Role of Proton Pump Inhibitors on the Gut Microbiome

So What?

Proton pump inhibitors (PPIs) treat gastric acid disorders, but their use is criticized for medication interactions and unfavorable side effects.[1] Altering the gastric environment with PPIs may negatively impact our gut microbiome: the microbial community in our gastrointestinal system that plays a role in our overall health.[1,2] This article highlights recent research on the impact of PPIs on the gut microbiome.

Current Concerns

Proton pump inhibitors block the production of gastric acid via H+/K+ATP-ase antiporter pumps, and their effect on microbiota is thought to be largely mediated by the resultant increase in pH.[3] Modification of the normal gastrointestinal flora can contribute to dysbiosis, overgrowth of pathologic organisms, and, in turn, gastrointestinal disorders.[4] Reduced gastric acid also facilitates the survival of oral bacteria in lower segments of the intestinal tract, which may increase intraluminal inflammation.[4] Figure 1 depicts some of the microbiota changes associated with the use of PPIs.


Figure 1: Potential impacts of proton pump inhibitors on the gastrointestinal microbiome.

Credit: Freedberg, Daniel E et al., 2014[3]


Clostridium difficile infection

A serious concern for the potential interaction of PPIs with the microbiome is the risk of Clostridium difficile infection (CDI), which is associated with dysbiosis: a disruption in the normal gut flora. Dysbiosis, with the potential for Clostridium difficile over-colonization, has many health implications, ranging from diarrhea to death.[6]


Adding to current knowledge, a meta-analysis[5] with nearly 300,000 patients estimated a 65% increase in Clostridium difficile-associated diarrhea for patients taking PPIs. This study suggested employment of strict guidelines for the use of PPIs for gastric ulcer prophylaxis in order to avoid some of the morbidity and healthcare costs caused by Clostridium difficile infections.[5] Another systematic review and meta-analysis of 67 studies found PPI use associated with a significantly increased risk of CDI in adult and pediatric patients. A subgroup analysis identified a similar relationship with recurrent Clostridium difficile infections. A similar study using data from 356,683 patients determined that PPI use was associated with an increased risk of C. difficile infection (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001).[7] This association remained significant throughout subgroup analyses.

A longitudinal study assessed gut microbial diversity in nine healthy subjects who were administered omeprazole for 28 days compared to five subjects with untreated C. difficile infection.[2] They used 16S rRNA sequencing and found that PPI administration was associated with decreased microbial diversity after 1 week and 1 month, giving healthy subjects diversity scores similar to those with C. difficile infections; interestingly, taxonomic units, which represent microbial diversity, increased one month after stopping the PPI (Figure 1). Additional prospective studies are needed to further explore the relationship between PPI use and C. difficile infection.

Figure 2: Observed taxonomic unit counts (measure of microbial diversity) effect on proton pump inhibitors. Early PPI is 1 week into treatment, Late-PPI is at day 28, and Recovery is 1 month after ceasing PPI use. Black horizontal bars represent group means.

Credit: Seto et al., 2014[2]


Small intestinal bacterial overgrowth

Small intestinal bacterial overgrowth (SIBO) is defined as greater than 105 bacterial colony-forming units per milliliter after culture of upper gut aspirates.[8] Symptoms of SIBO include abdominal pain, diarrhea, bloating, malabsorption, and weight loss.[8] Notably, PPI use was correlated with an increased risk for SIBO in some but not all studies. Conflicting results may be due to varied methods for diagnosing SIBO, study designs, and sample sizes.[1]


A systematic review and meta-analysis of 11 studies (N = 3134) identified a statistically significant risk for SIBO associated with PPI use when SIBO diagnosis was determined using a duodenal or jejunal aspirate culture, which is considered the gold standard.[9] There was no significant risk for SIBO diagnosed using glucose or lactose breath testing.[9]

Another meta-analysis (N = 7055) concluded that PPI use moderately increased the risk of developing SIBO (pooled OR 1.71, 95% confidence interval 1.20–2.43).[8] An increased risk was significant in subgroup analysis for both glucose hydrogen breath test and aspirate culture, but not for lactose breath testing. In summary, PPI use appears to influence the gut microbiome in a manner that increases the risk of SIBO; however, study design is an important factor in the current debate on PPIs and SIBO risk. Standardizing methods of diagnosing SIBO across studies may help us further understand this relationship.

Future Recommendations

Medication management

Prescribers should be prudent when determining the need for a PPI and its duration of use.[1,6]

Gastric acid reduction prophylaxis risks and benefits should be monitored, and symptomatic GERD or dyspepsia should be managed with time-limited trials of PPIs along with ongoing clinical evaluation.[1]

Diet and lifestyle

Dietary and lifestyle modification for managing peptic ulcers, gastro-esophageal reflux disease (GERD), or other gastric acid problems is always first-line and should be practiced in conjunction with medical intervention whenever possible:

  • For peptic ulcers: limiting consumption of alcohol and spicy foods, reducing stress, and tobacco cessation can help.[10]
  • For GERD: consuming multiple smaller meals, remaining upright after eating, and limiting alcohol, fatty foods, known triggers, and tobacco can provide relief.[10]

Practical Tips:

  1. PPIs are generally safe medications but should be used with caution and for limited periods of time to reduce adverse effects, such as gut microbiome disruption, which may increase susceptibility to Clostridium difficile infections and SIBO.
  2. Diet and lifestyle modifications as part of gastric acid disorder treatments may help limit PPI use.
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[1] A. Singh, G. A. Cresci, and D. F. Kirby, “Proton Pump Inhibitors: Risks and Rewards and Emerging Consequences to the Gut Microbiome,” Nutr. Clin. Pract., vol. 33, no. 5, pp. 614–624, Oct. 2018.

[2] C. T. Seto, P. Jeraldo, R. Orenstein, N. Chia, and J. K. DiBaise, “Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility,” Microbiome, vol. 2, p. 42, 2014.

[3] D. E. Freedberg, B. Lebwohl, and J. A. Abrams, “The Impact of Proton Pump Inhibitors on the Human Gastrointestinal Microbiome,” Clin. Lab. Med., vol. 34, no. 4, pp. 771–785, Dec. 2014.

[4] G. Bruno et al., “Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified,” World J. Gastroenterol., vol. 25, no. 22, pp. 2706–2719, Jun. 2019.

[5] S. Janarthanan, I. Ditah, D. G. Adler, and M. N. Ehrinpreis, “Clostridium difficile-Associated Diarrhea and Proton Pump Inhibitor Therapy: A Meta-Analysis,” Am. J. Gastroenterol., vol. 107, no. 7, pp. 1001–1010, Jul. 2012.

[6] Y. Naito, K. Kashiwagi, T. Takagi, A. Andoh, and R. Inoue, “Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use,” Digestion, vol. 97, no. 2, pp. 195–204, 2018.

[7] A. Trifan et al., “Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis,” World J. Gastroenterol., vol. 23, no. 35, pp. 6500–6515, Sep. 2017.

[8] T. Su, S. Lai, A. Lee, X. He, and S. Chen, “Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth,” J. Gastroenterol., vol. 53, no. 1, pp. 27–36, Jan. 2018.

[9] W. Lo and W. W. Chan, “Proton Pump Inhibitor Use and the Risk of Small Intestinal Bacterial Overgrowth: A Meta-analysis,” Clin. Gastroenterol. Hepatol., vol. 11, no. 5, pp. 483–490, May 2013.

[10] “H2 Blockers: Treatment Options for GERD | Healthline.” [Online]. Available: [Accessed: 22-Sep-2019].

[11] Y.-C. Shi et al., “Effects of Proton Pump Inhibitors on the Gastrointestinal Microbiota in Gastroesophageal Reflux Disease,” Genomics. Proteomics Bioinformatics, vol. 17, no. 1, pp. 52–63, Feb. 2019.