肠道微生物群驱动的代谢改变揭示了化疗诱发胃癌恶病质的独特致病性

IF 9.1 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Jian Wu , Ruijuan Zhang , Zhonghua Yin , Xu Chen , Runwen Mao , Xiaoxia Zheng , Mengyun Yuan , Huaizhi Li , Yujia Lu , Shenlin Liu , Xuejiao Gao , Qingmin Sun
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引用次数: 0

摘要

大约 50-80% 的晚期癌症患者会出现恶病质,尤其是胃癌患者。因此,早期发现恶病质对防止其恶化至关重要。针对肠道微生物群可能是预防和治疗胃癌患者恶病质的一种有希望的方法。化疗会明显降低 GC 患者肠道微生物群的多样性。具体来说,化疗后患者肠道中的乳酸菌属、链球菌属和普雷沃特菌属等细菌的丰度增加,这与恶病质的发生密切相关。血清代谢分析表明,化疗诱导的癌症恶病质患者体内的特定微生物与代谢物之间存在密切联系。我们进一步根据丰度排名前 6 位的菌属构建了一个随机森林模型,用于预测化疗相关 GC 恶病质的发生;该模型的接收者操作特征曲线下面积 (AUC) 为 93.5 % [95 % 置信区间 (CI),86.6 %-100 %],特异性和准确性均高于 75 %。此外,我们还发现肠毒素脆弱拟杆菌(ETBF)是化疗诱发 GC 恶病质的关键因素。在一个体内 GC 模型中,ETBF 在小鼠肠道中的定植明显加速了化疗诱导的肌肉和脂肪组织消耗,从而导致恶病质症状。此外,ETBF 还通过破坏细胞连接和吸引 M1 巨噬细胞来破坏肠粘膜屏障,从而加剧 GC 恶病质。总之,我们的研究结果表明,肠道微生物群失衡是导致 GC 恶病质的关键因素,这为早期诊断提供了潜在的生物标志物。临床试验注册:http://www.chictr.org.cn,鉴定号:ChiCTR2200064547
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Gut microbiota-driven metabolic alterations reveal the distinct pathogenicity of chemotherapy-induced cachexia in gastric cancer
Cachexia affects approximately 50–80 % of advanced cancer patients, particularly those with gastric cancer (GC). Therefore, early detection of cachexia is essential to prevent its progression. Targeting the gut microbiota may be a promising approach for preventing and treating cachexia in patients with GC. Chemotherapy significantly reduced gut microbiota diversity in GC patients. Specifically, the abundance of bacterial genera such as Bacteroides, Streptococcus, and Prevotella was increased in the gut of patients postchemotherapy, which was closely associated with the development of cachexia. Serum metabolic analysis revealed a strong link between specific microbes and metabolite in patients with chemotherapy-induced GC cachexia. We further constructed a random forest model based on the top 6 genera in terms of abundance for the prediction of chemotherapy-related GC cachexia development; this model had an area under the receiver operating characteristic curve (AUC) of 93.5 % [95 % confidence interval (CI), 86.6 %-100 %], with a specificity and accuracy above 75 %. Additionally, we identified Enterotoxin Bacteroides fragilis (ETBF) as a key factor in chemotherapy-induced GC cachexia. In an in vivo GC model, the colonization of ETBF in the intestines of mice significantly accelerated the muscle and adipose tissue consumption induced by chemotherapy, resulting in cachexia symptoms. Furthermore, ETBF damaged the intestinal mucosal barrier by disrupting cell connections and attracting M1 macrophages, which advances GC cachexia. In conclusion, our findings indicate that gut microbiota imbalance is crucial in GC cachexia development, suggesting potential biomarkers for early diagnosis. Clinical trial registration: http://www.chictr.org.cn, Identification No: ChiCTR2200064547
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来源期刊
Pharmacological research
Pharmacological research 医学-药学
CiteScore
18.70
自引率
3.20%
发文量
491
审稿时长
8 days
期刊介绍: Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.
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