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Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol

文献类型：期刊论文

作者Gao, Ruiyang3,4; Yue, Bei3,4; Lv, Cheng2; Geng, Xiaolong3,4; Yu, Zhilun3,4; Wang, Hao3,4; Zhang, Beibei3,4; Ai, Fangbin3,4; Wang, Ziyi3,4; Liu, Donghui3,4
刊名ACTA PHARMACEUTICA SINICA B
出版日期2024-12-01
卷号14期号:12页码:5286-5304
关键词Irinotecan Intestinal mucositis b-Glucuronidase Enterococcus faecalis Intestinal stem cells Epithelial regeneration bacteria-host irinotecan axis Dehydrodiisoeugenol
ISSN号2211-3835
DOI10.1016/j.apsb.2024.09.018
通讯作者Wang, Zhengtao(ztwang@shutcm.edu.cn) ; Chen, Kaixian(kxchen@simm.ac.cn) ; Dou, Wei(douwei@shutcm.edu.cn)
英文摘要Irinotecan (CPT11) chemotherapy-induced diarrhea affects a substantial cancer population due to b-glucuronidase (Gus) converting 10-O-glucuronyl-7-ethyl-10-hydroxycamptothecin (SN38G) to toxic 7-ethyl-10-hydroxycamptothecin (SN38). Existing interventions primarily address inflammation and Gus enzyme inhibition, neglecting epithelial repair and Gus-expressing bacteria. Herein, we discovered that dehydrodiisoeugenol (DDIE), isolated from nutmeg, alleviates CPT11-induced intestinal mucositis alongside a synergistic antitumor effect with CPT11 by improving weight loss, colon shortening, epithelial barrier dysfunction, goblet cells and intestinal stem cells (ISCs) loss, and wound-healing. The anti-mucositis effect of DDIE is gut microbiota-dependent. Analysis of microbiome profiling data from clinical patients and CPT11-induced mucositis mice reveals a strong correlation between CPT11 chemotoxicity and Gus-expressing bacteria, particularly Enterococcus faecalis (E. faecalis). DDIE counters CPT11-induced augmentation of E. faecalis, leading to decreased intestinal Gus and SN38 levels. The Partial Least Squares Path Model (PLS-PM) algorithm initially links E. faecalis to dysregulated epithelial renovation. This is further validated in a 3D intestinal organoid model, in which both SN38 and E. faecalis hinder the formation and differentiation of organoids. Interestingly, colonization of E. faecalis exacerbates CPT11-induced mucositis and disturbs epithelial differentiation. Our study unveils a microbiota-driven, epithelial reconstruction-mediated action of DDIE against mucositis, proposing the 'Gus bacteria-host-irinotecan axis' as a promising target for mitigating CPT11 chemotoxicity.
WOS关键词BETA-GLUCURONIDASE ; DRUG ; AMOXAPINE ; TOXICITY
资助项目National Natural Science Foundation of China[82274329] ; National Natural Science Foundation of China[82304991] ; National Natural Science Foundation of China[82130115] ; China Postdoctoral Science Foundation[2023M732336] ; Shanghai Science and Technology Committee Sailing Program Foundation[23YF1442500]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001390939600001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/315579]  
专题中国科学院上海药物研究所
通讯作者Wang, Zhengtao; Chen, Kaixian; Dou, Wei
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201210, Peoples R China
2.Hong Kong Baptist Univ, Ctr Chinese Herbal Med Drug Dev Ltd, Hong Kong 999077, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Inst Chinese Mat Med, SATCM Key Lab New Resources & Qual Evaluat Chinese, Shanghai 201203, Peoples R China
4.Shanghai Univ Tradit Chinese Med, MOE Key Lab Standardizat Chinese Med, Shanghai Key Lab Cpd Chinese Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Ruiyang,Yue, Bei,Lv, Cheng,et al. Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol[J]. ACTA PHARMACEUTICA SINICA B,2024,14(12):5286-5304.
APA Gao, Ruiyang.,Yue, Bei.,Lv, Cheng.,Geng, Xiaolong.,Yu, Zhilun.,...&Dou, Wei.(2024).Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol.ACTA PHARMACEUTICA SINICA B,14(12),5286-5304.
MLA Gao, Ruiyang,et al."Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol".ACTA PHARMACEUTICA SINICA B 14.12(2024):5286-5304.

入库方式： OAI收割

来源：上海药物研究所

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