Abstract
The gut microbiome is a dynamic community of microorganisms within the intestinal lumen. Many studies have suggested a role for gut-resident microbes in modulating host health, however the mechanisms by which these communities 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, in both flies and mice, the human commensal Lactobacillus rhamnosus GG (LGG) potently activated Nrf2 in the fat body and liver, respectively, and protected against acetaminophen hepatotoxicity. MS/MS characterization of the portal circulation of LGG-treated mice identified a small molecule activator of Nrf2, 5-methoxyindoleacetic acid (5-MIAA), produced by LGG. Taken together, these data demonstrate a mechanism by which intestinal microbes modulate hepatic homeostasis and susceptibility to oxidative injury.
Published Version
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