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Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury.

Authors
  • Saeedi, Bejan J1
  • Liu, Ken H2
  • Owens, Joshua A2
  • Hunter-Chang, Sarah1
  • Camacho, Mary C1
  • Eboka, Richard U1
  • Chandrasekharan, Bindu1
  • Baker, Nusaiba F1
  • Darby, Trevor M3
  • Robinson, Brian S1
  • Jones, Rheinallt M3
  • Jones, Dean P2
  • Neish, Andrew S4
  • 1 Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 2 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 3 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 4 Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell metabolism
Publication Date
May 05, 2020
Volume
31
Issue
5
Identifiers
DOI: 10.1016/j.cmet.2020.03.006
PMID: 32213347
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Many studies have suggested a role for gut-resident microbes (the "gut microbiome") in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Indeed, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the Drosophila liver analog and the murine liver. This activation was sufficient to protect against two models of oxidative liver injury, acetaminophen overdose and acute ethanol toxicity. Characterization of the portal circulation of LGG-treated mice by tandem mass spectrometry identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid, produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic susceptibility to oxidative injury. Copyright © 2020 Elsevier Inc. All rights reserved.

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