Abstract

Proton pump inhibitors (PPIs) are commonly prescribed for acid-related conditions like GERD and peptic ulcers, yet emerging research suggests they impact the gut microbiota, the diverse community of microorganisms in the gastrointestinal tract. This review consolidates current evidence on how PPIs affect gut microbiota composition and function. Studies indicate that PPI use alters gut microbiota diversity and composition, often leading to decreased microbial richness and shifts in specific bacterial taxa, such as increased potentially pathogenic bacteria like Enterococcus and Streptococcus, and decreased beneficial bacteria like Bifidobacterium and Lactobacillus. Long-term PPI use is associated with dysbiosis, a microbial imbalance linked to various gastrointestinal and systemic health issues. The mechanisms behind PPI-induced microbiota alterations are complex, involving direct effects on gastric pH, which influence bacterial survival and growth in the stomach and intestine. Additionally, PPIs may indirectly impact microbial ecology through changes in gastrointestinal motility, bile acid secretion, and nutrient availability. The clinical implications of PPI-induced gut microbiota changes are significant, with dysbiosis associated with conditions like Clostridium difficile infection, SIBO, and IBD. Altered gut microbiota may also affect systemic health, including immune function, metabolism, and antibiotic resistance. In conclusion, while PPIs are effective in managing acid-related disorders, their influence on gut microbiota warrants consideration. Further research is necessary to understand the mechanisms underlying PPI-induced dysbiosis and develop strategies to mitigate adverse microbiota-related effects of long-term PPI use. Clinicians should be mindful of the potential impact on gut microbiota when prescribing PPIs and advocate for microbiota-friendly approaches to acid suppression therapy.

Keywords

Introduction

Proton pump inhibitors (PPIs) are commonly prescribed medications that inhibit gastric acid secretion, used to treat acid-related conditions like peptic ulcer disease, gastro-oesophageal reflux disease, and H. pylori infection, and to prevent gastric ulcers induced by NSAIDs, GCs, and anticoagulants. Structurally, they are benzimidazole derivatives, typically including pyridine and benzimidazole groups linked by a methylsulfnyl group. Despite structural differences, PPIs share similar pharmacological properties and are pro-drugs activated upon protonation. Main PPIs include pantoprazole, esomeprazole, lansoprazole, omeprazole, and rabeprazole. After the introduction of PPI in 1980s, PPI usage has surged, making them among the most widely prescribed drugs globally. However, recent studies have associated PPIs with severe adverse effects such as osteoporosis and fractures, hypomagnesemia, community-acquired pneumonia, Clostridium difficile colitis, and cardiovascular morbidity.[1]  The PPI usage has been linked to an increased susceptibility to enteric infections caused by pathogens such as Clostridium difficile, Salmonella spp., Shigella spp., and Campylobacter spp. The term microbiome refers to the ecology and functionality of the microbial population within specific environments. Various sites in the human body harbor distinct microbiomes influenced by environmental and microbial interactions. Gut microbiota can either promote or alleviate gut inflammation. Favorable microbiota induce regulatory T-cells (Tregs), interleukin 10 (IL-10) production, and butyrate production, mitigating inflammation. Conversely, unfavorable microbiota produce toxins that exacerbate gut epithelial inflammation. Inflammatory Bowel Disease (IBD) often exhibits a disrupted balance between favorable and unfavorable gut microbiota, leading to gut inflammation. The PPI’s impact on the microbiota may influence lipid metabolism, affecting an individual's risk of cardiovascular events. [2]    PPIs and other common medication, such as antibiotics, metformin, statins and SSRIs are associated with distinct gut microbiota signatures. As a consequence, these types of medication could have an effect on the risk of developing enteric infections or gut inflammation, and they may also have an effect on host metabolism. PPI usage increases the risk of spontaneous bacterial peritonitis and overall bacterial infection in patients with cirrhosis and ascites, suggesting PPI use may pose a higher risk to individuals already susceptible to infection and other complications.[3]  Recently, problems associated with PPI use have begun to surface. PPIs influence the gut microbiota; therefore, PPI can increase the enteric infections risk and cause bacterial translocation. [4] The PPI usage can be associated with higher intestinal infection risk. Studies show that PPIs directly interfere with gastric acid secretion, thereby altering the gut microbiota. By reducing acidity in the stomach, PPIs allow more bacteria to overcome the barrier and enter the intestine.[5] Changes in this microbial equilibrium that is, dysbiosis can promote and influence the course of many intestinal and extra-intestinal diseases [6]

ROLE OF GUT MICROBIOTA:

The human microbiota, consisting of over 100 trillion symbiotic microorganisms, is considered an "essential organ" residing primarily in the gut. With approximately 150 times more genes than the human genome, it offers diverse metabolic capabilities, providing unique enzymes and pathways essential for human health. Key functions include nutrient acquisition, xenobiotic processing, protection against pathogens through competitive exclusion and antimicrobial substance production, and contribution to the development of the intestinal mucosa and immune system [9]

1.1 THE HUMAN MICROBIOTA IN HEALTH:

Symbiotic bacteria in the gut help break down compounds that are indigestible by the stomach and small intestine, provide essential nutrients, protect against harmful pathogens, and aid in shaping intestinal structure. For instance, gut microbiota play an important role in digesting certain dietary fibers, like xyloglucans found in vegetables, through specific species such as Bacteroides. These bacteria also support the development of both the humoral and cellular components of the mucosal immune system. [9]

THE HUMAN MICROBIOTA IN DISEASE:

Infection often arises from microbiota dysbiosis, with the human microbiota playing a crucial role in determining the outcome of infectious diseases. The gut-liver axis highlights the close interaction between the gastrointestinal tract (GIT) and the liver, with chronic exposure to gut-derived factors influencing liver health. The composition of gut microbiota is influenced by antibiotics, lifestyle factors like diet and exercise, and hygiene practices. Dysbiosis of intestinal flora can lead to immune dysregulation, chronic inflammation, and metabolic dysfunction. Such changes in the microbiota are seen in various diseases, including severe asthma, food allergies, autism, and major depressive disorder (MDD).[9] Recent advancements in high-throughput sequencing, particularly 16S rRNA sequencing, have provided valuable insights into the gastric and gut microbiota, yet the specific characteristics of PPI usage in GERD patients remain incompletely understood. Studies consistently indicate that gastric acid secretion inhibition through PPIs can disrupt the gastric microbiota, leading to dysbiosis and bacterial overgrowth in stomach and intestines. Long-term or excessive PPI use has been linked to an unhealthy shift in gastrointestinal microbiota composition. PPIs may directly target bacterial proton pumps or indirectly affect the microbiota's microenvironment by altering pH levels. For instance, PPI use in healthy dogs reduced H. pylori abundance while increasing Firmicutes and Fusobacteria in gastric mucosal microbiota. [10]

ASSOCIATION BETWEEN PROTON PUMP INHIBITORS AND GUT MICROBIOTA

Concerns arise from prolonged PPI use, which can heighten the risk of calcium malabsorption, fractures, and susceptibility to enteric infections like Clostridium difficile and Campylobacter, alongside community-acquired pneumonia. PPIs may also contribute to spontaneous bacterial peritonitis in cirrhotic patients, potentially via bacterial translocation. Alterations in gut microbiota triggered by PPIs may exacerbate these risks by promoting bacterial overgrowth and translocation, potentially leading to sepsis and adverse health effects. Additionally, changes in gut microbiota composition can impact organic acid production, vital for gastrointestinal functions like mucosal blood flow and pH regulation, thereby influencing intestinal health and function. [4]

PPI CAUSING RISK OF IMBALANCE IN MICROBIOTA COMPOSITION:           

It is well-established that the gut microbiota is crucial for metabolic, nutritional, physiological, defence, and immune functions in the body. Its composition is closely linked to the development of both intestinal and extraintestinal diseases. Proton pump inhibitors (PPIs) can alter the composition of the gut microbiota, potentially leading to significant adverse effects associated with this therapy. [5] PPI use is linked to altered gut microbiota composition and decreased diversity, directly associated with PPI utilization. Bacterial families more common in PPI users often come from oral, throat, nasal, and skin communities. Normally, gastric acid acts as a barrier preventing their colonization in GI tract, but PPIs remove this barrier, facilitating their presence in fecal samples. This microbiome imbalance, or dysbiosis, may lead to various intestinal and extra-intestinal diseases. [6]

PROTON PUMP INHIBITORS AND DYSBIOSIS:

1. ORAL CAVITY:

The oral microbiota exhibits less variability compared to other GI tract regions, primarily consisting of Firmicutes and Bacteroidetes, with Actinobacteria, Proteobacteria, and Fusobacteria also present. Inflammatory oral diseases like gingivitis and periodontitis can alter the oral microbial community, leading to the production of toxic metabolites and pathogen-derived lipopolysaccharide (LPS), which can colonize extra-oral sites via transient bacteraemia. PPI use has been associated with increased Leptotrichia and Fusobacterium in periodontal pockets, along with decreased Veillonella and Neisseria in saliva and increased Streptococcus in fecal samples, suggesting potential alterations in both gut and oral microbiota due to PPIs.

2. ESOPHAGUS:

The esophagus harbors a distinct microbiota with two identified types: Type I, predominant in healthy individuals, features Gram-positive taxa like Streptococcus, while Type II, associated with esophageal reflux disease (ERD) and Barrett's esophagus (BE), comprises Gram-negative taxa with a reduced abundance of Streptococcus. ERD and BE are precursors to esophageal adenocarcinoma (EAC). PPIs may alter esophageal microbiota, increasing Firmicutes and decreasing Bacteroidetes and Proteobacteria. Long-term PPI use, independent of other risk factors, correlates with increased EAC risk, possibly by preserving acid-sensitive bacteria crucial for maintaining a Type I microbiota through reduced gastric acid reflux into the esophagus. [6]

3. STOMACH:

The gastric microbiota comprises Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, with prevalent genera like Streptococcus, Veillonella, Prevotella, Fusobacterium, and Rothia. PPIs detrimentally affect gastric functions and host defenses, leading to delayed gastric emptying, decreased mucus viscosity, increased bacterial load, and translocation. Hypochlorhydria from PPIs reduces microbial diversity, promoting growth of potentially genotoxic microbes, elevating nitrate/nitrite reductase activity linked to cancer development. These bacteria may cause gastric cancer progression via metabolic pathways. Gastric dysbiosis, seen in H. pylori-related gastritis, alters the luminal microenvironment and microbiota composition due to H. pylori's proinflammatory activity, further influenced by changes in acid secretion. [6]

4. SMALL INTESTINE:

Various factors, including transit time, chemical composition, oxygen levels, and antimicrobial substances, shape the density and composition of bacterial populations in the small intestine (duodenum, jejunum, and ileum). Chronic PPI use significantly impacts small intestine microbiota, leading to small intestinal bacterial overgrowth (SIBO) due to diminished gastric acid barrier. SIBO, characterized by over 10^5 bacteria/ml in upper gut aspirate, manifests with symptoms like weight loss, diarrhea, bloating, and malabsorption. PPI-induced dysbiosis may heighten the risk of hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP) in cirrhotic [5] [6]

5. COLON:

The colon harbors the highest microbial density in the GI tract, with Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria as predominant phyla. PPIs elevate the enteric infections risks like Clostridium difficile, Salmonella, Campylobacter, and diarrheagenic E. coli. Long-term PPI use may reduce alpha diversity and alter bacterial family abundance, potentially fostering infections like CDI by promoting a pro-inflammatory environment via increased Proteobacteria. PPIs may also predispose individuals to IBS by affecting microbiota composition and gut-brain axis functions, supported by studies linking dysbiosis to IBS, especially in gut infection. Chronic hypergastrinemia during PPI usage may promote malignant colonic epithelial cell growth, contributing to adenoma-carcinoma progression. [6]

GUT MICROBIOME MARKERS RELATED TO PPI USE:

PPI use significantly influences the human gut microbiome, impacting conditions like liver cirrhosis and CDI. The inhibition of gastric acid secretion by PPIs disrupts the gut microbiota structure, particularly reducing genera from families like Ruminococcaceae and Lachnospiraceae. These changes may increase the risk of liver cirrhosis and hepatic encephalopathy. Biomarkers identified through random forest classification models, such as Phascolarctobacterium and genes in metabolic pathways, highlight the association between PPI use and gut microbiota alterations. These biomarkers were more abundant in control group participants, validating the model's efficacy in identifying PPI-related gut microbiota changes. [7]

ROLE OF PROBIOTICS IN GUT MICROBIOTA COMPOSITION:

Probiotics, known for their health benefits, can complement PPI therapy by addressing intestinal dysbiosis and associated issues. They may compete with pathogens for receptor sites, produce metabolites that modulate metabolic pathways, and release bacteriocins inhibiting pathogen growth. Moreover, probiotics interact with bile acids, modify bile acid metabolism, and regulate the host immune response, particularly in the gut-associated lymphoid tissue. Despite their benefits, long-term probiotic use has been linked to rare cases of fungemia and bacteremia. Hence, extensive research is needed to understand their effects before routine administration in PPI therapy. [5]

PRESCRIPTION PATTERN OF PPIS AND THE POTENTIAL UTILIZATION OF PROBIOTICS:

The surge in proton pump inhibitor (PPI) usage, driven by over-the-counter availability, has led to frequent prescriptions without clear clinical rationale, ranging from 14.6% to 54% in primary care and emergency settings. While individual harm from PPIs is minimal, their extensive use can lead to adverse effects and notable consequences. Long-term PPI usage often results in dysbiosis, characterized by elevated levels of harmful bacteria like Enterococcus and Escherichia coli, associated with various health issues. Symptoms include abnormal bowel habits, bloating, and abdominal discomfort. Probiotics, particularly for antibiotic-associated diarrhea (AAD), show promising outcomes in prevention by promoting beneficial microbial populations and inhibiting harmful bacteria growth. Combining probiotics with PPIs offers a promising strategy, believed by many healthcare professionals to lead to favorable outcomes and improve quality of life. Probiotics also serve as safe adjunctive therapy in various conditions, including metabolic syndrome, where PPI usage disrupts gut microbiota balance, increasing susceptibility to infections and intestinal diseases. Incorporating probiotic supplementation during PPI therapy enhances its effects and mitigates potential complications, alleviating intestinal dysbiosis and associated side effects.8]

CONCLUSION

The utilization of proton pump inhibitors (PPIs) is linked to specific gut microbiota compositions, which can impact resistance to enteric infections, gut inflammation, and host metabolism. This association indicates that PPIs, commonly used in gastroenterology, can modify the host microbiota across the gastrointestinal tract, potentially contributing to dysbiosis and the onset of gastrointestinal disorders. Additionally, PPI usage elevates the risk of spontaneous bacterial peritonitis and overall bacterial infections in cirrhotic patients with ascites, underscoring their heightened susceptibility to infections and complications. This study suggests that PPI use may increase indigenous lactobacilli levels, influenced by drug effects and/or dietary factors affecting the gut microbiota.

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