首页|Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol
Targeted inhibition of Gus-expressing Enterococcus faecalis to promote intestinal stem cell and epithelial renovation contributes to the relief of irinotecan chemotoxicity by dehydrodiisoeugenol
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
万方数据
维普
Irinotecan(CPT11)chemotherapy-induced diarrhea affects a substantial cancer population due to β-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 discov-ered that dehydrodiisoeugenol(DDIE),isolated from nutmeg,alleviates CPT11-induced intestinal muco-sitis 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 coun-ters 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.fae-calis 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.
The MOE Key Laboratory of Standardization of Chinese Medicines,Shanghai Key Laboratory of Compound Chinese Medicines,and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China
Centre for Chinese Herbal Medicine Drug Development Limited,Hong Kong Baptist University,Hong Kong SAR 999077,China
Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201210,China
万方数据
维普
