This proposal details a comprehensive four year training program to expand my clinical and translational research on the impact of bacterial translocation and the intestinal microbiome on recurrent disease following liver transplantation (LT), as well as extensive didactic and laboratory-based training in biostatistics and microbiome analysis methodology. The central hypothesis of this research proposal is that products of bacterial translocation from the gut, including lipopolysaccharide (LPS), contribute to hepatic fibrogenesis and steatosis in humans, specifically in patients with post-LT recurrent hepatitis C virus (HCV) and non-alcoholic fatty liver disease (NAFLD). We also hypothesize that these effects can be modulated through alteration of the intestinal microbiome. To test these hypotheses, my aims are to (1a) perform a prospective cohort study to assess whether elevations of bacterial translocation markers early post-LT are predictive of recurrent fibrosis in LT recipients with HCV, (1b) to test whether bacterial translocation and fibrosis are diminished with the use of the non-absorbed antibiotic rifaximin to alter the composition of the intestinal flora, and to (1c) compare the composition and diversity of the intestinal microbiome in patients with and without significant recurrent hepatic fibrosis. Given the strong evidence for the impact of this gut-liver axis on the pathogenesis of NAFLD and the growing number of NAFLD patients who undergo LT, I also aim to (2a) perform a prospective cohort study to determine the incidence of recurrent NAFLD post-LT, (2b) determine whether markers of bacterial translocation early post-LT are predictive of recurrent NAFLD and (2c) compare the composition and diversity of the intestinal microbiome in patients with and without recurrent NAFLD. If our hypotheses are correct, these experiments will lead to the development of novel biomarkers of fibrosis risk and a possible target for therapeutic intervention. These studies will form the foundation for future research, including multicenter trials to test whether alteration of gut flor and restoration of eubiosis could prevent hepatic fibrosis in the LT and non-LT settings. Through the proposed career development plan, I will gain advanced training in the statistical analysis of biomarkers. I will also pursue laboratory-based and didactic training in the analysis of the microbiome in order to develop a long-term research program to understand the relationship between the gut microbiome and chronic liver disease and establish effective therapeutic strategies to prevent cirrhosis. I will be mentored by Dr. Robert Brown, an expert in HCV, NAFLD, LT, outcomes research and clinical trials. I will be co-mentored by Dr. Robert Schwabe, an expert in the basic mechanisms of hepatic fibrosis and Dr. Joel Lavine, an expert in clinical and translational research in NAFLD. I am committed to a career as an independent investigator in patient oriented research and have constructed my training plan to provide the knowledge and skills needed to make substantial contributions to identifying and modifying risk factors for hepatic fibrosis.
Chronic liver disease leading to liver fibrosis and cirrhosis is a leading cause of hospitalization and death. We believe that bacteria in the gut (the microbiome) and bacterial components that circulate in the blood are important determinants of liver fibrosis, and that this mechanism of liver disease can be prevented with interventions that alter the composition of the microbiome. We plan to test this hypothesis in patients who have received liver transplants and are at risk of recurrent disease in the transplanted liver, and hope that thi line of research will help us to better understand what causes fibrosis and cirrhosis in patients with many types of chronic liver disease, and offer new strategies to prevent the life-threatening complications of cirrhosis.
| Verna, Elizabeth C (2017) Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in patients with HIV. Lancet Gastroenterol Hepatol 2:211-223 |
