Fasting-mimicking diet-enriched Bifidobacterium pseudolongum suppresses colorectal cancer by inducing memory CD8+ T cells

Abstract

Background: 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.

Objective: We aimed to investigate how FMD protects against CRC via gut microbiota modulation.

Design: 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.

Results: Faecal metagenomic profiling revealed Bifidobacterium pseudolongum enrichment in FMD-treated CRC mice. B. pseudolongum 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 B. pseudolongum 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 B. pseudolongum improved anti-CTLA-4 efficacy in the orthotopic mouse CRC model. In FMD-treated patients with CRC, the CD8⁺ TRM cell number increased as B. pseudolongum and L-arginine accumulated. The abundance of CD8⁺ TRM cells and B. pseudolongum was associated with a better prognosis in patients with CRC.

Conclusion: B. pseudolongum contributes to the FMD antitumour effects in CRC by producing L-arginine. This promotes CD8⁺ T-cell differentiation into memory cells. B. pseudolongum administration is a potential CRC therapeutic strategy.

Keywords: COLONIC MICROFLORA; COLORECTAL CANCER; IMMUNOTHERAPY.