Abstract
The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.
Original language | English |
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Article number | 89 |
Journal | Nature Communications |
Volume | 10 |
Issue number | 1 |
DOIs | |
Publication status | Published - Dec 1 2019 |
Bibliographical note
Funding Information:This work is financially supported by NIH/NCI (R21CA216090), NIH/NIGMS CoBRE grant (P20GM125504-01) and pilot grants from Microbiology and Immunology (U of L), Rounsavall Foundation and The Jewish Heritage Fund for Excellence Research Enhancement Grant and JGBCC to V.R.J.; V.R.J. and R.S. are partially supported by funds from NIH/NCI (CA191683). Part of RNA-Seq experiment was performed with assistance of the U of L Genomics Facility, which is supported by NIH P20GM103436 (KY IDeA Networks of Biomedical Research Excellence), NIH P30GM106396 (UofL J. G. Brown Cancer Center Phase III CoBRE), the J. G. Brown Foundation, and user fees. We thank JGBCC imaging core facilites at U of L. This work is financially supported by Department of Biotechnology (DBT) (BT/PR12490/AAQ/3/716/2015) to P.K.V., and core-funds from the Institute for Stem Cell Biology and Regenerative Medicine (inStem). P.K.V. is supported by Ramalingaswami ReEntry Fellowship (DBT), India. S.C. is supported by Department of Science and Technology (DST) under the Scheme for Young Scientists and Technologies program (SP/YO/078/2017). A.A.H. is supported by Senior Research Fellowship by Council of Scientific & Industrial Research (CSIR). We thank animal house facility/members and Central Imaging & Flow Cytometry, NMR facilities at inStem and NCBS.
Publisher Copyright:
© 2019, The Author(s).
ASJC Scopus Subject Areas
- General Chemistry
- General Biochemistry,Genetics and Molecular Biology
- General Physics and Astronomy