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.
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Date of publication: 09 January 2019; Nature Communications
Author information: Rajbir Singh (1); Sandeep Chandrashekharappa (2); Sobha R. Bodduluri (1); Becca V. Baby (1); Bindu Hegde (1); Niranjan G. Kotla (2); Ankita A. Hiwale (2); Taslimarif Saiyed (3); Paresh Patel (3); Matam Vijay-Kumar (4); Morgan G. I. Langille (5); Gavin M. Douglas (5); Xi Cheng (4); Eric C. Rouchka (6); Sabine J. Waigel (7); Gerald W. Dryden (7); Houda Alatassi (8); Huang-Ge Zhang (1); Bodduluri Haribabu (1); Praveen K. Vemula (2); & Venkatakrishna R. Jala (1)
(1) Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
(2) Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus, Bangalore, Karnataka 560065, India
(3) Centre for Cellular and Molecular Platforms (C-CAMP), GKVK campus, Bangalore, Karnataka 560065, India
(4) Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA
(5) Department of Pharmacology, Dalhousie University, Halifax B3H 4R2, Nova Scotia, Canada
(6) Computer Engineering and Computer Science, Kentucky Biomedical Research Infrastructure Network, University of Louisville, Louisville, KY 40202, USA
(7) Department of Medicine, University of Louisville, Louisville, KY 40202, USA
(8) Department of Pathology, University of Louisville, Louisville, KY 40202, USA