TY - JOUR T1 - Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. JF - Nat Commun Y1 - 2019 A1 - Singh, Rajbir A1 - Chandrashekharappa, Sandeep A1 - Bodduluri, Sobha R A1 - Baby, Becca V A1 - Hegde, Bindu A1 - Kotla, Niranjan G A1 - Hiwale, Ankita A A1 - Saiyed, Taslimarif A1 - Patel, Paresh A1 - Vijay-Kumar, Matam A1 - Langille, Morgan G I A1 - Douglas, Gavin M A1 - Cheng, Xi A1 - Rouchka, Eric C A1 - Waigel, Sabine J A1 - Dryden, Gerald W A1 - Alatassi, Houda A1 - Zhang, Huang-Ge A1 - Haribabu, Bodduluri A1 - Vemula, Praveen K A1 - Jala, Venkatakrishna R KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Caco-2 Cells KW - Coumarins KW - Epithelial Cells KW - Gene Expression Regulation KW - HT29 Cells KW - Humans KW - Intestinal Mucosa KW - Macrophages KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - NF-E2-Related Factor 2 KW - Receptors, Aryl Hydrocarbon KW - Specific Pathogen-Free Organisms KW - Tight Junction Proteins AB -

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.

VL - 10 IS - 1 ER -