Alcoholic Hepatitis (AH) is an important cause of morbidity, mortality, and health care costs. Only a limited number (<25% of those who drink heavily) develop this more advanced liver disease. Thus, there must be modifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a critical macronutrient disease modifier for AH. The American diet has increased dramatically in omega 6- polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodent models, dietary PUFA enriched in linoleic acid (LA), promotes alcohol-induced liver damage. Mice fed an alcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as well as a highly reactive and toxic aldehyde lipid peroxidation product, (i.e., acrolein), which causes ER stress and liver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of the critical short chain fatty acid, butyrate. We postulate that human subjects with AH will have (i) increased levels of the lipid peroxidation product, acrolein (toxic aldehyde), (ii) increased levels of OXLAMs, and (iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria, all of which correlate with severity of liver injury. We also postulate that certain lipid products (resolvins, butyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique human samples generated through the NIAAA-funded U01-consortium in AH.
Specific Aim #1 : Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue are elevated in AH, and correlate these levels with biomarkers of gut permeability, hepatic cell death/injury and disease severity.
Specific Aim #2 : Determine whether serum levels of OXLAMS are elevated in human AH, and correlate those levels with biomarkers of severity of AH, hepatocyte death, and gut permeability. Determine whether serum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivo decreases proinflammatory cytokines.
Specific Aim #3 : Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AH, and determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery with abstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production in AH patients. !
This translational application related to the Alcoholic Hepatitis Network project, AlcHepNet, comprised of nine leading partner institutions in the field, will examine new and promising treatments for severe liver damage caused by alcohol. Combined, these two approaches will improve treatment and how we care for patients with this devastating liver condition. !
