Butyrate-producing Eubacterium rectale inhibits gastric carcinogenesis and augments the efficacy of immunotherapy

Immunotherapy has transformed gastric cancer (GC) treatment, but therapeutic resistance remains a major limitation. Recent evidence suggests that the gut microbiota can modulate anti-tumor immunity and enhance immunotherapy response, offering a promising avenue to overcome resistance. Using a prospective GC cohort, we identified Eubacterium rectale (E. rectale) as a bacterium associated with improved efficacy of tislelizumab plus chemotherapy and longer progression-free survival (PFS). We then conducted in vitro and in vivo experiments to evaluate the effects of E. rectale and its metabolite butyrate on tumor growth, apoptosis, PD-L1 expression, and CD8+ T-cell infiltration. Targeted metabolomics was performed on gut, serum, and tumor samples to assess compartment-specific distribution of short-chain fatty acids (SCFAs). E. rectale and butyrate significantly inhibited tumor growth, promoted apoptosis, downregulated PD-L1 expression, and increased CD8+ T-cell infiltration in mouse models. Metabolomic analysis revealed that SCFAs exert antitumor effects primarily within the gut, despite cross-compartment diffusion. Furthermore, administration of E. rectale or butyrate led to adaptive remodeling of the gut microbiota network, characterized by a shift toward deterministic assembly processes. Our study demonstrates that E. rectale and butyrate enhance antitumor immunity and may help overcome immunotherapy resistance in GC. These findings support a novel therapeutic strategy of combining E. rectale or butyrate with immunotherapy to improve treatment outcomes in GC.