Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

To investigate the role of enhancer of zeste homolog (EZH) 1 and EZH2 in liver homeostasis, mice were generated that carried Ezh1 ^‐/‐ and EZH2 ^fl/fl alleles and an Alb‐ Cre transgene. Only the combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global trimethylation on Lys 27 of histone H3 (H3K27me3) marks and the specific loss of over ~1900 genes at 3 mo of age. Ezh1 ^‐/‐ ,Ezh2 ^fl/fl Alb‐Cre mice exhibited progressive liver abnormalities manifested by the development of regenerative nodules and concomitant periportal fibrosis, inflammatory infiltration, and activation of A6‐positive hepatic progenitor cells at 8 mo of age. In response to chronic treatment with carbon tetrachloride, all experimental mice, but none of the controls ( n = 27 each), showed increased hepatic degeneration associated with liver dysfunction and reduced ability to proliferate. After two‐thirds partial hepatectomy, mutant mice ( n = 5) displayed increased liver injury and a blunted regenerative response. Genomewide analyses at 3 mo of age identified 51 genes that had lost H3K27me3 marks, and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 globally or EZH2 specifically in hepatocytes. This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis and regeneration.—Bae, W. K., Kang, K., Yu, J. H., Yoo, K. H., Factor, V. M., Kaji, K., Matter, M., Thorgeirsson, S., Hennighausen, L. The methyltransferases enhancer of zeste homolog (EZH) 1 and EZH2 control hepatocyte homeostasis and regeneration. FASEB J. 29, 1653‐1662 (2015). www.fasebj.org

Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called “leaky gut”. Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.