A microbiota-dependent gut bile acid axis links germline mutant p53 to distal tumour growth.

Abstract

The gut microbiome can influence cancer development, but its contribution to cancer predisposition in Li-Fraumeni Syndrome (LFS) remains poorly understood. Here, we investigated whether germline mutant p53 alters the intestinal environment using Trp53R172H/+ mice. Tumour-naive mutant mice exhibited increased intestinal permeability and a pro-inflammatory colonic phenotype, including elevated inflammatory cytokines and enhanced NF-{kappa}B signalling. Untargeted metabolomic profiling revealed a striking alteration in bile acid metabolism, with targeted analysis identifying increases in multiple primary and microbiota-derived secondary bile acids. Notably, these changes occurred despite no detectable differences in overall microbial community composition, suggesting altered host-microbial metabolic output in the absence of broad compositional change. Several faecal bile acids were positively associated with distal tumour burden, with the microbiota-derived secondary bile acid deoxycholic acid (DCA) showing the strongest relationship. Microbiota depletion reduced distal tumour growth in mutant mice and attenuated intestinal barrier dysfunction, colonic inflammation and the altered faecal bile acid profile, including DCA. Conversely, transfer of cell-free faecal filtrate from mutant donors to WT recipients induced colonic inflammation and enhanced distal tumour growth. Together, these findings identify a mutant p53-gut axis in which germline mutant p53 establishes a microbiota-shaped metabolic and inflammatory intestinal environment capable of promoting tumour growth beyond the gut.