Use of PPIs and Gut Dysbiosis: Review and Therapeutic Opportunity for Probiotics

Proton-pump inhibitors (PPIs) have been used clinically for around thirty years. Because of their well-established efficacy, PPIs have significantly improved the approach to treating acid-related diseases. PPIs have been extensively used for the treatment of gastroesophageal reflux disease, H.pylori infections, NSAID-induced gastric ulcers, etc.[1] Though typically well tolerated, recent scientific research suggests that long-term PPI usage may cause gut microbial imbalance via effects through reduced gastric acid secretion.[2]

Disruption of homeostasis in the small intestinal microbial flora can lead to significant clinical consequences. Many studies have suspected that rampant use of PPIs leads to small intestinal bacterial overgrowth (SIBO) which is clinically defined as the presence of more than 105 colony-forming units (CFU)/ml of microbes in the proximal jejunal aspirate. [3]

Studies have also demonstrated that PPIs cause dysbiosis of the small intestinal bacterial flora, aggravating NSAID-induced small intestinal injury.[4]

PPI and its correlation with Gut Dysbiosis

The impact of PPIs on the gut microbiota and the potential effects of PPI-induced dysbiosis in health and illness were examined in a systematic review by Lukas et al. The review included 12 observational cohorts with 708 PPI users and 11 interventional cohorts with 180 PPI users. [9] According to the findings, PPI use caused distinct taxonomic changes in the gut microbiota. Based on six independent cohorts, there was an overgrowth of orally derived bacteria, primarily Streptococcaceae, in the upper gastrointestinal tract of PPI users. PPIs increased several species from families Pasteurellaceae and Enterobacteriaceae, the orders Bacillales, Lactobacillales, Actinomycetales, and the genus Veillonella, in fecal samples. Based on data from fecal sample investigations in 19 independent cohorts, taxa lowered by using PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae, and Mollicutes. This study suggests that utilizing PPIs was linked to moderate alterations to upper and distal gut microbiota.[9]

Long-term effects of PPI on Gut Microbiome and its Ramifications

PPIs interfere with gastric functions and the host’s defensive mechanisms, delaying gastric emptying and increasing bacterial load and bacterial translocation. [2]

  • Long-term acid suppression by PPIs results in hypochlorhydria, a reduction in microbial diversity, and the simultaneous growth of potentially carcinogenic genotoxic bacteria. According to data from meta-analyses, long-term PPI users had a 2.4-times greater risk of developing gastric cancer.
  • Chronic use of PPIs causes loss of gastric acid protective barrier, leading to a considerable negative influence on the microbiota of the small intestine and, in particular, results in small intestinal bacterial overgrowth (SIBO).
  • PPI-induced dysbiosis in liver cirrhotic individuals may increase their risk of developing hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP).
  • Salmonella, Campylobacter, Clostridium difficile infection (CDI), and several Escherichia coli infections may become more common if PPI usage is continued.
  • Enteric infections have been associated with long-term PPI usage. Disrupting the gut-brain axis, they produce secondary alterations in the microbiota composition causing IBS.

Effect of Probiotics on Gut Health: Review of Scientific Evidence

Global research has yielded encouraging findings pointing to the advantages of probiotics in gut dysbiosis.

Probiotics help in the maintenance of gut microbiome: Probiotics generate metabolic compounds and also anti-bacterial agents that inhibit the growth of microbes or compete with other intestinal microbes for receptor binding sites on the intestinal mucosa. Certain probiotics like Lactobacillus strains strengthen the intestinal barrier resulting in the maintenance of immune tolerance and decrease the translocation of bacteria across the intestinal mucosa and also reduce disease phenotypes such as gastrointestinal infections, IBS and IBD.[5] In a study, both Lactobacillus casei and L. acidophilus strains were successful in treating chronic diarrhea related to bacterial overgrowth; further studies demonstrated the effectiveness of both strains in treating SIBO and functional intestinal distention. [3]

Immunomodulation of the gut by probiotics: Probiotics may also aid in modulating gastrointestinal motility and nociception by regulating the expression of pain receptors and the secretion of neurotransmitters.[5]

Gut alterations made by PPI reversed by probiotics: An analysis of the effects of a three-month multispecies probiotic administration on intestinal inflammation, gut barrier function, microbiome composition, routine laboratory markers, and quality of life in 36 patients receiving long-term PPI therapy was published by Angela Horvat et al. The findings showed that probiotics supplementation might considerably lower elevated zonulin levels (-46.3ng/mg; p<0.001). GIQLI (Gastro-Intestinal Quality of Life Index) scores demonstrated significant improvements. The study concluded that multi-species probiotics-based therapies can significantly reduce the microbiome-related side effects of long-term PPI usage.[10]

Probiotics attenuate PPI-mediated intestinal microbial alterations: Singh et al. conducted a randomized, double-blind controlled study with participants (n=30) who received either a PPI (n=15) or a placebo (n=15) over a period of 6 weeks, followed by multistrain probiotics from weeks 2-6, to evaluate the potential role of probiotics in attenuating the side effects of PPIs. According to the study, the diminution of the microbial flora of the Leuconostacaceae family (p=0.01) and an increase in the metabolite 1H-Indole-4-carbaldehyde were exhibited in the probiotic intervention group. It was concluded that combining probiotics with PPIs may be a helpful treatment strategy that promotes probiotic colonization and reduces microbial disturbances brought about by the use of PPIs. [11]

Summary

Although there has been rampant use of PPIs in today’s clinical settings, we need to be aware and prudent of its ill effects on gut microbial flora, and its sequelaes. Interfering with the intestinal microbiome could lead to further multiple health repercussions. To mitigate such PPI-induced gut dysbiosis, probiotics can act as a possible remedial measure with evidence supporting it, as they help maintain a healthy gut.

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

References

[1] The appropriate use of proton-pump inhibitors-Vincenzo Savarino 1, Elisa Marabotto 2, Patrizia Zentilin 2, Manuele Furnari 2, Giorgia Bodini 2, Costanza De Maria 2, Gaia Pellegatta 2, Claudia Coppo 2, Edoardo Savarino 3

[2] Bruno G, Zaccari P, Rocco G, Scalese G, Panetta C, Porowska B, Pontone S, Severi C. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol 2019; 25(22): 2706-2719

[3] Chen, W. C., & Quigley, E. M. Probiotics, prebiotics & synbiotics in small intestinal bacterial overgrowth: opening up a new therapeutic horizon!.2014. The Indian journal of medical research, 140(5), 582.

[4] Fujimori S. What are the effects of proton pump inhibitors on the small intestine? World J Gastroenterol 2015; 21(22): 6817-6819 Available from: URL: http://www.wjgnet.com/1007-9327/full/ v21/i22/6817.htm DOI: http://dx.doi.org/10.3748/wjg.v21

[5] Hemarajata, P., & Versalovic, J. (2013). Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therapeutic advances in gastroenterology, 6(1), 39-51.

[6] Pflughoeft, K. and Versalovic, J. (2012) Human microbiome in health and disease. Annu Rev Pathol 7: 99–122.

[7]. W. Gou, Y. Fu, L. Yue, G.-d. Chen, X. Cai, M. Shuai, F. Xu, X. Yi, H. Chen, Y.J. Zhu, Gut microbiota may underlie the predisposition of healthy individuals to COVID-19, medRxiv (2020)

[8]. K. Xu, H. Cai, Y. Shen, Q. Ni, Y. Chen, S. Hu, J. Li, H. Wang, L. Yu, H. Huang, Y. Qiu, G. Wei, Q. Fang, J. Zhou, J. Sheng, T. Liang, L. Li, Management of corona virus disease-19 (COVID-19): the Zhejiang experience, Zhejiang Da Xue Bao Yi Xue Ban 49 (1) (2020) 147–157.

[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

[11] Singh G, Haileselassie Y, Briscoe L, et al. The effect of gastric acid suppression on probiotic colonization in a double-blinded randomized clinical trial. Clin Nutr ESPEN. 2022;47:70-77. doi:10.1016/j.clnesp.2021.11.005

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