Zhang Song-Xia, Hu Fang-Fang, Chen Huan, Guo Jing, Xiang Zhong-Wen, Ding Xin, Ye Meng-Ling, Ye Wen-Li, Chen Jun-Hong, Wang Xin, Han Wen-Jing, Zhou Hong-Hao, Zhang Wei, Huang Yun, Wu Lie-Lin, Lian Guang-Hui, Chen Yao
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
NPJ Biofilms Microbiomes. 2025 Jul 14;11(1):132. doi: 10.1038/s41522-025-00766-y.
Drug tolerance is clinically common but its mechanism is unclear. Previous studies found RSV tolerance in ALD treatment. This study explores mechanisms involving gut bacteria and host factors. Male C57BL/6J mice were induced into ALD with the Lieber-DeCarli alcohol diet, then ALD-RSV group mice were gavaged RSV (150 mg/kg/day) for 5 weeks. Throughout the experiment, ALD and ALD-RSV mice were on the Lieber-DeCarli alcohol diet, while the Vehicle group received a control diet. By week 5, tolerance to RSV efficacy emerged, with markedly reduced RSV exposure at the final dose. ALD-RSV group exhibited increased levels of Eggerthella lenta (E.lent), which metabolizes RSV into dihydroresveratrol (DHR). Chronic RSV treatment upregulated UGT1A1, the enzyme converting RSV into its primary metabolite, trans-resveratrol-3-O-β-D-glucuronide (R3G). The synergy between gut bacteria and host factors enhances RSV metabolism in ALD mice, driving tolerance and offering insights into other clinical drugs tolerance mechanisms.
药物耐受性在临床上很常见，但其机制尚不清楚。先前的研究发现酒精性肝病（ALD）治疗中存在呼吸道合胞病毒（RSV）耐受性。本研究探讨了涉及肠道细菌和宿主因素的机制。采用Lieber-DeCarli酒精饮食诱导雄性C57BL/6J小鼠患ALD，然后对ALD-RSV组小鼠灌胃RSV（150mg/kg/天），持续5周。在整个实验过程中，ALD和ALD-RSV小鼠采用Lieber-DeCarli酒精饮食，而载体组接受对照饮食。到第5周时，对RSV疗效的耐受性出现，最终剂量时RSV暴露显著减少。ALD-RSV组中迟缓埃格特菌（E.lent）水平升高，该菌将RSV代谢为二氢白藜芦醇（DHR）。长期RSV治疗上调了UGT1A1，该酶将RSV转化为其主要代谢产物反式白藜芦醇-3-O-β-D-葡萄糖醛酸苷（R3G）。肠道细菌与宿主因素之间的协同作用增强了ALD小鼠体内RSV的代谢，导致耐受性产生，并为其他临床药物耐受性机制提供了见解。
