Bacteroides intestinalis mediates the sensitivity to irinotecan toxicity via tryptophan catabolites

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: 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: and bioengineered bacteria that produce IAA exacerbated irinotecan-induced intestinal epithelial injury in mice. Mechanistically, IAA suppressed PI3K-Akt signalling, thereby impairing the renewal of intestinal epithelia under the insult of irinotecan. In clinical patients receiving irinotecan therapy, faecal IAA level was closely associated with the diarrhoea severity. CONCLUSION: Our study uncovers the mechanism of endogenous bacterial metabolite in shaping the individual susceptibility to irinotecan toxicity and suggests IAA as a potential predictive biomarker.