<i>Bifidobacterium animalis</i> subsp. <i>lactis</i> V9 Improves Quality of Life in Advanced Gastrointestinal Cancer Through Gut Microbiota-Metabolite Modulation

Abstract Chemotherapy for advanced gastric and esophageal cancer is often limited by severe gastrointestinal and systemic toxicities that profoundly impair patients’ quality of life. We conducted a randomized, double-blind, placebo-controlled trial in 104 patients to evaluate whether Bifidobacterium animalis subsp. lactis V9 (V9; 2 × 1010 CFU/day) mitigates these effects. Participants received V9 or placebo daily for 18 weeks alongside standard chemotherapy. Supplementation with V9 significantly improved EORTC QLQ-C30 scores for overall health status, fatigue, nausea, vomiting, appetite loss, cognitive functioning, role functioning, and insomnia (all P &amp;lt; 0.01). Integrated metagenomic and metabolomic analyses of stool samples revealed that V9 did not alter overall microbial α- or β-diversity but induced targeted shifts: it enriched beneficial taxa, such as Bifidobacterium pseudocatenulatum, Agathobacter rectalis, and Lachnospira hominis, while depleting pathobionts such as Fusobacterium varium and Enterocloster clostridioformis. These microbial changes correlated with favorable metabolic reprogramming, including increased fecal levels of pyridoxamine, 5’-methylthioadenosine, and palmitoylcarnitine, as well as decreased levels of taurine-conjugated bile acids and several amino acids (P &amp;lt; 0.05). Critically, these metabolite alterations were significantly associated with clinical improvements. Our findings demonstrate that V9 enhances quality of life during chemotherapy not through global microbiota restructuring, but via precise modulation of functionally relevant bacteria and their metabolic outputs. This supports V9 as a mechanistically grounded, targeted adjuvant therapy to improve resilience and well-being in patients with advanced upper gastrointestinal cancers.