Original articles
Yisheng He, Jiang Ma, Xiaoyu Fan, Liang Ding, Xinxin Ding, Qing-Yu Zhang, Ge Lin. The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3820-3835

The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity
Yisheng Hea, Jiang Maa, Xiaoyu Fanb, Liang Dingb, Xinxin Dingb, Qing-Yu Zhangb, Ge Lina
a. School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR 999077, China;
b. Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
Pyrrolizidine alkaloids (PAs) are the most common phytotoxins with documented human hepatotoxicity. PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts, thereby causing cytotoxicity. This study investigated the role of the gut–liver axis in PA intoxication and the underlying mechanisms. We exposed mice to retrorsine (RTS), a representative PA, and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function. Using mice with tissue-selective ablation of P450 activity, we found that hepatic P450s, but not intestinal P450s, were essential for PA bioactivation. Besides, in RTS-exposed, bile duct-cannulated rats, we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity. The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione, thereby suppressing the PA detoxification pathway. Compared to RTS-exposed normal mice, the colitic mice displayed more severe RTS-induced hepatic vasculature damage, fibrosis, and steatosis. Overall, our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.
Key words:    Pyrrolizidine alkaloid    Cytochrome P450    Inflammatory bowel disease    Intestinal injury    Liver injury    Gut–liver axis   
Received: 2021-04-06     Revised: 2021-06-12
DOI: 10.1016/j.apsb.2021.07.013
Funds: This work was supported by Research Grants Council of Hong Kong Special Administrative Region (GRF Project Nos. 14160817 and 14106318 to Ge Lin, China), and a grant from the National Institutes of Health (No. R01 GM082978 to Qing-Yu Zhang, USA). We thank Ms. Weizhu Yang for assistance with mouse breeding and genotyping analysis, Dr. Lei Yin and Dr. Xiangmeng Wu for assistance with analytical instruments, and Dr. Weiguo Han and Dr. Nataliia Kovalchuk for assistance with histological assays.
Corresponding author: Qing-Yu Zhang,E-mail:qyzhang@pharmacy.arizona.edu;Ge Lin,E-mail:linge@cuhk.edu.hk     Email:qyzhang@pharmacy.arizona.edu;linge@cuhk.edu.hk
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Yisheng He
Jiang Ma
Xiaoyu Fan
Liang Ding
Xinxin Ding
Qing-Yu Zhang
Ge Lin

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