Home LiteratureArticle Details
PMID: 30626868 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 10 ·No. 1 ·2019-00-09 ·Pages 89

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 HG, Haribabu B, Vemula PK, Jala VR

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.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/genetics,metabolism Caco-2 Cells Coumarins/chemistry,pharmacology Epithelial Cells/metabolism Gene Expression Regulation/drug effects HT29 Cells Humans Intestinal Mucosa/metabolism Macrophages Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2/genetics,metabolism Receptors, Aryl Hydrocarbon/genetics,metabolism Specific Pathogen-Free Organisms Tight Junction Proteins/genetics,metabolism
Chemicals
Ahr protein, mouse Basic Helix-Loop-Helix Transcription Factors Coumarins NF-E2-Related Factor 2 NFE2L2 protein, human Nfe2l2 protein, mouse Receptors, Aryl Hydrocarbon Tight Junction Proteins 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Singh Rajbir
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Chandrashekharappa Sandeep
Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus, Bangalore, Karnataka, 560065, India.
Bodduluri Sobha R
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Baby Becca V
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Hegde Bindu
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Kotla Niranjan G
Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus, Bangalore, Karnataka, 560065, India.
Hiwale Ankita A
Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus, Bangalore, Karnataka, 560065, India.
Saiyed Taslimarif
Centre for Cellular and Molecular Platforms (C-CAMP), GKVK campus, Bangalore, Karnataka, 560065, India.
Patel Paresh
Centre for Cellular and Molecular Platforms (C-CAMP), GKVK campus, Bangalore, Karnataka, 560065, India.
Vijay-Kumar Matam
Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Langille Morgan G I
Department of Pharmacology, Dalhousie University, Halifax, B3H 4R2, Nova Scotia, Canada.
Douglas Gavin M
Department of Pharmacology, Dalhousie University, Halifax, B3H 4R2, Nova Scotia, Canada.
Cheng Xi ORCID
Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Rouchka Eric C ORCID
Computer Engineering and Computer Science, Kentucky Biomedical Research Infrastructure Network, University of Louisville, Louisville, KY, 40202, USA.
Waigel Sabine J
Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.
Dryden Gerald W
Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.
Alatassi Houda
Department of Pathology, University of Louisville, Louisville, KY, 40202, USA.
Zhang Huang-Ge
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Haribabu Bodduluri
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA.
Vemula Praveen K ORCID
Institute for Stem Cell Biology and Regenerative Medicine (inStem), GKVK campus, Bangalore, Karnataka, 560065, India. praveenv@instem.res.in.
Jala Venkatakrishna R
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA. jvrao001@louisville.edu.
References (68)
68 references, click to expand
  1. Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia.
    J Exp Med. 2001 May 7;193(9):1027-34 PMID: 11342587
  2. Claudin-based barrier in simple and stratified cellular sheets.
    Curr Opin Cell Biol. 2002 Oct;14(5):531-6 PMID: 12231346
  3. Dysbiosis in inflammatory bowel disease.
    Gut. 2004 Jan;53(1):1-4 PMID: 14684564
  4. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.
    J Biol Chem. 2005 May 27;280(21):20340-8 PMID: 15790560
  5. Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds.
    J Agric Food Chem. 2005 Jul 13;53(14):5571-6 PMID: 15998116
  6. Alterations in intestinal permeability.
    Gut. 2006 Oct;55(10):1512-20 PMID: 16966705
  7. Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis.
    Cancer Res. 2006 Dec 15;66(24):11580-4 PMID: 17178849
  8. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis.
    Mol Cell Biol. 2007 Oct;27(20):7188-97 PMID: 17709388
  9. Impaired barrier function by dietary fructo-oligosaccharides (FOS) in rats is accompanied by increased colonic mitochondrial gene expression.
    BMC Genomics. 2008 Mar 27;9:144 PMID: 18371188
  10. Tight junctions and the modulation of barrier function in disease.
    Histochem Cell Biol. 2008 Jul;130(1):55-70 PMID: 18415116
  11. Multitargeted therapy of cancer by ellagitannins.
    Cancer Lett. 2008 Oct 8;269(2):262-8 PMID: 18468784
  12. The aryl hydrocarbon receptor complex and the control of gene expression.
    Crit Rev Eukaryot Gene Expr. 2008;18(3):207-50 PMID: 18540824
  13. Cytokine regulation of tight junctions.
    Biochim Biophys Acta. 2009 Apr;1788(4):864-71 PMID: 18952050
  14. Introducing the "TCDD-inducible AhR-Nrf2 gene battery".
    Toxicol Sci. 2009 Oct;111(2):238-46 PMID: 19474220
  15. Epithelial tight junctions in intestinal inflammation.
    Ann N Y Acad Sci. 2009 May;1165:294-300 PMID: 19538319
  16. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism.
    J Nutr Biochem. 2010 Aug;21(8):717-25 PMID: 19616930
  17. Cross-talk between transcription factors AhR and Nrf2: lessons for cancer chemoprevention from dioxin.
    Toxicol Sci. 2009 Oct;111(2):199-201 PMID: 19628587
  18. Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock.
    Mol Cell Biol. 2009 Dec;29(24):6391-400 PMID: 19822660
  19. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation.
    J Immunol. 2009 Nov 15;183(10):6469-77 PMID: 19841166
  20. In vitro permeability enhancement in intestinal epithelial cells (Caco-2) monolayer of water soluble quaternary ammonium chitosan derivatives.
    AAPS PharmSciTech. 2010 Jun;11(2):497-508 PMID: 20333490
  21. Intestinal macrophages and response to microbial encroachment.
    Mucosal Immunol. 2011 Jan;4(1):31-42 PMID: 20962772
  22. Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn's disease.
    Toxicol Sci. 2011 Mar;120(1):68-78 PMID: 21131560
  23. A role of the aryl hydrocarbon receptor in attenuation of colitis.
    Dig Dis Sci. 2011 Sep;56(9):2532-44 PMID: 21374063
  24. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract.
    Gastroenterology. 2011 Jul;141(1):237-48, 248.e1 PMID: 21600206
  25. Investigating intestinal inflammation in DSS-induced model of IBD.
    J Vis Exp. 2012 Feb 01;(60):null PMID: 22331082
  26. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks.
    Nat Protoc. 2012 Mar 01;7(3):562-78 PMID: 22383036
  27. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-α-induced inflammation and associated molecular markers in human aortic endothelial cells.
    Mol Nutr Food Res. 2012 May;56(5):784-96 PMID: 22648625
  28. Differential analysis of gene regulation at transcript resolution with RNA-seq.
    Nat Biotechnol. 2013 Jan;31(1):46-53 PMID: 23222703
  29. Evidence for a protective effect of polyphenols-containing foods on cardiovascular health: an update for clinicians.
    Ther Adv Chronic Dis. 2012 Mar;3(2):87-106 PMID: 23251771
  30. The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism.
    Front Oncol. 2012 Dec 26;2:200 PMID: 23272301
  31. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions.
    Genome Biol. 2013 Apr 25;14(4):R36 PMID: 23618408
  32. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far.
    Evid Based Complement Alternat Med. 2013;2013:270418 PMID: 23781257
  33. Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats.
    PLoS One. 2013 Aug 28;8(8):e72517 PMID: 24015255
  34. Ensembl 2014.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55 PMID: 24316576
  35. Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis.
    Immunol Cell Biol. 2014 May-Jun;92(5):460-5 PMID: 24518984
  36. The aryl hydrocarbon receptor: multitasking in the immune system.
    Annu Rev Immunol. 2014;32:403-32 PMID: 24655296
  37. Role of the microbiota in immunity and inflammation.
    Cell. 2014 Mar 27;157(1):121-41 PMID: 24679531
  38. Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species.
    Food Funct. 2014 Aug;5(8):1779-84 PMID: 24909569
  39. Macrophages in intestinal homeostasis and inflammation.
    Immunol Rev. 2014 Jul;260(1):102-17 PMID: 24942685
  40. Cytotoxicity of dietary flavonoids on different human cancer types.
    Pharmacogn Rev. 2014 Jul;8(16):122-46 PMID: 25125885
  41. A guide to histomorphological evaluation of intestinal inflammation in mouse models.
    Int J Clin Exp Pathol. 2014 Jul 15;7(8):4557-76 PMID: 25197329
  42. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology.
    Pharmacol Rev. 2015;67(2):259-79 PMID: 25657351
  43. Nrf2 in health and disease: current and future clinical implications.
    Clin Sci (Lond). 2015 Dec;129(12):989-99 PMID: 26386022
  44. Mitochondrial dysfunction in inflammatory bowel disease.
    Front Cell Dev Biol. 2015 Oct 01;3:62 PMID: 26484345
  45. Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways.
    Biochem Soc Trans. 2015 Aug;43(4):621-6 PMID: 26551702
  46. Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.
    World J Gastroenterol. 2016 Mar 21;22(11):3117-26 PMID: 27003989
  47. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism.
    Cell Mol Life Sci. 2016 Sep;73(17):3221-47 PMID: 27100828
  48. Urolithins, the rescue of "old" metabolites to understand a "new" concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status.
    Mol Nutr Food Res. 2017 Jan;61(1): PMID: 27158799
  49. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription.
    Nat Commun. 2016 May 23;7:11624 PMID: 27211851
  50. Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases.
    PLoS One. 2016 Jun 02;11(6):e0156811 PMID: 27254317
  51. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: a tripartite pathophysiological circuit with implications for new therapeutic directions.
    Therap Adv Gastroenterol. 2016 Jul;9(4):606-25 PMID: 27366227
  52. Diet-microbiota interactions as moderators of human metabolism.
    Nature. 2016 Jul 06;535(7610):56-64 PMID: 27383980
  53. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.
    Nat Med. 2016 Aug;22(8):879-88 PMID: 27400265
  54. The TNBS-induced colitis animal model: An overview.
    Ann Med Surg (Lond). 2016 Aug 19;11:9-15 PMID: 27656280
  55. Ellagic Acid and Its Role in Chronic Diseases.
    Adv Exp Med Biol. 2016;928:473-479 PMID: 27671829
  56. Ultrastructural abnormalities in endoscopically and histologically normal and involved colon in ulcerative colitis.
    Am J Gastroenterol. 1989 Sep;84(9):1038-46 PMID: 2773897
  57. Human Intestinal Barrier Function in Health and Disease.
    Clin Transl Gastroenterol. 2016 Oct 20;7(10):e196 PMID: 27763627
  58. AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice.
    Cell Rep. 2016 Oct 25;17(5):1318-1329 PMID: 27783946
  59. The Human Intestinal Microbiome in Health and Disease.
    N Engl J Med. 2016 Dec 15;375(24):2369-2379 PMID: 27974040
  60. Microbes and Cancer.
    Annu Rev Immunol. 2017 Apr 26;35:199-228 PMID: 28142322
  61. Feedback control of AHR signalling regulates intestinal immunity.
    Nature. 2017 Feb 9;542(7640):242-245 PMID: 28146477
  62. Dysbiosis and the immune system.
    Nat Rev Immunol. 2017 Apr;17(4):219-232 PMID: 28260787
  63. Cardioprotective Effects of Pomegranate (Punica granatum) Juice in Patients with Ischemic Heart Disease.
    Phytother Res. 2017 Nov;31(11):1731-1738 PMID: 28913846
  64. Effect of pomegranate extract on blood pressure and anthropometry in adults: a double-blind placebo-controlled randomised clinical trial.
    J Nutr Sci. 2017 Aug 9;6:e39 PMID: 29152243
  65. Evidence for the effectiveness of pomegranate supplementation for blood pressure management is weak: A systematic review of randomized clinical trials.
    Nutr Res. 2017 Oct;46:38-48 PMID: 29173650
  66. The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy.
    Cancer Cell. 2018 Apr 9;33(4):570-580 PMID: 29634945
  67. The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity.
    Immunity. 2018 Aug 21;49(2):353-362.e5 PMID: 30119997
  68. Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin.
    Dig Dis Sci. 1993 Sep;38(9):1722-34 PMID: 8359087
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/s41467-018-07859-7
Email
praveenv@instem.res.in
jvrao001@louisville.edu
Published
2019-00-09
Epub
2019-00-09
Pages
89
Language
English
Region
England
NLM ID
101528555
PMCID
PMC6327034
Subset
IM
Grants
NCI NIH HHS · R21 CA216090 · United States
NIH HHS · R21CA216090 · United States
NIGMS NIH HHS · P20 GM125504 · United States
NIGMS NIH HHS · P20 GM103436 · United States
NCI NIH HHS · R21 CA191683 · United States
NIGMS NIH HHS · P30 GM106396 · United States
NIH HHS · P20GM125504-01 · United States
External Links
PubMed source DOI: 10.1038/s41467-018-07859-7 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2