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

• Published in: Cell metabolism Vol. 31; no. 5; pp. 956 - 968.e5
• Main Authors: Saeedi, Bejan J., Liu, Ken H., Owens, Joshua A., Hunter-Chang, Sarah, Camacho, Mary C., Eboka, Richard U., Chandrasekharan, Bindu, Baker, Nusaiba F., Darby, Trevor M., Robinson, Brian S., Jones, Rheinallt M., Jones, Dean P., Neish, Andrew S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.05.2020
• Subjects: 5-methoxyindoleacetic acid; Animals; Drosophila; Gastrointestinal Microbiome; Hep G2 Cells; hepatotoxicity; Humans; Lacticaseibacillus rhamnosus - metabolism; Lactobacillus; Liver - injuries; Liver - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; microbiome; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidation-Reduction; Tumor Cells, Cultured; 5-methoxyindoleacetic acid; Nrf2; microbiome; hepatotoxicity; Lactobacillus
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.03.006

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. [Display omitted] •The gut microbiome induces the Nrf2 antioxidant response pathway in the liver•Gut-resident Lactobacilli induce hepatic Nrf2 in both Drosophila and mice•Oral delivery of Lactobacillus rhamnosus GG protects against oxidative liver injury•Lactobacilli-derived 5-methoxyindoleacetic acid activates Nrf2 Saeedi et al. demonstrate that the gut microbiome acts at a distance to activate host antioxidant responses in the liver. These responses can be amplified by exogenous administration of Lactobacilli and protect against oxidative liver injury. Finally, they identify a Lactobacilli-derived small molecule that mediates, in part, these effects.