Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Cell Infect Microbiol. 2017 Oct 26;7:455. doi: 10.3389/fcimb.2017.00455. eCollection 2017.
Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.
肠道微生物群的稳态失衡已被认为与 5-氟尿嘧啶（5-Fu）诱导的黏膜炎密切相关。然而，目前对 5-Fu 扰乱肠道微生物群的整体概况了解有限，到目前为止，还没有直接令人信服的证据证明 5-Fu 扰乱的微生物群与结肠黏膜炎之间存在因果关系。在小鼠中，与先前的报道一致，5-Fu 导致严重的结肠黏膜炎，表现为体重减轻、腹泻、血便、结肠缩短和炎症细胞浸润。它显著改变了血清和结肠中炎症细胞因子/趋化因子的谱。黏附分子如血管细胞黏附分子-1（VCAM-1）、细胞间黏附分子-1（ICAM-1）和 VE-钙黏蛋白增加。而紧密连接蛋白闭合蛋白减少，但在 5-Fu 处理的小鼠结肠组织中，闭合蛋白-1（ZO-1）和连接黏附分子-A（JAM-A）增加。同时，结肠中炎症相关信号通路，包括 NF-κB 和丝裂原激活蛋白激酶（MAPKs）被激活。进一步的研究表明，5-Fu 降低了细菌群落的丰富度和多样性，导致粪便和盲肠内容物中厚壁菌门和拟杆菌门（F/B）比值相对较低。5-Fu 还降低了变形菌门、梭杆菌门、蓝藻门和候选分类 TM7 的比例，但增加了粪便和/或盲肠内容物中疣微菌门和放线菌门的比例。来自健康小鼠的粪便移植可预防 5-Fu 处理小鼠的体重减轻和结肠缩短。此外，来自 5-Fu 处理小鼠的粪便移植可降低万古霉素预处理小鼠的体重和结肠长度。总之，我们的研究表明，肠道微生物群积极参与 5-Fu 诱导的肠道黏膜炎的病理过程，提示通过操纵肠道微生物群的稳态可能减轻 5-Fu 诱导的肠道黏膜炎。
