Pterostilbene inhibits Gus-expressing microbiota that relieves irinotecan induced enterotoxicity in mice model

: The clinical use of irinotecan (CPT-11), a first-line chemotherapeutic agent for solid tumors, is severely compromised by the side effect of diarrhea and enterotoxicity. This toxicity is largely driven by the reactivation of the metabolite SN-38G to cytotoxic SN-38 by bacterial β-glucuronidases (GUS) in the gut. In this study, we investigated the protective effects of Pterostilbene (PTE), a natural active compound extracted from blueberry and grape, against CPT-11-induced intestinal injury in mice. We found that oral administration of PTE significantly alleviated CPT-11-induced weight loss, diarrhea, and colonic pathological damage. PTE treatment preserved the integrity of the intestinal mucosal barrier as restoring tight junction proteins and preventing goblet cell depletion, while concurrently suppressing pro-inflammatory cytokines. Metagenomic sequencing and functional assays revealed that PTE administration partially restores gut microbial homeostasis, most notably by significantly reducing the abundance and activity of GUS-expressing bacteria such as Enterococcus faecalis . Furthermore, PTE exerted direct inhibitory activity against Enterococcus faecalis both in vitro and in vivo , thereby significantly reducing the intestinal accumulation of the toxic metabolite SN-38. Importantly, PTE mitigated enterotoxicity without compromising the anti-tumor efficacy of CPT-11 in a colorectal cancer xenograft model. Collectively, our findings suggest that PTE represents a natural functional food ingredient to enhance the tolerability of irinotecan-based chemotherapy.