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

Ruiyang Gao; Bei Yue; Cheng Lv; Xiaolong Geng; Zhilun Yu; Hao Wang; Beibei Zhang; Fangbin Ai; Ziyi Wang; Donghui Liu; Zhengtao Wang; Kaixian Chen; Wei Dou

doi:10.1016/j.apsb.2024.09.018

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 Pharm Sin B. 2024 Dec;14(12):5286-5304. doi: 10.1016/j.apsb.2024.09.018. Epub 2024 Oct 18.

Authors

Ruiyang Gao¹, Bei Yue¹, Cheng Lv², Xiaolong Geng¹, Zhilun Yu¹, Hao Wang¹, Beibei Zhang¹, Fangbin Ai¹, Ziyi Wang¹, Donghui Liu¹, Zhengtao Wang¹, Kaixian Chen^{1

3}, Wei Dou¹

Affiliations

¹ 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.
² Centre for Chinese Herbal Medicine Drug Development Limited, Hong Kong Baptist University, Hong Kong SAR 999077, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China.

Abstract

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 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.

Keywords: Dehydrodiisoeugenol; Enterococcus faecalis; Epithelial regeneration; Gus bacteria–host–irinotecan axis; Intestinal mucositis; Intestinal stem cells; Irinotecan; β-Glucuronidase.