This K23 application describes a five year mentored training program. The application has two main objectives. First, it will provide the PI with protected time to complete an integrated research and training program guided by multidisciplinary team of mentors. This will include use of high throughput technologies, basic molecular biology techniques, bioinformatics and systems biology approach to study intestinal microbiomics, metabolomics, and interactions of alcohol and obesity related to liver disease. The PI will also complete formal coursework leading to a Masters in Clinical and Translational Research. In addition, the research utilizes an established network of community treatment programs, providing a unique opportunity for the PI to put new knowledge into actual practice. Taken together, this rigorous training program will provide the PI with information and experience integral to his transition from mentored scientist to independent research physician. The second objective is to investigate the effect of alcohol on obesity related liver disease. The PI will focus on the hypothesis that """"""""In obese subjects, alcohol consumption alters the circulating profile of metabolites of intestinal microbial origin. Specific differentially expresse intestinal microbiome- derived metabolites promote development of fatty liver disease by directly activating disease related pathways (steatosis, inflammation, apoptosis etc.) and/or indirectly by activation of inflammatory cells"""""""". The proposed research has two specific aims: (1) to phenotype the intestinal metabonome in lean and obese subjects with varying amounts and patterns of alcohol consumption, and (2) to define how regular alcohol intake increases the development and severity of fatty liver disease in obese subjects. The research will interface directly with coe elements of the PI's training plan and is expected to demonstrate that alcohol consumption in obese subjects will alter the profile of intestinal microbiome and systemic metabolome that will modulate hepatic transcriptome and activate disease pathways over and above those seen in obesity. The activation of these pathways can promote liver disease in obese patients with alcohol use. These results will provide novel insights into (1) understanding mechanisms of how alcohol and obesity interact to promote liver disease, (2) development of biomarkers to identify those at risk or have developed liver disease, and (3) identification of specific targets for therapy. The proposed research will address the biologically and behaviorally complex interaction of alcohol and obesity as they relate to liver disease. This is directly aligned with te priorities of the NIH and contribute to their efforts to encourage and support growth of translational scientists, committed to bridging the gap between basic and clinical/community research and treatment.

Public Health Relevance

The economic and social costs of obesity and problem drinking are formidable and both of these are major public health problems that can lead to end stage liver disease. The proposed research investigates the role of intestinal microbiome and its metabolites as a potential link in how alcohol promotes and accelerates liver damage in obese individuals. Study aims are directly aligned with the NIH strategic plan, with a focus on translational research and opportunities to bridge basic science with clinical and community-based research.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Health Services Research Review Subcommittee (AA)
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Brooks, Pj
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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Puri, Puneet; Daita, Kalyani; Joyce, Andrew et al. (2017) The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology :
Puri, Puneet; Liangpunsakul, Suthat; Christensen, Jeffrey E et al. (2017) The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. Hepatology :
Li, Xiaojiaoyang; Liu, Runping; Yang, Jing et al. (2017) The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice. Hepatology 66:869-884
Puri, Puneet; Thursz, Mark (2016) Intensive Enteral Nutrition in Alcoholic Hepatitis: More Food for Thought. Gastroenterology 150:803-5
Puri, Puneet; Xu, Jun; Vihervaara, Terhi et al. (2016) Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese. J Lipid Res 57:1017-28
Mangray, Sasha; Zweit, Jamal; Puri, Puneet (2015) Zinc Deficiency in Cirrhosis: Micronutrient for Thought? Dig Dis Sci 60:2868-70
Puri, Puneet; Sanyal, Arun J (2013) The BAFFling problem of B cell-activating factor in nonalcoholic fatty liver disease. Hepatol Int 7:309-12
Bouhaidar, Claudia M; DeShazo, Jonathan P; Puri, Puneet et al. (2013) Text messaging as adjunct to community-based weight management program. Comput Inform Nurs 31:469-76