The Commensal Microflora Suppresses Liver Fibrosis

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DESCRIPTION (provided by applicant): Liver fibrosis is the result of chronic liver damage from various etiologies including alcohol abuse, obesity, or viral hepatitis. Chronic liver disease may progress to cirrhosis, an end stage disease and major cause of morbidity and mortality in the United States and in particular among Veterans. Patients with chronic liver disease show intestinal bacterial overgrowth and dysbiosis. They also demonstrate increased intestinal permeability, and disease severity correlates with systemic levels of bacterial products. Although experimental liver fibrosis is dependent on gut derived bacterial products, yet the exact contribution of the commensal microflora to liver fibrosis is unknown. Since the interaction of pathogen associated molecular patterns (PAMPs) with the innate immune system can also confer protection to the host, we subjected germfree mice to experimental models of liver fibrosis. Results from our laboratory demonstrate that germfree mice show exacerbated liver fibrosis as compared with conventional mice. Livers of germfree mice have a decreased expression of the antioxidant heat shock protein (Hsp)-25, more oxidative stress and a higher rate of apoptosis. The focus of this application is to further characterize the relationship between the intestinal microflora and the progression of chronic liver disease. We hypothesize that the commensal microflora is an important suppressor of oxidative stress and hence fibrosis upon chronic liver injury in mice. Our experimental approach is to apply mouse models of toxin-induced and cholestatic liver fibrosis to germfree and conventional mice and to investigate the contribution of the bacterial microflora to chronic liver disease (Aim 1). We will then assess the mechanism by which the microflora ameliorates experimental liver fibrosis. The focus will be on Hsp25 that is lower expressed in hepatocytes of germfree mice as compared with conventional mice and that has antioxidant properties. We will test the new concept that bacterial products or metabolites induce Hsp25 in hepatocytes. We will also focus on hepatic stellate cells to explain the phenotype with increased fibrosis under germ-free conditions (Aim 2). We will then supplement germfree mice with one bacterial metabolite or colonize germ-free mice with indole-3-propionic acid (IPA) synthesizing bacteria, and subject them to experimental liver fibrosis. A preventive and therapeutic approach will be chosen. Bacterial products or metabolites might confer antioxidant properties directly or via the induction of antioxidant molecules to the liver (Aim 3). We believe these studies will provide important insights into the contribution of the commensal microflora to liver fibrosis. This will establish a novel shift in the current paradigm that all translocated bacteria and their products are bad for liver injury and chronic liver disease. Eventually this approach might lead to new therapeutic targets and therapies for patients with chronic liver disease.