Potential mechanism of pyrotinib-induced diarrhea was explored by gut microbiome and ileum metabolomics

作者：Jingjiang Lai, Xiaoli Zhuo, Ke Yin, Fengxian Jiang, Lei Liu, Xiaoying Xu, Hongjing Liu, Jingliang Wang, Jing Zhao, Wei Xu, Shuping Yang, Honglin Guo, Xiaotian Yuan, Xiaoyan Lin, Fanghua Qi, Guobin Fu · 发表于：Anti-Cancer Drugs · 年份：2022 · DOI：10.1097/cad.0000000000001440 · 被引用次数：8 · 研究领域：Pancreatic and Hepatic Oncology Research、Gut microbiota and health、Colorectal Cancer Treatments and Studies

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study. First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling. Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbi...