Regulation of the innate immune response and gut microbiome by p53

p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/-) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier. p53-knockout mice were more susceptible to radiation-induced gastrointestinal (GI) toxicity and had a significantly shorter survival than p53-wild-type mice following radiation; however, antibiotics administration improved the survival and conferred protection against GI toxicity, thus linking p53 to the gut microbiome. Furthermore, p53-knockout mice were also discovered to have a different gut microbiota profile compared with p53-wild-type mice. Two innate immunity-related genes, Mbl2 and Lcn2, both having antimicrobial activity, were found directly transactivated by p53. This elucidates p53's involvement in shaping the gut microbiome through its downstream targets in the innate immune system and protecting the intestinal barrier.image