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Background Host  tp53  mutations are frequently found during the early stages of colitis-associated colorectal cancer (CAC), but whether such mutations induce gut microbiota dysbiosis and chronic intestinal inflammation that contributes to the development of CAC, remains unknown. Results We found that zebrafish  tp53  mutant larvae exhibited elevated intestinal inflammation, by monitoring the  NFκB  activity in the mid-distal intestines of zebrafish larvae using an  NFκB:EGFP  transgenic reporter line in vivo as well as neutrophil infiltration into the intestine. This inflammation was due to dysbiotic gut microbiota with reduced diversity, revealed using both 16S rRNA amplicon sequencing and a germfree larva model. In this dysbiosis,  Aeromonas  spp. were aberrantly enriched as major pathobionts and exhibited the capacity for aggressive colonization in  tp53  mutants. Importantly, the ex-germfree experiments supported the causality of the host  tp53  mutation for inducing the inflammation. Transcriptome and high-performance liquid chromatography analyses of the host gastrointestinal tracts identified dysregulated sialic acid (SA) metabolism concomitant with increased host Neu5Gc levels as the key determinant of aberrant inflammation, which was reversed by the sialidase inhibitors oseltamivir and Philippin A. Conclusions These results demonstrate a crucial role for host  tp53  in maintaining symbiosis and immune homeostasis via SA metabolism. Disturbed SA metabolism via a  tp53  mutation may be exploited by specific elements of the gut microbiome, eliciting both dysbiosis and inflammation. Manipulating sialometabolism may therefore provide an efficacious therapeutic strategy for  tp53  mutation-induced dysbiosis, inflammation, and ultimately, related cancers.

Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism