Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway

Rajbir Singh, Sandeep Chandrashekharappa, Sobha R. Bodduluri, Becca V. Baby, Bindu Hegde, Niranjan G. Kotla, Ankita A. Hiwale, Taslimarif Saiyed, Paresh Patel, Matam Vijay-Kumar, Morgan G. I. Langille, Gavin M. Douglas, Xi Cheng, Eric C. Rouchka, Sabine J. Waigel, Gerald W. Dryden, Houda Alatassi, Huang-Ge Zhang, Bodduluri Haribabu, Praveen K. Vemula () and Venkatakrishna R. Jala ()
Additional contact information
Rajbir Singh: University of Louisville
Sandeep Chandrashekharappa: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus
Sobha R. Bodduluri: University of Louisville
Becca V. Baby: University of Louisville
Bindu Hegde: University of Louisville
Niranjan G. Kotla: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus
Ankita A. Hiwale: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus
Taslimarif Saiyed: Centre for Cellular and Molecular Platforms (C-CAMP), GKVK campus
Paresh Patel: Centre for Cellular and Molecular Platforms (C-CAMP), GKVK campus
Matam Vijay-Kumar: University of Toledo College of Medicine and Life Sciences
Morgan G. I. Langille: Dalhousie University
Gavin M. Douglas: Dalhousie University
Xi Cheng: University of Toledo College of Medicine and Life Sciences
Eric C. Rouchka: University of Louisville
Sabine J. Waigel: University of Louisville
Gerald W. Dryden: University of Louisville
Houda Alatassi: University of Louisville
Huang-Ge Zhang: University of Louisville
Bodduluri Haribabu: University of Louisville
Praveen K. Vemula: Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus
Venkatakrishna R. Jala: University of Louisville

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07859-7

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