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

被引:555
作者
Singh, Rajbir [1 ]
Chandrashekharappa, Sandeep [2 ]
Bodduluri, Sobha R. [1 ]
Baby, Becca, V [1 ]
Hegde, Bindu [1 ]
Kotla, Niranjan G. [2 ]
Hiwale, Ankita A. [2 ]
Saiyed, Taslimarif [3 ]
Patel, Paresh [3 ]
Vijay-Kumar, Matam [4 ]
Langille, Morgan G., I [5 ]
Douglas, Gavin M. [5 ]
Cheng, Xi [4 ]
Rouchka, Eric C. [6 ]
Waigel, Sabine J. [7 ]
Dryden, Gerald W. [7 ]
Alatassi, Houda [8 ]
Zhang, Huang-Ge [1 ]
Haribabu, Bodduluri [1 ]
Vemula, Praveen K. [2 ]
Jala, Venkatakrishna R. [1 ]
机构
[1] Univ Louisville, James Graham Brown Canc Ctr, Dept Microbiol & Immunol, Louisville, KY 40202 USA
[2] Inst Stem Cell Biol & Regenerat Med inStem, GKVK Campus, Bangalore 560065, Karnataka, India
[3] Ctr Cellular & Mol Platforms C CAMP, GKVK Campus, Bangalore 560065, Karnataka, India
[4] Univ Toledo, Dept Physiol & Pharmacol, Coll Med & Life Sci, Toledo, OH 43614 USA
[5] Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4R2, Canada
[6] Univ Louisville, Kentucky Biomed Res Infrastruct Network, Comp Engn & Comp Sci, Louisville, KY 40202 USA
[7] Univ Louisville, Dept Med, Louisville, KY 40202 USA
[8] Univ Louisville, Dept Pathol, Louisville, KY 40202 USA
关键词
ARYL-HYDROCARBON RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; TIGHT JUNCTIONS; CROSS-TALK; INTESTINAL INFLAMMATION; STRESS-RESPONSE; ELLAGIC ACID; GENE; HEALTH; UROLITHIN;
D O I
10.1038/s41467-018-07859-7
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:18
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