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

Microbiome

Hyun-Ju Cho¹  Jae-Geun Lee²  Kweon Yu³  Jeong-Soo Lee³  Juhee Jeon⁴  Ki Hun Park⁵  Daum Lee⁶  Myung Jin Oh⁶  Hyun Joo An⁶  Nari Seo⁶  Soohyun Lee⁷  Hyun Gi Kong⁸  Choong-Min Ryu⁹  Jong-Hwan Kim^1,10  Seon-Young Kim^1,11 

[1] Disease Target Structure Research Center, KRIBB, 34141, Daejeon, Republic of Korea;Dementia DTC R&D Convergence Program, KIST, Hwarang-ro 14 gil 5, Seongbuk-gu, 02792, Seoul, Republic of Korea;Disease Target Structure Research Center, KRIBB, 34141, Daejeon, Republic of Korea;KRIBB School, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, 34113, Daejeon, Republic of Korea;Disease Target Structure Research Center, KRIBB, 34141, Daejeon, Republic of Korea;KRIBB School, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, 34113, Daejeon, Republic of Korea;Dementia DTC R&D Convergence Program, KIST, Hwarang-ro 14 gil 5, Seongbuk-gu, 02792, Seoul, Republic of Korea;Disease Target Structure Research Center, KRIBB, 34141, Daejeon, Republic of Korea;Stembio. Ltd, Entrepreneur 306, Soonchunhyang-ro 22, Sinchang-myeon, 31538, Asan-si, Chungcheongnam-do, Republic of Korea;Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, 52828, Jinju-si, Gyeongsangnam-do, Republic of Korea;Graduate School of Analytical Science and Technology, Chungnam National University, 34134, Daejeon, Republic of Korea;Infectious Disease Research Center, KRIBB, 34141, Daejeon, Republic of Korea;Infectious Disease Research Center, KRIBB, 34141, Daejeon, Republic of Korea;Crop Protection Division, National Institute of Agricultural Sciences, Rural Development Administration, 54875, Wanju-gun, Jeollabuk-do, Republic of Korea;KRIBB School, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, 34113, Daejeon, Republic of Korea;Infectious Disease Research Center, KRIBB, 34141, Daejeon, Republic of Korea;Korean Bioinformation Center, KRIBB, 34141, Daejeon, Republic of Korea;Korean Bioinformation Center, KRIBB, 34141, Daejeon, Republic of Korea;KRIBB School, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, 34113, Daejeon, Republic of Korea;

关键词: Zebrafish;    Larval intestine;    Host;    tp53;    Inflammation;    Microbiota;    Dysbiosis;    Sialometabolism;    Germfree;    Sialidase inhibition;   

DOI  :  10.1186/s40168-021-01191-x

来源: Springer

【 摘 要 】

BackgroundHost 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.ResultsWe 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.ConclusionsThese 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.-YW-NrG28r8zR7UJjY8FmQVideo Abstract

【 授权许可】

CC BY