Fasting-mimicking diet-enriched <i>Bifidobacterium pseudolongum</i> suppresses colorectal cancer by inducing memory CD8⁺ T cells.

Abstract

Fasting-mimicking diet (FMD) boosts the antitumour immune response in patients with colorectal cancer (CRC). The gut microbiota is a key host immunity regulator, affecting physiological homeostasis and disease pathogenesis. We aimed to investigate how FMD protects against CRC via gut microbiota modulation. We assessed probiotic species enrichment in FMD-treated CRC mice using faecal metagenomic sequencing. The candidate species were verified in antibiotic-treated conventional and germ-free mouse models. Immune landscape alterations were evaluated using single-cell RNA sequencing and multicolour flow cytometry. The microbiota-derived antitumour metabolites were identified using metabolomic profiling. Faecal metagenomic profiling revealed <i>Bifidobacterium pseudolongum</i> enrichment in FMD-treated CRC mice. <i>B. pseudolongum</i> mediates the FMD antitumour effects by increasing the tissue-resident memory CD8⁺ T-cell (TRM) population in CRC mice. The level of L-arginine, a <i>B. pseudolongum</i> functional metabolite, increased in FMD-treated CRC mice; furthermore, L-arginine induced the TRM phenotype in vivo and in vitro. Mechanistically, L-arginine is transported by the solute carrier family 7-member 1 (SLC7A1) receptor in CD8⁺ T cells. Both FMD and <i>B. pseudolongum</i> improved anti-CTLA-4 efficacy in the orthotopic mouse CRC model. In FMD-treated patients with CRC, the CD8⁺ TRM cell number increased as <i>B. pseudolongum</i> and L-arginine accumulated. The abundance of CD8⁺ TRM cells and <i>B. pseudolongum</i> was associated with a better prognosis in patients with CRC. <i>B. pseudolongum</i> contributes to the FMD antitumour effects in CRC by producing L-arginine. This promotes CD8⁺ T-cell differentiation into memory cells. <i>B. pseudolongum</i> administration is a potential CRC therapeutic strategy.