Bacteroides intestinalis mediates the sensitivity to irinotecan toxicity via tryptophan catabolites

作者：Yuanlong Hou, Hao Wu, Zhuangyi Zhang, Jie Wang, Qifan Chen, Chun‐Ang Lian, Dandan He, Ziguang Li, Wei Wei, Xin Lin, Daming Sun, Baoshan Cao, Ting Xu, Min Cai, Guangji Wang, Xueli Zhang, Liping Duan, Haiping Hao, Xiao Zheng · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2024-334699 · 被引用次数：8 · 研究领域：Cancer therapeutics and mechanisms、Cancer Research and Treatments、Gut microbiota and health

Background Late-onset diarrhoea remains a poorly managed concern for clinical irinotecan therapy. Although bacterial β-glucuronidases (β-GUS) mediated SN-38 production is prevailingly thought to mediate intestinal toxicity, β-GUS inhibitors confer limited benefits in the clinic. Objective This study aimed to explore the role and mechanism of endogenous bacterial metabolites in susceptibility to irinotecan toxicity. Design Gut microbiota profiles and metabolites in patients with colorectal cancer (CRC) with or without diarrhoea were investigated via 16S rRNA sequencing, shotgun metagenomics and metabolomics. The role of microbial metabolites was investigated in mice by metabolic bioengineering and intestinal organoid culture. The mechanism of microbial metabolites on intestinal stem cells was investigated by transcriptional profiling and chemical intervention. Results Gut microbial configuration was differentially remodelled in diarrhoea and non-diarrhoea patients with irinotecan therapy, and the susceptibility was transmissible to recipient mice via transplantation of baseline faecal microbiome. Bacteroides intestinalis ( B. intestinalis ) was notably expanded in the diarrhoea-prone cohorts as well as in irinotecan-treated mice. B. intestinalis colonisation sensitised intestinal epithelia to irinotecan-induced chemical injury, partially via tryptophan metabolite indole-3-acetate (IAA). Both B. intestinalis and bioengineered bacteria that produce IAA exacerbated irinotecan-ind...