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

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Title
Host tp53 mutation induces gut dysbiosis eliciting inflammation through disturbed sialic acid metabolism
Author(s)
Jae-Geun Lee; Soohyun Lee; Juhee Jeon; Hyun Gi Kong; Hyun-Ju ChoJong Hwan KimSeon-Young Kim; M J Oh; D Lee; N Seo; K H Park; Kweon Yu; H J An; Choong-Min RyuJeong Soo Lee
Bibliographic Citation
Microbiome, vol. 10, pp. 3-3
Publication Year
2022
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.
Keyword
ZebrafishLarval intestineHosttp53 mutationInflammationMicrobiotaDysbiosisSialometabolismGermfreeSialidase inhibition
ISSN
2049-2618
Publisher
Springer-BMC
DOI
http://dx.doi.org/10.1186/s40168-021-01191-x
Type
Article
Appears in Collections:
Division of Research on National Challenges > Infectious Disease Research Center > 1. Journal Articles
Division of Biomedical Research > Microbiome Convergence Research Center > 1. Journal Articles
Ochang Branch Institute > Division of National Bio-Infrastructure > 1. Journal Articles
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