Critical evaluation of protective effect of berberine against NSAID-induced small intestinal injury: unresolved mechanistic gaps and translation challenges

To the Editor, The recent article by Ishiguro et al (2025) was of interest to us as it studies the protective functions of berberine (BBR) in the case of NSAIDs-inflicted damage to the small intestine. The research has real preclinical potential through a mouse model and intestinal organoids. However, having reviewed the findings, we would also like to mention several key limitations that should be considered and indicate a more reserved approach to the interpretation of the data. To begin with, the author suggests that BBR may become a possible therapeutic option only based on animal and organoid evidence. Nevertheless, there were no human clinical investigations, especially concerning NSAID-related enteropathy. Although such models have relevant insights, their translational capacity is relatively weak. To identify efficacy, the amount to be administered, and inter-individual variability, human trials will have to be conducted[1]. Second, the safety assessment within the study is limited to only 5 days of follow-up in mice. Generally, it focuses on the monitoring of weight and behavior, which fails to account for the known pharmacokinetic actions of BBR in human beings. Being able to block cytochrome P450 enzymes and having the risk of drug-drug interactions and systemic toxicity, BBR demands greater and long-term safety data[2]. It has also been acknowledged by two recent meta-analyses, showing restricted cardiovascular applications and limited pharmacovigilance data on adverse events in BBR trials[3,4]. Hence, long-duration clinical trials could safely address the existing safety gap with the use of BBR. Third, the mechanism of action of inflammasome suppression and downregulation of NLRC4, NLRP6, and caspase-1 were postulated. Still, no functional experiments (e.g., via knockout models or inhibitors of the pathway) were conducted to demonstrate any causality using inflammasome-deficient mouse models. Moreover, apoptosis or pyroptosis, as the main downstream consequences of the inflammasome stimulation, was not evaluated. In contrast, Sun et al (2024) provided functional validation of the involvement of NLRP3 inflammasome and M1 macrophage polarization inhibitory properties of BBR, providing a more comprehensive mechanism of action in inflammatory study models[5]. Fourth, despite the established role of gut microbiota in NSAID-induced enteropathy by activating TLR4 and inflammasomes via the LPS pathway, this research does not look into the composition or activity of microbes. The lack of microbiome analysis, despite a brief mention in the introduction, overlooks a significant upstream variable in gastrointestinal injuries. However, Yokota et al (2017) demonstrate that microbiome modulation in the intestine can significantly influence the injury related to NSAIDs use, thus validating its mechanistic relevance and translational significance[6]. Although Ishiguro et al offer contributions to the investigation of the protective role of BBR against NSAID-induced intestinal injury, this study constrains immediate translation due to a lack of clinical validation, long-term safety, and microbiota analysis. The existing literature highlights the restrictions and must inform further studies that need to be carried out to promote BBR as an option in the treatment of NSAID-induced enteropathy in clinical practice. TITAN Guidelines: This manuscript complies with TITAN Guidelines, 2025, declaring no use of AI[7].