한빛사 논문
Jae‑Geun Lee1,2,†, Soohyun Lee3,†, Juhee Jeon1,4,†, Hyun Gi Kong3,5, Hyun‑Ju Cho1,6, Jong‑Hwan Kim7, Seon‑Young Kim7,2, Myung Jin Oh8, Daum Lee8, Nari Seo8, Ki Hun Park9, Kweon Yu1,2,6, Hyun Joo An8, Choong‑Min Ryu2,3,* and Jeong‑Soo Lee1,2,6,*,†
1Disease Target Structure Research Center, KRIBB, Daejeon 34141, Republic of Korea. 2KRIBB School, University of Science and Technology, 217 Gajeong‑ro, Yuseong‑gu, Daejeon 34113, Republic of Korea. 3Infectious Disease Research Center, KRIBB, Daejeon 34141, Republic of Korea. 4Stembio. Ltd, Entrepreneur 306, Soonchunhyang‑ro 22, Sinchang‑myeon, Asan‑si, Chungcheongnam‑do 31538, Republic of Korea. 5Crop Protection Division, National Institute of Agricultural Sciences, Rural Development Administration, Wanju‑gun, Jeollabuk‑do 54875, Republic of Korea. 6Dementia DTC R&D Convergence Program, KIST, Hwarang‑ro 14 gil 5, Seongbuk‑gu, Seoul 02792, Republic of Korea. 7Korean Bioinformation Center, KRIBB, Daejeon 34141, Republic of Korea. 8Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea. 9Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju‑si, Gyeong‑sangnam‑do 52828, Republic of Korea
*Correspondence
†Jae-Geun Lee, Soohyun Lee, Juhee Jeon contributed equally to this work.
†Jeong-Soo Lee is the lead contact.
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.
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