目的 探究基于肠道菌群的洛铂抗结肠癌作用及增效策略，并探讨其相关机制。方法 构建基于荧光素酶标记的结肠癌细胞Luci-CT26结肠癌原位移植瘤模型，尾iv洛铂15 mg·kg^-1观察其对小鼠瘤质量、肝脏系数、脾脏系数的影响，并计算抑瘤率；广谱抗生素复合物（ABX）联合洛铂干预观察肠道菌群对于洛铂抗结肠癌疗效的影响；含盐饮食（8% NaCl）联合洛铂观察其对于洛铂抗结肠癌疗效的增效作用； 16S rRNA扩增子测序联合非目标代谢组学分析挖掘含盐饮食增强洛铂疗效的潜在机制。结果 ABX干预后可引起小鼠体质量明显下降，并引起小鼠死亡；与洛铂及ABX组比较，ABX-洛铂组肿瘤质量显著下降（P＜0.05、0.01）；洛铂单药治疗结肠癌原位移植瘤药效有限，其肿瘤抑制率仅为27.22%，但洛铂联合ABX后，其肿瘤抑制率上升至44.57%，显著高于洛铂组和ABX组（P＜0.05、0.01）；洛铂及ABX干预均不影响小鼠肝脏系数；与模型组比较，洛铂组脾脏系数显著降低（P＜0.01）；与ABX组比较，ABX-洛铂组脾脏系数显著降低（P＜0.01）。含盐饮食联合洛铂后，可将其抗肿瘤抑制率从24.59%提升至44.27%，并具有统计学差异（P＜0.05），且盐的摄入并未影响小鼠体质量，并未引起小鼠死亡；洛铂及含盐饮食干预均不影响小鼠肝脏系数，与模型组比较，洛铂组脾脏系数显著降低（P＜0.01）；与含盐饮食组比较，含盐饮食联合洛铂组脾脏系数显著降低（P＜0.001）。16S rRNA和代谢组学分析结果显示盐的摄入可显著上调小鼠粪便中Bacteroides vulgatus、Helicobacter typhlonius的相对丰度（P＜0.05），显著下调Acinetobacterradioresistens、Clostridium sp Clone-44、Lachnospiraceae bacterium COE1、Eubacterium sp 14-2、Lactobacillus johnsonii的相对丰度（P＜0.05），同时短肽、肉碱、胆汁酸、脂肪酸等代谢物的相对水平显著变化。结论 盐的摄入可能通过调节肠道菌群代谢增强洛铂的抗结肠癌疗效。

Objective To evaluate the anti-colon cancer effect of lobaplatin, and explore the gut microbiota based strategy to increase its efficacy. Methods A luciferase-labeled colon cancer cell line Luci-CT26 orthotopic transplantation tumor model was established. The effects of intravenous injection of lobaplatin at 15 mg·kg^-1 on tumor weight, liver coefficient and spleen coefficient in mice were examined, and the tumor inhibition rate was calculated. The effects of broad-spectrum antibiotic complex (ABX) combined with lobaplatin on the anti-colon cancer efficacy of lobaplatin were investigated. The synergistic effect of a high-salt diet (8% NaCl) combined with lobaplatin on the anti-colon cancer efficacy of lobaplatin was examined. 16s rRNA amplicon sequencing and nontargeted metabolomics analysis were used to explore the potential mechanism of the enhanced efficacy of lobaplatin by a high-salt diet. Results ABX intervention caused a significant decrease in body weight and death in mice. Compared with the lobaplatin and ABX groups, the tumor weight in the ABX-lobaplatin group was significantly reduced (P <0.05, 0.01). The anti-tumor efficacy of lobaplatin alone in the orthotopic transplantation tumor model was limited, with a tumor inhibition rate of only 27.22%. However, the tumor inhibition rate increased to 44.57% after the combination of lobaplatin and ABX, which was significantly higher than that of the lobaplatin and ABX groups (P <0.05, 0.01). Lobaplatin and ABX intervention did not affect the liver coefficient in mice. Compared with the model group, the spleen coefficient in the lobaplatin group was significantly reduced (P <0.01). Compared with the ABX group, the spleen coefficient in the ABX-lobaplatin group was significantly reduced (P <0.01). After the combination of a high-salt diet and lobaplatin, the tumor inhibition rate increased from 24.59% to 44.27%, with a statistically significant difference (P <0.05). The intake of salt did not affect the body weight of mice and did not cause death. Lobaplatin and high-salt diet intervention did not affect the liver coefficient in mice. Compared with the model group, the spleen coefficient in the lobaplatin group was significantly reduced (P <0.01). Compared with the high-salt diet group, the spleen coefficient in the high-salt diet-lobaplatin group was significantly reduced (P <0.001). 16s rRNA and metabolomics analysis showed that the intake of salt significantly increased the relative abundance of Bacteroides vulgatus, and Helicobacter typhlonius in mouse feces (P < 0.05), and significantly decreased the relative abundance of Acinetobacter radioresistens, Clostridium sp Clone-44, Lachnospiraceae bacterium COE1, Eubacterium sp 14-2, and Lactobacillus johnsonii (P <0.05). At the same time, the relative levels of short peptides, carnitine, bile acids, and fatty acids were significantly changed. Conclusion The intake of salt may enhance the anti-colon cancer efficacy of lobaplatin by regulating the metabolism of gut microbiota.

R965

国家自然科学基金资助项目（82204416）；武汉市知识创新专项曙光计划项目（2023010201020448）