TwinsUK and the Department of Twin Research and Genetic Epidemiology are involved in the initiation and running of the British Gut Project, the European arm of the American Gut Project.
Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world and one most profitable (1). They are extremely effective medications used to suppress gastric acid production in a range of disorders from indigestion to the treatment of peptic ulcers. They have been widely adopted, with up to 12% of individuals having used PPIs (2,3), and have generally been considered to be relatively safe drugs. However, there have been a number of reports recently that have shown a number of side effects associated with their use. These include increased risks of enteric infection, in particular Clostridium difficile infection and pneumonia (4,5). It is known that antibiotic use is associated with a greatly increased risk of C.difficile infection where C.difficile capitalises on the antibiotic induced disruption to the gut microbiome. Therefore, at the Department of Twins Research at King’s College London, we aimed to determine the influence of PPIs on the gut microbiota to see if similar alterations were mediating the observed increases of bacterial infections with their use.
We investigated PPI and microbiome associations using data from over 1800 individuals from TwinsUK, a large healthy cohort of British twins. Our study, recently published in the Journal Gut (2), identified only a modest association between the overall diversity of gut bacteria and proton pump inhibitor use, with users have slightly less diverse gut microbiomes. However, we observed significant changes to the abundances of specific taxa with PPI use.
We found that a number of bacterial taxa were significantly increased in abundance within the gut of PPI users. These included the generaRothia and Streptococcus, the families Streptococcaceae and Micrococcaceae, and the order Lactobacilliales amongst others. We also observed lower abundances of members of the classes Clostridia and Erysipelotrichi. To ensure these associations were effects of PPI use we examined differences between identical twin pairs where one twin had used PPIs and the other had not, and examined data from a previous interventional study where healthy volunteers had been given PPIs; and in both cases we observed similar taxonomic changes, particularly increases in bacteria from the Streptococcaceae clade.
Utilising data from the Human Microbiome Project we then aimed to determine if these bacteria were often gut commensals or from an alternate body site. We found that bacteria increasing with PPI use were more likely to be found in the mouth and throat or at nose and skin sites. We believe that the removal of gastric acid by PPIs is removing a barrier to the bacteria that normally live in the upper digestive tract and oral cavity and can’t survive the harsh conditions. This is then allowing them to colonise further down the gastro intestinal tract.
Coincidentally, our findings replicated almost perfectly an entirely independent study published at the same time, in the same journal, by a separate group from the University of Groningen in the Netherlands (3). Using a similar approach in a meta-analysis of three other cohorts, they observed the same taxonomic changes, particularly increases in Streptococcaceae and Micrococcaceae, as those seen within the TwinsUK cohort. They also observe a similar increase in oral bacteria with PPI use.
There are clinical consequences to these observations; they provide evidence that infection risks associated with PPI use may be driven by changes to the gut microbiome. The bacteria we have observed to increase in abundance with PPI use have been shown to predispose toC.difficile infection in mice (6). There is also evidence for exchange of bacteria between the gastrointestinal tract and lung fluid in PPI users (7), which may explain the increase in Streptococcus-derived pneumonia in with their use (8).
This new side effect of PPIs warrants caution against their use where it may not be necessary or alternate approaches are possible. This may be a particular issue given reports of widespread over-utilisation the drugs (9). However, it should be noted that PPIs remain an effective treatment for acid related gastrointestinal disorders when used appropriately.
IMS Health Top-Line Market Data 2014. http://www.imshealth.com/portal/site/imshealth/menuitem.18c196991f79283fddc0ddc01ad8c22a/?vgnextoid=6521e590cb4dc310VgnVCM100000a48d2ca2RCRD&vgnextfmt=default. (accessed 6 Jul 2015)
Jackson MA, Maxan M, Freedberg DE, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut
Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut 2015;:gutjnl – 2015–310376. doi:10.1136/gutjnl-2015-310376
Laheij RJF, Sturkenboom MCJM, Hassing R-J, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA2004;292:1955–60. doi:10.1016/S8756-3452(08)70155-5
Janarthanan S, Ditah I, Adler DG, et al. Clostridium difficile-Associated Diarrhea and Proton Pump Inhibitor Therapy: A Meta-Analysis. Am J Gastroenterol 2012;107:1001–10. doi:10.1038/ajg.2012.179
Schubert AM, Sinani H, Schloss PD. Antibiotic-Induced Alterations of the Murine Gut Microbiota and Subsequent Effects on Colonization Resistance against Clostridium difficile. 2015;6:1–10. doi:10.1128/mBio.00974-15.Editor
Dumoulin G. Aspiration of gastric bacteria in antacid-treated patients: a frequent cause of postoperative colonisation of the airway. Lancet1982;319:242–5. doi:10.1016/S0140-6736(82)90974-6
De Jager CPC, Wever PC, Gemen EF a, et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther 2012;36:941–9. doi:10.1111/apt.12069
Heidelbaugh JJ, Kim a. H, Chang R, et al. Overutilization of proton-pump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol 2012;5:219–32. doi:10.1177/1756283X12437358