Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability a...Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.展开更多
基金Supported by NIH grants No. K08 DK081830 and No. R01 AA020703the Pilot Project Program of the Southern California Research Center for ALPD and Cirrhosis No. P50AA11999 funded by the National Institute on Alcohol Abuse and AlcoholismABMRF/The Foundation for Alcohol Research to Schnabl B
文摘Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.
