuesta-Zuluaga,et al.  Impact of DNA extraction, sample dilution, and reagent contamination on 16S rRNA gene sequencing of human feces , 2017, Applied Microbiology and Biotechnology.

[41]  K. Song,et al.  Differences in Gastric Mucosal Microbiota Profiling in Patients with Chronic Gastritis, Intestinal Metaplasia, and Gastric Cancer Using Pyrosequencing Methods , 2014, Helicobacter.