ARRA IMPACT REPORT:
Alcohol-Induced Organ and Tissue Damage


Public Health Burden
About 18 million Americans suffer from Alcohol Use Disorders (AUDs), putting them at risk for liver and heart disease, pancreatitis, brain damage, and certain types of cancer, especially liver and esophogeal cancer. In 2008, alcoholic liver disease alone accounted for over 14,000 deaths and was responsible for nearly 18 percent of liver transplants in the United States.

Metabolism
Chronic alcohol use can result in fatty liver disease, alcoholic hepatitis (i.e., inflammation of liver cells) and cirrhosis (i.e., late stage liver disease). These problems are collectively known as Alcoholic Liver Disease and are a major cause of morbidity and mortality in the United States. Alcoholic Liver Disease is affected by interactions between the liver, the immune system, and the gut, where alcohol, along with food, is absorbed into the body. Dietary intake of saturated and unsaturated fatty acids also correlates with mortality from cirrhosis. ARRA funds have been used to better understand the underlying molecular mechanisms of how alcohol, diet, and the gut interact to cause Alcoholic Liver Disease.

  • Alcohol Consumption and Fat Metabolism: Increases in fatty liver deposits and decreases in body fat are early signs of Alcoholic Liver Disease. ARRA-funded researchers at the University of Louisville, in collaboration with the University of North Carolina, University of Louisville Alcohol Research Center, and Louisville Veterans Affairs Medical Center, studied the relationship between alcohol consumption, fat metabolism, and fat distribution in mice. They demonstrated that the drug rosiglitazone, which binds to white body fat cells, reversed some of alcohol’s effects on fat metabolism.The same team of investigators collaborated with researchers from Jilin Agricultural University, Wenzhou Medical College, and the Robley Rex Veterans Medical Center to examine the effects of saturated and unsaturated dietary fat in a mouse model of Alcoholic Liver Disease. Unsaturated fat, by itself, loosened junctions between intestinal cells, allowing more nutrients and toxins into the body. The presence of alcohol in the diet magnified this effect.2 In addition, they demonstrated that a probiotic supplement, the bacterium Lactobacillus rhamnosus GG, could counter alcohol’s deleterious effects on junctions between cells, suggesting a possible mechanism for probiotic treatment of Alcoholic Liver Disease.3
  • Alcohol’s Effect on the Gut Microbiome: Mounting evidence suggests that gut-derived bacterial endotoxins may contribute to alcohol-induced tissue injury and Alcoholic Liver Disease. ARRA-supported investigators at Rush University Medical Center, in cooperation with Northwestern University and George Mason University, examined gut microbial populations (“microbiomes”) in colonic biopsies from alcohol dependent subjects. The researchers found altered microbiomes in a subgroup of alcohol dependent subjects, e.g. the levels of Bacteroidete bacteria were reduced compared to healthy controls. These changes correlated with high levels of serum endotoxin in a subset of the samples within the subgroup. Interestingly, the effects were observed even after extended periods of sobriety. Understanding the basic mechanisms underlying alcohol’s effect on the gut microbiome could inform future approaches to prevent and treat alcohol-related consequences.4

Liver Cancer
Alcohol and Hepatitis C Virus and the Development of Liver Cancer: Chronic alcohol consumption can contribute to the development of liver cancer. ARRA-funded researchers investigated how alcohol interacts with other factors to affect the early stages of cancer development in the liver. Alcohol itself can cause liver damage, but it can also accelerate liver damage caused by the hepatitis C virus (HCV). ARRA-funded investigators at the University of Southern California, in cooperation with the University of California and Department of Veterans Affairs Greater Los Angeles Healthcare System, searched for potential genetic mechanisms underlying the synergistic effect of alcohol and HCV on the development of liver cancer. Combining basic and clinical research, they collected tumor-initiating stem-like cells from laboratory mice and from alcohol dependent patients with or without HCV infection. Analysis of both human and rodent cells suggested that induction and activation of TLR4 signaling might induce liver tumor development. TLR4 signaling is critical to activating the innate immune system. These studies implicate the TLR4 signaling pathway as a potential drug target for treating HCV-associated liver tumors.5

Contributing NIH Institutes & Centers

  • National Institute on Alcohol Abuse and Alcoholism (NIAAA)

  1. 1RC2AA019385-01, http://www.ncbi.nlm.nih.gov/pubmed/22173916 - MCCLAIN, CRAIG J. - UNIVERSITY OF LOUISVILLE - LOUISVILLE - KY
  2. 1RC2AA019385-01, http://www.ncbi.nlm.nih.gov/pubmed/22150547 - MCCLAIN, CRAIG J. - UNIVERSITY OF LOUISVILLE - LOUISVILLE - KY
  3. 1RC2AA019385-01, http://www.ncbi.nlm.nih.gov/pubmed/22093263 - MCCLAIN, CRAIG J. - UNIVERSITY OF LOUISVILLE - LOUISVILLE - KY
  4. 1RC2AA019405-01, http://www.ncbi.nlm.nih.gov/pubmed/22241860 - KESHAVARZIAN, ALI - RUSH UNIVERSITY MEDICAL CENTER - CHICAGO - IL
  5. 1RC2AA019392-01, http://www.ncbi.nlm.nih.gov/pubmed/22320911 - TSUKAMOTO, HIDEKAZU - UNIVERSITY OF SOUTHERN CALIFORNIA - LOS ANGELES - CA