Fusobacterium nucleatum Infection Drives Glutathione Depletion in Gastric Cancer: Integrated Multi-Omics and...

The colonization of Fusobacterium nucleatum (F. nucleatum) in the microenvironment of gastric cancer (GC) is closely associated with tumor progression, but its impact on host metabolic remodeling remains unclear. This study aims to elucidate the mechanistic link between F. nucleatum infection and metabolic changes in GC tissue. By integrating 16S rRNA microbiome sequencing and LC-MS/MS metabolomics, the differences in microbial composition and metabolic profiles between Fusobacterium sp.-positive and -negative GC tissues were systematically compared, and the correlation of differential microbes and differential metabolites was analyzed. The impact of F. nucleatum on the glutathione (GSH) metabolic pathway was validated through in vitro tissue testing and the use of the infection model of GC cell lines (such as AGS and HGC27). Integrative omics analysis showed a strong negative correlation between Fusobacterium sp. infection and antioxidant metabolite GSH levels in GCs (p < 0.001). Metabolic reprogramming features: Eleven differentially expressed metabolites were identified using LC-MS/MS metabolomics screening (p < 0.05). GSH was significantly depleted in the Fusobacterium sp.-positive group. Experimental validation: At the histological level, the abundance of F. nucleatum in GC tissues was higher than that in the paired adjacent non-cancerous (NC) tissues; at the cellular level, after F. nucleatum infection of GC cells, the intracellular GSH level decreased (p < 0.01), accompanied by a decrease in glutathione synthetase (GSS) mRNA expression and reactive oxygen species (ROS). This study is the first to demonstrate that F. nucleatum suppresses the GSH synthesis pathway, leading to the breakdown of antioxidant capacity and the formation of an oxidative stress microenvironment in GC cells. These findings provide new insights into the metabolic mechanism of F. nucleatum in promoting GC progression and suggest that targeting the F. nucleatum-GSH axis could offer a novel strategy for GC therapeutic intervention.