State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
Pharmacol Res. 2020 May;155:104752. doi: 10.1016/j.phrs.2020.104752. Epub 2020 Mar 10.
As a potential drug for treating inflammatory, autoimmune diseases and cancers, triptolide (TP) is greatly limited in clinical practice due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.
作为一种治疗炎症性、自身免疫性疾病和癌症的潜在药物，雷公藤红素（TP）由于其严重的毒性，特别是肝毒性，在临床实践中受到极大限制。最近，代谢平衡与药物性肝损伤密切相关，肠道微生物群被认为发挥着重要作用。在本研究中，我们旨在通过代谢组学研究肠道微生物群在 TP 诱导的肝毒性中的作用。在这里，抗生素预处理可显著加重肝损伤，并在 0.5mg/kg 相对安全剂量的 TP 治疗后导致死亡率增加，而肠道微生物移植可逆转这一结果。在 TP 治疗前失去肠道微生物群可显著增加血浆和肝脏中的长链脂肪酸和胆汁酸。进一步的研究表明，肠道微生物群衍生的丙酸盐有助于肠道微生物群对 TP 的保护作用，表现为炎症水平（Tnfa、Il6 和 Cox2）、ATP、丙二醛和肝组织学的改善。补充丙酸盐可显著降低参与脂肪酸生物合成的基因（Srebp1c、Fasn 和 Elovl6）的 mRNA 水平，从而减少肝脏中的长链脂肪酸。此外，TP 限制了厚壁菌门的生长，并导致盲肠内容物中短链脂肪酸的缺乏。总之，本研究警告当抗生素与 TP 同时使用时存在风险。通过食物、益生元和益生菌干预肠道微生物群或补充丙酸盐可能是改善 TP 诱导毒性的临床策略。
