目的 探究基于腸道菌群的洛鉑抗結(jié)腸癌作用及增效策略，并探討其相關(guān)機(jī)制。方法 構(gòu)建基于熒光素酶標(biāo)記的結(jié)腸癌細(xì)胞Luci-CT26結(jié)腸癌原位移植瘤模型，尾iv洛鉑15 mg·kg^-1觀察其對(duì)小鼠瘤質(zhì)量、肝臟系數(shù)、脾臟系數(shù)的影響，并計(jì)算抑瘤率；廣譜抗生素復(fù)合物（ABX）聯(lián)合洛鉑干預(yù)觀察腸道菌群對(duì)于洛鉑抗結(jié)腸癌療效的影響；含鹽飲食（8% NaCl）聯(lián)合洛鉑觀察其對(duì)于洛鉑抗結(jié)腸癌療效的增效作用； 16S rRNA擴(kuò)增子測序聯(lián)合非目標(biāo)代謝組學(xué)分析挖掘含鹽飲食增強(qiáng)洛鉑療效的潛在機(jī)制。結(jié)果 ABX干預(yù)后可引起小鼠體質(zhì)量明顯下降，并引起小鼠死亡；與洛鉑及ABX組比較，ABX-洛鉑組腫瘤質(zhì)量顯著下降（P＜0.05、0.01）；洛鉑單藥治療結(jié)腸癌原位移植瘤藥效有限，其腫瘤抑制率僅為27.22%，但洛鉑聯(lián)合ABX后，其腫瘤抑制率上升至44.57%，顯著高于洛鉑組和ABX組（P＜0.05、0.01）；洛鉑及ABX干預(yù)均不影響小鼠肝臟系數(shù)；與模型組比較，洛鉑組脾臟系數(shù)顯著降低（P＜0.01）；與ABX組比較，ABX-洛鉑組脾臟系數(shù)顯著降低（P＜0.01）。含鹽飲食聯(lián)合洛鉑后，可將其抗腫瘤抑制率從24.59%提升至44.27%，并具有統(tǒng)計(jì)學(xué)差異（P＜0.05），且鹽的攝入并未影響小鼠體質(zhì)量，并未引起小鼠死亡；洛鉑及含鹽飲食干預(yù)均不影響小鼠肝臟系數(shù)，與模型組比較，洛鉑組脾臟系數(shù)顯著降低（P＜0.01）；與含鹽飲食組比較，含鹽飲食聯(lián)合洛鉑組脾臟系數(shù)顯著降低（P＜0.001）。16S rRNA和代謝組學(xué)分析結(jié)果顯示鹽的攝入可顯著上調(diào)小鼠糞便中Bacteroides vulgatus、Helicobacter typhlonius的相對(duì)豐度（P＜0.05），顯著下調(diào)Acinetobacterradioresistens、Clostridium sp Clone-44、Lachnospiraceae bacterium COE1、Eubacterium sp 14-2、Lactobacillus johnsonii的相對(duì)豐度（P＜0.05），同時(shí)短肽、肉堿、膽汁酸、脂肪酸等代謝物的相對(duì)水平顯著變化。結(jié)論 鹽的攝入可能通過調(diào)節(jié)腸道菌群代謝增強(qiáng)洛鉑的抗結(jié)腸癌療效。

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

國家自然科學(xué)基金資助項(xiàng)目（82204416）；武漢市知識(shí)創(chuàng)新專項(xiàng)曙光計(jì)劃項(xiàng)目（2023010201020448）