Abstract

Lactobacillus johnsonii ( LJ ) has demonstrated therapeutic potential in various human diseases, but its direct impact on colorectal cancer (CRC) remains unclear. This study evaluated the prophylactic and therapeutic effects of LJ on colorectal tumors using AOM/DSS-induced CRC models and MC38 syngeneic tumor models. Gut microbiome/metabolomic and tumor transcriptomic analyses identified candidate metabolites and molecular targets, which were further validated in microbiota-depleted mice, normal human intestinal epithelial cells, and CRC cell lines. LJ treatment activated tumor necrosis factor (TNF)-related signaling and upregulated apoptosis-associated gene sets in tumor tissues. Mechanistic investigations showed that LJ treatment was associated with increased intestinal statine (STA) abundance, whereas exogenous STA upregulated CCL5 expression, induced tumor cell apoptosis, and slowed tumor progression. These findings suggest that intestinal STA may serve as a candidate mediator linking LJ -associated metabolic changes to CCL5-related tumor cell apoptosis. Thus, LJ shows potential as a prophylactic and adjunctive therapeutic strategy for CRC management.