Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified

Abstract

Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.

Keywords: Cancer; Dysbiosis; Gastrointestinal infections; Gastrointestinal tract; Gut microbiota; Helicobacter pylori; Hypochloridria; Proton pump inhibitors.

Figure 1

Distribution of main bacterial families of human microbiota in physiological condition and during proton pump inhibitor treatment. This figure shows the effect of proton pump inhibitor (PPI) treatment on the composition of gut microbiota families. The left side of the figure shows the principal bacterial families under normal physiological conditions; the right side of the figure shows the increase (↑) and decrease (↓) in bacterial families present in the gut microbiota during PPI treatment. PPI: Proton pump inhibitor.

Figure 2

Proton pump inhibitors promote non-steroidal anti-inflammatory drug-induced enteropathy via microbiota. Murine models demonstrate that proton pump inhibitor (PPI) treatment, in addition to non-steroidal anti-inflammatory drugs (NSAIDs) therapy, brings about an exacerbation of mucosal damage in the small intestine. PPIs cause a bacterial imbalance, such as the reduction (↓) of Actinobacteria and Bifidobacteria spp., which is responsible for the mucosal damage. Specifically, PPIs increase the expression of bacteria with beta-glucuronidases activity and the consequent spreading of NSAIDs into enterohepatic circulation; ultimately, bile cytotoxicity then causes ulcerative intestinal lesions. The co-administration of Bifidobacteria-enriched suspension restores the gut microbiota and reduces mucosal damage. Germ-free mice are less susceptible to NSAIDs’ harmful effects and they develop NSAID-induced enteropathy through microbiota transfer. PPI: Proton pump inhibitor; NSAID: Non-steroidal anti-inflammatory drugs.