Probiotics Complex Synergizes with FOLFOX to Enhance Antitumor Response and Ameliorate Chemotherapy-induced Intestinal Toxicity via Upregulation of NAD+ Metabolism

Modulating the gut microbiota can improve chemotherapy efficacy, but strategies that simultaneously reduce toxicity and enhance therapeutic outcomes remain understudied. This study developed a NAD⁺-enhanced composite probiotic formulation (derived from fermented yak milk from the Qinghai-Tibet Plateau) to alleviate FOLFOX-induced intestinal toxicity and enhance efficacy in a colitis-associated colorectal cancer (CAC) mouse model. Metabolomics revealed significant contributions of nicotinic acid and nicotinamide metabolism to the body's response to chemotherapy. Consequently, RNA-seq was employed to validate the criticality of nicotinamide metabolism at the gene expression level: probiotics counteracted FOLFOX-induced NAD⁺ depletion, restored SIRT1/3 activity, and suppressed FoxO3a-mediated chemotherapy resistance. A clinical cohort of 53 gastrointestinal cancer patients confirmed serum NAD⁺ levels correlate with gut microbiota and intestinal toxicity. Collectively, we propose a microbiota-targeting strategy synergizing with FOLFOX, providing a translatable paradigm for precision oncology.