Ishiguro Mikako, Takahara Masahiro, Takaki Akinobu, Hiraoka Sakiko, Toyosawa Jyunki, Aoyama Yuki, Igawa Shoko, Yamasaki Yasushi, Inokuchi Toshihiro, Kinugasa Hideaki, Otsuka Motoyuki
Department of Gastroenterology and Hepatology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.
Dig Dis Sci. 2025 Aug 2. doi: 10.1007/s10620-025-09276-5.
Nonsteroidal anti-inflammatory drugs (NSAID), which are commonly used to manage pain and inflammation, often cause gastrointestinal injuries, including small intestinal damage. Berberine (BBR) is a traditional Chinese medicine that protects against these injuries. However, the mechanism of action is not fully understood.
This study aimed to evaluate the protective effects of BBR against NSAID-induced intestinal injury and elucidate the underlying molecular mechanisms.
We evaluated the effects of BBR on NSAID-induced intestinal injury using a combination of mouse models and human gut organoids. Mice were treated with indomethacin with or without BBR to induce small intestinal injury. Human gut organoids were exposed to NSAID, with or without BBR, to assess their direct epithelial effects. Histological analyses, cytokine measurements, and Western blotting were performed to evaluate intestinal damage, tight junction integrity, and inflammasome-associated activation.
In NSAID-treated mice, BBR markedly reduced ulcers and adhesions and preserved ileal Claudin-1, Occludin, and Zonula Occludens-1 (ZO-1) levels. BBR inhibited both NOD-like receptor family pyrin domain-containing 6 and NOD-like receptor family caspase recruitment domain-containing protein 4 inflammasome activation, reducing Caspase-1 maturation and downstream interleukin-1β and tumor necrosis factor-α release. In human gut organoids, BBR demonstrated comparable protective effects by directly mitigating NSAID-induced epithelial barrier disruption caused by Claudin-1 and Occludin downregulation, although it did not restore ZO-1 expression.
BBR effectively prevented NSAID-induced small intestinal injury by maintaining tight junction integrity and inhibiting inflammasome-associated activation, indicating its potential as a therapeutic agent against such damage.
非甾体抗炎药（NSAID）常用于控制疼痛和炎症，但常导致胃肠道损伤，包括小肠损伤。黄连素（BBR）是一种可预防此类损伤的传统中药。然而，其作用机制尚未完全明确。
本研究旨在评估黄连素对NSAID诱导的肠道损伤的保护作用，并阐明其潜在的分子机制。
我们结合小鼠模型和人肠道类器官评估了黄连素对NSAID诱导的肠道损伤的影响。给小鼠使用吲哚美辛，同时或不同时使用黄连素以诱导小肠损伤。将人肠道类器官暴露于NSAID，同时或不同时使用黄连素，以评估其对上皮细胞的直接作用。进行组织学分析、细胞因子检测和蛋白质印迹法，以评估肠道损伤、紧密连接完整性和炎性小体相关激活。
在接受NSAID治疗的小鼠中，黄连素显著减少了溃疡和粘连，并维持了回肠中闭合蛋白-1、闭锁蛋白和紧密连接蛋白-1（ZO-1）的水平。黄连素抑制了含NOD样受体家族吡啉结构域蛋白6和含NOD样受体家族半胱天冬酶募集结构域蛋白4炎性小体的激活，减少了半胱天冬酶-1的成熟以及下游白细胞介素-1β和肿瘤坏死因子-α的释放。在人肠道类器官中，黄连素通过直接减轻由闭合蛋白-1和闭锁蛋白下调引起的NSAID诱导的上皮屏障破坏，表现出类似的保护作用，尽管它没有恢复ZO-1的表达。
黄连素通过维持紧密连接完整性和抑制炎性小体相关激活，有效预防了NSAID诱导的小肠损伤，表明其作为抗此类损伤治疗药物的潜力。
