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

Microbiome

Kweon Yu¹  Hyun-Ju Cho¹  Juhee Jeon¹  Jae-Geun Lee¹  Jeong-Soo Lee¹  Ki Hun Park²  Daum Lee³  Myung Jin Oh³  Hyun Joo An³  Nari Seo³  Soohyun Lee⁴  Hyun Gi Kong⁴  Seon-Young Kim⁵  Choong-Min Ryu⁵  Jong-Hwan Kim⁶ 

[1] Disease Target Structure Research Center, KRIBB;Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University;Graduate School of Analytical Science and Technology, Chungnam National University;Infectious Disease Research Center, KRIBB;KRIBB School, University of Science and Technology;Korean Bioinformation Center, KRIBB;

关键词: Zebrafish;    Larval intestine;    Host;    tp53 mutation;    Inflammation;    Microbiota;   

DOI  :  10.1186/s40168-021-01191-x

来源: DOAJ

【 摘 要 】

Abstract 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. Video Abstract

【 授权许可】

Unknown