Effect of Long-term PPI use on gut microbiome and Potential Role of Probiotics

The human gut is a vast, complex ecosystem wherein bacteria, nutrients, and host cells interact intricately to maintain gut homeostasis and support host development. Disturbance in the gut ecology termed gut dysbiosis has detrimental repercussions, and many diseases have been linked to gut microbiota dysfunction. (1) Proton pump inhibitors (PPIs) are the most extensively used acid-suppressing agents globally. Acid-related illnesses such as peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), erosive esophagitis(EE), and dyspepsia subtypes are usually treated with these PPIs. Though generally well tolerated, emerging scientific literature indicates that chronic use of PPIs may lead to microbiota imbalance in the gut mediated through a reduction in gastric acid output. (2) Rigorous research now confirms that modulating the gut microbiota with probiotics represents a strong possibility for developing nutritional or pharmacological strategies to sustain gut health. (3)

To seek deeper scientific insights in this direction, this review focuses on the effects of the use of long-term PPIs on gut ecology. It outlines the scope of probiotics to overcome the same while conferring various physiological benefits.

Understanding the importance of a healthy gut microbiome-

The intestinal microbiome is critical to the function and integrity of the gastrointestinal tract, immunological homeostasis, and host energy metabolism. Shedding light on the composition of a healthy gut microbiome, research now confirms that in terms of microbial taxa and genes, the biological variety and richness of the distal intestine surpasses the relative richness of microbiomes at other sites of the body. (4) Alterations in microbial flora's quantitative and qualitative composition, known as gut dysbiosis, can disturb interactions between microorganisms and their hosts. These changes in the composition and function of the microbiome may contribute to disease susceptibility. (4)

Gut Dysbiosis and Chronic Diseases: The Beginning of All Bad Things!

Several studies (4,5,6,7) have linked associations between intestinal dysbiosis and persistent low-grade inflammatory and dysregulated metabolic states, which could lead to metabolic syndrome, obesity, and diabetes. Gastrointestinal infections, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) link with changes in the microbiome makeup. With research consistently highlighting the increased susceptibility to diseases due to altered gut ecology, treatment options for manipulating and restoring the richness and variety of the gut microbiome are under evaluation. (4)

Gut Microbiota - Effects on Human Health

• Investigating the gut microbiota in Japanese PPIs users, Takagi et al (8) concluded that there were significant differences in the microbial structure between PPI nonusers and PPI users. The team further noted that such differences induce a mechanism by which the use of PPIs predisposes individuals to enteric infections such as Clostridium difficile infection.
• Studies show that intestinal microorganisms can modulate gene expression in the mammalian gut mucosa, influencing the gastrointestinal tract's function. (4)
• Interestingly, recent research reveals that probiotics restore the composition of gut microbes in the gastrointestinal system and can influence gene expression patterns, conferring a potential beneficial effect on intestinal micro-organisms. (4)

Proton pump inhibitors modify microbial flora of GI tract: Emerging Evidence

A systematic review published by Lukas et al. in 2020 assessed the effect of PPIs on the intestinal microbiome and the possible implications of PPI-induced dysbiosis in health and disease. The review included 12 observational and 11 interventional cohorts consisting of 708 & 180 PPI users, respectively. (9) The results suggested that PPI treatment led to distinct taxonomic alterations in the gut microbiota in most studies. Based on six independent cohorts, the upper gastrointestinal tract of PPI users showed overgrowth of orally derived bacteria, mostly Streptococcaceae. In fecal samples, PPIs increased multiple taxa from the orders, Bacillales, Lactobacillales, and Actinomycetales; Pasteurellaceae and Enterobacteriaceae; and the genus Veillonella. Taxa decreased by the use of PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae, and Mollicutes, based on findings from fecal samples studies in 19 independent cohorts. This finding concludes that using PPIs was associated with colonization of more distal parts of the gastrointestinal tract by upper gastrointestinal microbiota (9) 

PPIs and Gut dysbiosis: Effect of long-term PPI use on the gut microbiome-

PPIs affect physiological stomach processes and host defense mechanisms, resulting in delayed gastric emptying, decreased gastric mucus viscosity, increased bacterial load, and bacterial translocation. (2)

1. Long-term acid suppression by PPIs causes hypochlorhydria and leads to a decrease in microbial diversity, with the simultaneous proliferation of genotoxic microorganisms which may be involved in carcinogenesis. Data from Meta-analyses confirms that long-term PPI users have a 2.4-fold increased chance of developing gastric cancer.

2. Chronic use of PPIs has a significant impact on the microbiota of the small intestine and, in particular, causes small intestinal bacterial overgrowth (SIBO), owing to the loss of the gastric acid protective barrier.

3. In liver cirrhotic patients, PPI-induced dysbiosis may be a risk factor for developing hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP).

4. PPIs have also been shown to worsen the mucosal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs) in the distal portion of the small bowel to the ligament of Treitz, an interesting contrast to its perceived protective effects on NSAID-induced upper GI mucosal injury.

5. PPIs use may potentially increase the risk of Clostridium difficile infection (CDI), Salmonella, Campylobacter, and certain Escherichia coli infections.

6. Long-term PPI use has been linked to recurrent enteric infections. They cause secondary changes in microbiota composition and may induce IBS, through disruption of the gut-brain axis.

Managing dysbiosis: Role of Probiotics

Food and Agricultural Organization(FAO) of the United Nations(UN) and the World Health Organization(WHO), describe probiotics as living microorganisms when administered in adequate amounts confer health benefits on the host (4). Lactobacillus and Bifidobacterium are among the most widely used genera of probiotics today. (1)

Among the many ways in which probiotics confer a beneficial effect on the gut microbiome, some of the noteworthy mechanisms have been presented below.

Probiotics in counteracting the gut microbial alterations: Lactobacillus Strengthens Intestinal Barriers

• Probiotics produce antimicrobial agents or metabolic compounds that suppress the growth of microorganisms or compete for receptors and binding sites with other intestinal microbes on the intestinal mucosa.
• Probiotic Lactobacillus strains strengthen the integrity of the intestinal barrier. This leads to maintenance of immune tolerance and decreased translocation of bacteria across the intestinal mucosa. (4)

Probiotics and intestinal immunomodulation-

• Probiotic-mediated immunomodulation may occur via cytokine secretion mediation via signaling pathways such as NFκB (Nuclear Factor Kappa B) and MAPKs (mitogen-activated protein kinases), which can also alter the proliferation and differentiation of immune cells (such as T cells) or epithelial cells.
• Probiotics have the potential to modify intestinal microbial populations and limit pathogen development by increasing the host's production of beta-defensin and IgA.
• Probiotics may help to regulate pain receptor expression and neurotransmitter production, thus controlling gut motility and nociception. (4)

Therapeutic Efficacy of Probiotics: Improve GI symptoms induced by PPIs

A study published by Angela Horvat et al evaluated the effects of three-month treatment with a multispecies probiotic on intestinal inflammation, gut barrier function, microbiome composition, routine laboratory parameters, and quality of life in patients with long-term PPI therapy. Thirty-six patients were included. The results demonstrated that after probiotic supplementation, elevated zonulin levels could be significantly reduced (−46.3ng/mg; p<0.001). The abundance of Stomatobaculum was reduced and Bacillus increased with treatment. Furthermore, notable markers like albumin and thrombocyte count were significantly increased, and aspartate transaminase (AST) was significantly decreased during the intervention. Gastrointestinal quality of life showed significant improvements through GIQLI (Gastro-Intestinal Quality of Life Index) scores. The study concluded that microbiome-related side effects of long-term PPI use can be substantially reduced by multi-species probiotics-based interventions. (10)

Key pointers-

• Chronic PPI use could alter the gut microbiome and cause intestinal dysbiosis, leading to GI illnesses.
• Given a solid associative link between gut microbiota, health, and disease, there has been a lot of interest in considering probiotics (living microorganisms) or prebiotics (non-digestible substrates) to alter the gut microbiota positively.
• Probiotics induce beneficial effects on the gastrointestinal system and improve the functionality of existing microbial populations. By competing for resources, producing growth substrates or inhibitors, and modulating gut immunity, probiotics can influence the composition and function of microbial communities in the gut. The Lactobacillus probiotic strains strengthen the intestinal barrier.

The way forward: With more studies indicating the use of PPIs leads to alterations in healthy gut microbiota and is linked to several diseases; the use of PPIs, when advocated over a long period, should be rationally justified.

Having said that, the medical fraternity rests on tremendous hope regarding the positive results concerning the use of probiotics to restore PPI-induced gut changes physiologically.

As research continues to unveil the fullest potential of probiotics in managing PPI-induced dysbiosis, physicians may like to consider their appropriate use to restore gut physiology in the interest of patients in the longer run.

In summary

Proton pump inhibitors (PPIs) remain one the most used and often abused drugs in Indian settings. There is acceptable evidence of the association of qualitative alterations in gut microbiota with PPIs, leading to a risk of a broad spectrum of enteric infections. Probiotic-based therapeutic interventions may have a potential role in mitigating such untoward effects. While further studies are warranted, based on available evidence, multi-species probiotics (10) are beneficial and could be considered.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Probiotics, click here.

References

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8. Takagi, T., Naito, Y., Inoue, R., Kashiwagi, S., Uchiyama, K., Mizushima, K., ... & Itoh, Y. (2018). The influence of long-term use of proton pump inhibitors on the gut microbiota: an age-sex-matched case-control study. Journal of clinical biochemistry and nutrition, 62(1), 100-105.

9. Macke L, Schulz C, Koletzko L, Malfertheiner P. Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract-evidence from next-generation sequencing studies. Aliment Pharmacol Ther. 2020 Mar;51(5):505-526. doi: 10.1111/apt.15604. Epub 2020 Jan 28. PMID: 31990420.

10. Horvath A et al, The effects of a multispecies synbiotic on microbiome-related side effects of long-term proton pump inhibitor use: A pilot study. Sci Rep. 2020 Feb 17;10(1):2723. doi: 10.1038/s41598-020-59550-x