Mechanisms of gut microbiota/metabolite interface-mediated hepatic inflammation

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Project Summary/Abstract The liver is now recognized as an immunological organ with unique properties. Its immune response is tightly controlled to ensure immune tolerance to microbial, dietary, and metabolic products flowing from gut to liver through the portal vein. However, certain risk factors induce hepatic immune dysregulation, resulting in the development of liver disease. A high-fat and high-sugar diet (HFS), a typical Western-type diet (WD), is identified as a major risk factor contributing to the development of nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH). Given dietary changes worldwide, NAFLD is rapidly becoming the leading cause of liver disease affecting 25% of the population worldwide. Mounting evidence indicates that the HFS and gut microbiota interaction generates a spectrum of dietary and microbial components and outcome metabolites that can induce inappropriate hepatic immune activation, suggesting a key role of the Diet/Gut/Liver/Immune axis in NASH . However, the underlying mechanisms are poorly understood. Furthermore, very little is known about the specific microbes and metabolites that regulate intrahepatic immunity. To address these major knowledge gaps, the investigators have developed a NASH model by feeding wild-type mice with a choline-low HFS (CL-HFS) (0.05% choline) which closely approximates a typical WD in composition. This model is characterized by gut dysbiosis, metabolic disarray, abnormal hepatic immune response, and liver-resident macrophage (MΦ) and hepatic stellate cell (HSC) activation, reflecting typical pathologic properties in human NASH patients. Using the model, the investigators demonstrate that selective suppression of gut microbiota preventively and therapeutically inhibits CL-HFS-induced NASH. Metagenomic and metabolomic analyses in combination with in vitro and in vivo experiments identified Blautia producta (B. producta) and its product 2-oleoyglycerol (2-OG) as an unrecognized bacterium and metabolite contributing to CL-HFS-induced abnormal hepatic immune response. Of particular clinical relevance, enrichment of gut Blautia and high levels of hepatic 2-OG are found in human NASH patients. Mechanistic studies suggest that 2-OG primes MΦs via G protein-coupled receptor 119 signaling, subsequently activating HSCs. These exciting results support the hypothesis: CL-HFS, B. producta, and 2-OG, by activating MΦs through GPR119 signaling pathways, cause hepatic pathogenesis and HSC activation. This hypothesis will be tested in the following Aims: Aim 1: Determine MΦ as a cellular basis of CL- HFS-induced NASH pathogenesis mediating crosstalk between gut microbiota, HFS, and liver; Aim 2: Determine GPR119 as a molecular basis of MΦ mediating hepatic pathogenesis induced by CL-HFS, B. product, and 2-OG. This study will dissect the underlying cellular and molecular mechanisms to advance the understanding of the role of the Diet-Gut-Liver axis in hepatic immunity, which will advance the development of dietary and microbial interventions that therapeutically suppress this global health threat.