Abstract
Gefitinib improves outcomes in patients with EGFR-mutant non-small cell lung cancer; however, treatment-related gastrointestinal and hepatic toxicity can limit its long-term use. Here, we investigate whether probiotic strains can improve gefitinib efficacy while reducing treatment-associated toxicity. Among the tested strains, Lacticaseibacillus rhamnosus GG (LGG) shows the strongest enhancement of gefitinib efficacy while reducing intestinal and hepatic injury without altering systemic gefitinib exposure. Metabolomic analyses identify propionyl-L-carnitine as an LGG-associated metabolite detected in both LGG culture and LGG-treated mice. Propionyl-L-carnitine treatment reproduces the antitumor effects of LGG and is associated with altered mitochondrial metabolism, decreased NF-κB/IL-6 signaling, and increased apoptosis. A gut-liver-tumor organ-on-a-chip model further supports these effects. LGG treatment also improves short-chain fatty acid profiles, intestinal barrier markers, and bile acid-related metabolism. Together, these findings suggest that LGG may represent a microbiota-based strategy to enhance gefitinib response while limiting treatment-associated toxicity.