Mechanism of Atractylenolide Ⅲ alleviating pyrotinib-induced diarrhea by regulating AMPK/CFTR pathway through metabolite of gut microbiota

作者：Fengxian Jiang, Pancen Ran, Liyin Pan, Jingjiang Lai, Junlei Zhang, Jing Zhao, Wei Xu, Jingliang Wang, Shu Yang, Yahui Wang, Rui Zhao, Wei-Hao Wang, Jian Wei, Guobin Fu · 发表于：Journal of Traditional and Complementary Medicine · 年份：2024 · DOI：10.1016/j.jtcme.2024.11.015 · 被引用次数：4 · 研究领域：Gut microbiota and health、Ginseng Biological Effects and Applications、Helicobacter pylori-related gastroenterology studies

Atractylenolide III, a sesquiterpene extracted from the rhizome of Atractylodes macrocephala (Asteraceae), exhibits pharmacological effects, including improvement of gastrointestinal function, regulation of immune function, anti-inflammatory and antibacterial properties. Pyrotinib, a representative TKI originally developed in China, is classified as a Class 1.1 novel drug, exhibits superior efficacy compared to similar drugs. Notably, the overall incidence of pyrotinib-induced diarrhea stands at 95 %, with 40 % of cases classified as grade ≥3 diarrhea. Currently, the effect of Atractylenolide III on pyrotinib-induced diarrhea and the underlying mechanisms remain unclear. Therefore, in this study, we established a pyrotinib (80 mg/kg/day) Wistar rat diarrhea model to explore the effect of Atractylenolide III on pyrotinib-induced diarrhea. We exploded the potential mechanism of Atractylenolide III via MQAE chloride fluorescent probe, RT-qPCR, Western blot, 16S rRNA sequencing, metabolomics, etc. We found that Atractylenolide III demonstrated the ability to alleviate pyrotinib-induced diarrhea without compromising its anti-tumor effects, inhibited pyrotinib-induced chloride secretion, and the potential mechanism of action involved enhancing AMPK phosphorylation while decreasing CFTR protein expression. Additionally, Atractylenolide III alleviated pyrotinib-induced diarrhea by modulating intestinal flora structure and increasing lithocholic acid content. This study could provide ...