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...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 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 bacteriaehosteirinotecan axis’as a promising target for mitigating CPT11 chemotoxicity.展开更多
基金supported by the National Natural Science Foundation of China(No.82274329,82304991,82130115)the China Postdoctoral Science Foundation(No.2023M732336)the Shanghai Science and Technology Committee Sailing Program Foundation(No.23YF1442500,China).
文摘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 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 bacteriaehosteirinotecan axis’as a promising target for mitigating CPT11 chemotoxicity.
