Induction and Amelioration of Methotrexate-Induced Gastrointestinal Toxicity are Related to Immune Response and Gut MicrobiotaResearch in context
Bailing Zhou,
Xuyang Xia,
Peiqi Wang,
Shuang Chen,
Chaoheng Yu,
Rong Huang,
Rui Zhang,
Yantai Wang,
Lian Lu,
Fengjiao Yuan,
Yaomei Tian,
Yingzi Fan,
Xueyan Zhang,
Yang Shu,
Shouyue Zhang,
Ding Bai,
Lei Wu,
Heng Xu,
Li Yang
Affiliations
Bailing Zhou
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Xuyang Xia
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine and Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Sichuan, China
Peiqi Wang
State Key laboratory of Oral diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University and Collaborative Innovation Center, Chengdu, China
Shuang Chen
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Chaoheng Yu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Rong Huang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Rui Zhang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Yantai Wang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Lian Lu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Fengjiao Yuan
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Yaomei Tian
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Yingzi Fan
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Xueyan Zhang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Yang Shu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine and Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Sichuan, China
Shouyue Zhang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine and Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Sichuan, China
Ding Bai
State Key laboratory of Oral diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University and Collaborative Innovation Center, Chengdu, China
Lei Wu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
Heng Xu
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Department of Laboratory Medicine, Research Center of Clinical Laboratory Medicine and Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Sichuan, China; Corresponding authors at: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 17, South Renmin Road, Chengdu, Sichuan 610041, China.
Li Yang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China; Corresponding authors at: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 17, South Renmin Road, Chengdu, Sichuan 610041, China.
As a widely used anticancer and immunosuppressive agent, methotrexate (MTX) can induce multiple adverse drug reactions (ADRs), such as gastrointestinal toxicity, the mechanisms are poorly understood. Gut microbiota has been widely reported to be associated with the onset of multiple diseases as well as treatment outcomes of different drugs. In this study, mucosal injury was observed in MTX-treated mice, leading to significant changes in macrophages (i.e., M1/M2 ratio, P < 0.05) but not in dendritic cells. Moreover, the population, diversity and principal components of the gut microbiota in mice were dramatically altered after MTX treatment in a time-dependent manner, and Bacteroidales exhibited the most distinct variation among all the taxa (P < 0.05). Bacteroides fragilis was significantly decreased with MTX treatment (P < 0.01) and tended to decrease proportionately with increasing macrophage density. Gavage of mice with B. fragilis ameliorated MTX-induced inflammatory reactions and modulate macrophage polarization. In conclusion, our results delineate a strong impact of the gut microbiota on MTX-induced intestinal mucositis and provide a potential method for the prevention of such ADRs. Keywords: Methotrexate, Gastrointestinal toxicity, Gut microbiota, Mononuclear phagocyte
