Lactobacillus johnsonii metabolites D-cycloserine inhibit colorectal tumors by suppressing inflammation and promoting tumor apoptosis

Lactobacillus johnsonii (LJ) has demonstrated therapeutic potential in various human diseases, but its prophylactic and therapeutic effects of LJ and its metabolites on colorectal tumors using comprehensive experimental models. Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse models of CRC and subcutaneous tumor mouse models were employed to assess the effects of LJ. Metagenomic, transcriptomic, and metabolomic analyses identified key metabolites and molecular targets, which were validated in AOM/DSS-induced antibiotic-treated (ABX) mouse models, MC38 xenografts, normal human intestinal epithelial cell lines, and CRC cell lines. LJ treatment significantly alleviated intestinal inflammation, enhanced tumor necrosis factor (TNF) signaling pathways, and up-regulated apoptotic gene sets in tumor tissues. Mechanistic investigations revealed that LJ inhibited the NLRP3-Caspase-1-GSDMD signaling pathway through its metabolite D-cycloserine (DC), suppressing inflammation and tumorigenesis. Additionally, the metabolite STA increased CCL5 expression, induced apoptosis in tumor cells, and slowed tumor progression. These findings highlight the dual anti-inflammatory and pro-apoptotic mechanisms of LJ and its metabolites, DC and STA, in mitigating CRC development and progression. Thus, LJ shows considerable potential as a prophylactic and adjunctive therapeutic strategy for CRC management.