Regulation of the Hepatic Antioxidant Response by the Probiotic Lactobacillus rhamnosus GG
Authors: Saeedi Bejan Jon , Robinson Brian S , Owens Joshua , Liu Ken , Eboka Richard , Darby Trevor , Luo Liping , Jones Dean , Jones Rheinallt , Neish Andrew 
Published: June 2021

The gut microbiome is composed of a diverse and dynamic community of microorganisms colonizing the intestinal lumen and mucosa. Using germ‐free systems, recent research has established the importance of these communities in influencing key metabolic, endocrine, and immunologic processes in the host. The majority of this research has focused on the effects of the microbiome on the intestine, the tissue with which it is in the most intimate contact. Recent studies, however, have revealed that these effects are significantly more far‐reaching, with roles in hepatic, cardiovascular, and even neurological health. As the primary metabolic and detoxification hub, the liver is a critical checkpoint between the digestive functions of the gut and the rest of the body. Therefore, it is likely that alterations in the gut microbiota affect liver health and homeostasis. To investigate this, we undertook analysis of hepatic metabolite composition using LC MS/MS mass spectrometry. These data demonstrate a significant shift in hepatic metabolism between germ‐free (GF) and conventionalized (CV) mice. Subsequent in‐silico pathway analysis of these altered metabolites suggests alterations in antioxidant and xenobiotic response pathways. A master regulator of these pathways is Nrf2, a basic leucine zipper transcription factor. Indeed, RNAseq analysis of liver tissue revealed a significant induction of Nrf2 target transcripts in CV animals. These data suggest a key role for the microbiome in fine‐tuning host xenobiotic metabolism through activation of Nrf2. We hypothesize that this signaling was mediated by discreet members of the gut microbiome. To identify bacteria capable of inducing hepatic Nrf2, we monocolonized germ‐free drosophila and measured Nrf2 activation in the fat body, an organ analogous to the liver. These data revealed a potent activation of fat body Nrf2 by lactobacilli, particularly Lactobacillus rhamnosus GG (LGG). To extend these findings we next investigated the ability of LGG to augment this pathway in mammals. We performed daily administration of LGG by oral gavage to conventional mice. In these mice we observe increased hepatic Nrf2 activity relative to vehicle control as determined by increased Nrf2 stabilization, nuclear localization, and target transcription. While these findings provide a novel insight into the role of the gut microbiome in influencing signaling pathways in the liver, the functional significance of these findings was still unclear. Given the critical role for Nrf2 in protecting against oxidative liver injury, such as that induced by acetaminophen overdose, we next investigated the role of LGG against acetaminophen challenge. Indeed, in both drosophila and in mice, LGG treatment significantly attenuated morbidity and mortality after acetaminophen overdose in a Nrf2‐dependent manner. These data provide novel mechanistic insight into probiotic mediated impacts on hepatic health. In future studies, we will attempt to identify the bacterial‐produced or induced small molecule mediators of the observed Nrf2 induction and subsequent hepatoprotection.Support or Funding InformationRO1AI64462;F30DK117570This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.