Chen Wen-Jung, Chen Yng-Tay, Ko Jiunn-Liang, Chen Jian-Yuan, Zheng Jun-Yao, Liao Jiunn-Wang, Ou Chu-Chyn
Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Graduate Institute of Food Safety, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan; Department of Food Science and Biotechnology, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
Biomed Pharmacother. 2024 Dec;181:117689. doi: 10.1016/j.biopha.2024.117689. Epub 2024 Nov 23.
In our previous research, we reported that administering probiotics Lactobacillus reuteri and Clostridium butyricum (LCs) before cisplatin treatment effectively modifies structures of the gut microbiota and restore ecological balance and significantly increases butyrate levels, a process closely associated with reducing cisplatin-induced nephrotoxicity. This study aims to investigate further whether the elevation of metabolite butyrate in the gut, promoted by probiotics LCs, can effectively mitigate the nephrotoxic effects of cisplatin and the progression of renal senescence in rats. Results show that butyrate administration significantly improved kidney function and decreased renal fibrosis in a dose-dependent manner compared to the cisplatin group. Its effects were associated with reductions in inflammatory responses, evidenced by decreased levels of key inflammatory markers, including KIM-1, MPO, NOX2, F4/80, and TGF-β1, alongside increased production of the anti-inflammatory cytokine IL-10. Furthermore, the butyrate intervention ameliorated cisplatin-induced gut microbiota dysbiosis, preserving the structure and diversity of healthy microbial communities. Specifically, we observed a decrease in the abundance of Escherichia_Shigella and Blautia, alongside an increase in the abundance of the butyrate-producing genus Roseburia. Notably, Escherichia_Shigella exhibited a positive correlation with the pro-inflammatory factor MPO, while displaying a negative correlation with the anti-inflammatory cytokine IL-10. Butyrate also attenuated the cisplatin-induced expression of senescence markers p21 and p16 in kidney tissue. It alleviated the cisplatin-increased senescence-associated beta-galactosidase activity and reactive oxygen species production in SV40 MES-13 cells. These results indicate that butyrate, derived from the gut microbiota, may exert a protective effect against cisplatin-induced kidney damage by regulating microbiota balance and anti-inflammatory effects.
在我们之前的研究中，我们报告称在顺铂治疗前给予益生菌罗伊氏乳杆菌和丁酸梭菌（LCs）可有效改变肠道微生物群的结构，恢复生态平衡，并显著提高丁酸盐水平，这一过程与降低顺铂诱导的肾毒性密切相关。本研究旨在进一步探究由益生菌LCs促进的肠道中代谢物丁酸盐的升高是否能有效减轻顺铂对大鼠的肾毒性作用以及肾衰老的进程。结果表明，与顺铂组相比，给予丁酸盐能以剂量依赖的方式显著改善肾功能并减少肾纤维化。其作用与炎症反应的减少有关，关键炎症标志物水平降低证明了这一点，这些标志物包括KIM-1、MPO、NOX2、F4/80和TGF-β1，同时抗炎细胞因子IL-10的产生增加。此外，丁酸盐干预改善了顺铂诱导的肠道微生物群失调，保留了健康微生物群落的结构和多样性。具体而言，我们观察到大肠杆菌-志贺氏菌属和布劳特氏菌属的丰度降低，同时产生丁酸盐的罗斯氏菌属的丰度增加。值得注意的是，大肠杆菌-志贺氏菌属与促炎因子MPO呈正相关，而与抗炎细胞因子IL-10呈负相关。丁酸盐还减弱了顺铂诱导的肾组织中衰老标志物p21和p16的表达。它减轻了顺铂增加的SV40 MES-13细胞中衰老相关β-半乳糖苷酶活性和活性氧的产生。这些结果表明，源自肠道微生物群的丁酸盐可能通过调节微生物群平衡和抗炎作用对顺铂诱导的肾损伤发挥保护作用。
