Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.
|Title||Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, Hiwale AA, Saiyed T, Patel P, Vijay-Kumar M, Langille MGI, Douglas GM, Cheng X, Rouchka EC, Waigel SJ, Dryden GW, Alatassi H, Zhang H-G, Haribabu B, Vemula PK, Jala VR|
|Date Published||2019 01 09|
|Keywords||Animals, Basic Helix-Loop-Helix Transcription Factors, Caco-2 Cells, Coumarins, Epithelial Cells, Gene Expression Regulation, HT29 Cells, Humans, Intestinal Mucosa, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Receptors, Aryl Hydrocarbon, Specific Pathogen-Free Organisms, Tight Junction Proteins|
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.
|Alternate Journal||Nat Commun|
|Grant List||R21CA216090 / NH / NIH HHS / United States |
P20GM125504-01 / NH / NIH HHS / United States