Earticle

초록

영어

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. 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. 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.

저자

• Jae-Geun Lee [ Disease Target Structure Research Center, Infectious Disease Research Center, 4KRIBB school, University of Science and Technology, Daejeon ]
• Soohyun Lee [ Infectious Disease Research Center ]
• Juhee Jeon [ Disease Target Structure Research Center, Stembio. Ltd, Entrepreneur 306, Asan-si, Chungcheongnam-do ]
• Hyun Gi Kong [ Infectious Disease Research Center, Crop Protection Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju-gun, Jeollabuk-do ]
• Hyun-Ju Cho [ Disease Target Structure Research Center ]
• Jong-Hwan Kim [ Genome Editing Research Center, KRIBB ]
• Seon-Young Kim [ Genome Editing Research Center, KRIBB, KRIBB school, University of Science and Technology, Daejeon ]
• Myung Jin Oh [ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon ]
• Daum Lee [ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon ]
• Nari Seo [ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon ]
• Ki Hun Park [ Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju-si, Gyeongsangnam-do ]
• Kweon Yu [ Disease Target Structure Research Center, Infectious Disease Research Center, 4KRIBB school, University of Science and Technology, Daejeon ]
• Hyun Joo An [ Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon ]
• Choong-Min Ryu [ Infectious Disease Research Center, KRIBB school, University of Science and Technology, Daejeon ] Corresponding Author
• Jeong-Soo Lee [ Disease Target Structure Research Center, Infectious Disease Research Center, 4KRIBB school, University of Science and Technology, Daejeon ] Corresponding Author

참고문헌

발행기관

간행물

표지보기 관심저널 등록

• 간행물명

  한국당과학회 학술대회

• 간기

  연간

• 수록기간

  2006~2022

• 십진분류

  KDC 517 DDC 614