The Influence of Proton Pump Inhibitors on the Fecal Microbiome of Infants with Gastroesophageal Reflux—A Prospective Longitudinal Interventional Study

Abstract

Proton pump inhibitors (PPIs) are the standard therapy for gastroesophageal reflux disease. In adults, PPI treatment is associated with Clostridium difficile infections (CDI). In contrast to adults the microbiome of infants develops from sterility at birth toward an adult-like profile in the first years of life. The effect of PPIs on this developing microbiome has never been studied. The aim of the present study was to determine the effect of oral PPIs on the fecal microbiome in infants with gastroesophageal reflux disease (GERD). In this prospective longitudinal study 12 infants with proven GERD received oral PPIs for a mean period of 18 weeks (range 8–44). Stool samples were collected before (“before PPI”) and 4 weeks after initiation of PPI therapy (“on PPI”). A third sample was obtained 4 weeks after PPI discontinuation (“after PPI”). The fecal microbiome was determined by NGS based 16S rDNA sequencing. This trial was registered with clinicaltrials.gov (NCT02359604). In a comparison of “before PPI” and “on PPI” neither α- nor β-diversity changed significantly. On the genus level, however, the relative abundances showed a decrease of Lactobacillus and Stenotrophomonas and an increase of Haemophilus. After PPI therapy there was a significant increase of α- and β-diversity. Additionally, the relative abundances of the phyla Firmicutes, Bacteroidetes, and Proteobacteria were significantly changed and correlated to patients' age and the introduction of solid foods. PPI treatment has only minor effects on the fecal microbiome. After discontinuation of PPI treatment the fecal microbiome correlated to patients' age and nutrition.

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

“…In a cohort of 12 infants younger than 1 year with gastro‐oesophageal reflux disease, in whom the microbiome is still unstable, a 4‐week‐course of esomeprazole was not associated with alterations in alpha or beta diversity, but resulted in significant alterations of the phyla Firmicutes, Bacteroidetes and Proteobacteria and, at the genus level, decreased relative abundance of Lactobacillus and Stenotrophomonas and an increase of Haemophilus. PPI withdrawal resulted in increasing alpha and beta diversity correlating with patients’ age and dietary habits …”

“…In 12 of the 23 reported study cohorts, less than 20 individuals were exposed to PPIs. 68,[71][72][73][75][76][77][78]80,82,86 In addition to the small sample sizes, the high interindividual and temporal variations in the gut microbiome do not allow firm conclusions about PPI-induced microbiome alterations.…”

Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy

“…An alternative theory is that PPI treatment induces a bacterial overgrowth with a secondary response of the immune system in the gut. PPIs have been shown to promote bacterial growth due to the inhibition of acid production in the stomach, which may result in a response of neutrophils to bacteria in the gut [39][40][41]. Naturally occurring bacteria and fungi contain H þ K þ ATPase.…”

“…PPIs may affect these microorganisms by direct interaction with the H þ K þ ATPase and thereby altering the pH-level [39]. There are several studies indicating that PPIs can change the gut microbiota [39][40][41]. In patients with systemic sclerosis there was an association between dysbiosis and increased FC levels [42].…”

Dysbiosis of the gut and lung microbiome has a role in asthma

“…The changes affect from oral, esophageal, gastric to intestinal microbiota and enhance the risk for Clostridium difficile infections [103], especially after long-term use [104,108]. As PPIs are used also in gastroesophageal reflux disease (GERD) in infants, subsequent dysbiosis has been investigated [105,107] ( Table 3).…”