Regulation of the innate immune response and gut microbiome by p53

Area of Science:

• Oncology
• Microbiology
• Immunology

Background:

• The tumor suppressor p53 is frequently mutated in human cancers.
• p53 regulates diverse cellular functions beyond its canonical role.
• Its role in innate immunity and the gut microbiome is an emerging area of research.

Purpose of the Study:

• To investigate the role of p53 in innate immunity and its impact on gut microbiome composition and radiation response.
• To identify p53-regulated genes involved in innate immunity and gut barrier function.

Main Methods:

• Transcriptome analysis of irradiated mouse tissues.
• Gene Ontology (GO) enrichment analysis.
• 16S rRNA sequencing to analyze gut microbiome composition.
• Assessment of radiation-induced gastrointestinal (GI) toxicity and survival rates in p53-knockout and wild-type mice.
• Evaluation of antibiotic administration effects on survival and GI toxicity.
• Analysis of Mbl2 and Lcn2 expression in liver cancer tissues with and without p53 mutations.

Main Results:

• p53 markedly induces 553 genes, with innate immunity being a highly associated biological process.
• Akkermansia abundance decreased in p53-knockout mice post-radiation.
• p53-knockout mice exhibited increased susceptibility to radiation-induced GI toxicity and reduced survival.
• Antibiotic administration significantly improved survival and protected against GI toxicity in p53-knockout mice.
• Mbl2 and Lcn2, antimicrobial factors, are directly transactivated by p53 and secreted into circulation.
• MBL2 and LCN2 expression is reduced in liver cancers with p53 mutations.

Conclusions:

• p53 plays a crucial role in shaping the gut microbiome via innate immune targets.
• p53-mediated regulation of antimicrobial factors (Mbl2, Lcn2) contributes to intestinal barrier protection.
• Targeting the gut microbiome or p53-regulated innate immune pathways may offer therapeutic strategies against radiation toxicity and cancer.