Comment on “Association of Proton Pump Inhibitor and Potassium‐Competitive Acid Blocker Use With Discontinuation and Intolerance of Oral 5‐Aminosalicylic Acid in Patients With Ulcerative Colitis”

Dear Editor,

I recently read with great interest the article by Otagiri et al. [1] titled, “Association of Proton Pump Inhibitor and Potassium‐Competitive Acid Blocker Use With Discontinuation and Intolerance of Oral 5‐Aminosalicylic Acid in Patients With Ulcerative Colitis”. This study is noteworthy, and the authors should be commended for providing important insight into an understudied question by analyzing the effect of PPI/PCAB on 5‐ASA intolerance in patients with UC. The study makes an important contribution to the field, but certain methodological elements need further refinement to strengthen the study's findings.

First, the authors reported alterations in the microbiota as a potential mechanism; however, the study does not provide a direct assessment of gut microbial composition. Increasing evidence suggests that both PPI use and 5‐ASA intolerance are independently associated with distinctive alterations in the gut microbiome, such as decreased microbial diversity and elevated streptococcal species number. Based on research by Mizuno et al. [2]. The group that was intolerant to 5‐ASA shows marked dysbiosis as compared with those who tolerate the treatment, indicating that disruptions in the microbiome may function as a biological mediator rather than just a confounding factor. Consequently, it remains unclear if PPI/PCAB treatment drives this intolerance or if it merely identifies patients who are already on dysbiosis that makes them more vulnerable to negative reactions. A long‐term prospective trial with repeated longitudinal microbiome monitoring is required to comprehend this causal sequence.

Evidence that PCAB can alter the gut microbiota of a healthy individual supports the biological plausibility of this theory. Otsuka et al. demonstrated that vanoprazan has greater potency to alter the intestinal microbiota of Helicobacter pylori ‐negative individuals, as compared with traditional PPIs [3]. Because the current study merged PPIs/PCAB into the single exposure category despite possible distinct microbiological effects, these findings are especially relevant. Therefore, additional mechanistic insights into the connection between acid suppression and 5‐ASA intolerance may be obtained from separate investigations of PPI and PCAB users.

Additionally, the study included 10 of 181 patients who had concomitant PPI/PCAB medication, which resulted in a wide confidence interval and increased model instability, even though the authors recognized that a small number of PPI/PCAB users [1]. As Hackshaw noted in his article, small studies yield the fastest results, but those results are unreliable and do not provide an exact estimate of effect size [4]. Moreover, PPI/PCAB exposure was defined at the baseline only; the study could not account for varying changes introducing misinterpretation of long‐term follow up possible. Additionally, the trial lacked pharmacokinetic assessment despite the evidence that esomeprazole can speed up melasamine absorption from colon‐targeted formulation, leading to higher than expected levels of drug in the blood [5]. Independent of symbiosis, such an alteration in drug delivery can contribute to intolerance and discontinuation.

In conclusion, the study highlighted the understudied question and provided a preliminary link between PPI/PCAB use and 5‐ASA intolerance in UC. However, microbiome alterations, confounding by indication, and unmeasured pharmacokinetic assessment should be taken into account when interpreting these results. To validate the result and clarify the result behind this clinically significant correlation, larger multicenter prospective studies are required.

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Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.