Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) may lead to hepatic fibrosis. Dietary habits affect gut microbiota composition, whereas endotoxins produced by Gram‐negative bacteria stimulate hepatic fibrogenesis. However, the mechanisms of action and the potential effect of microbiota in the liver are still unknown. Thus, we sought to analyze whether microbiota may interfere with liver fibrogenesis. Mice fed control (CTRL) or high‐fat diet (HFD) were subjected to either bile duct ligation (BDL) or CCl4 treatment. Previously gut‐sterilized mice were subjected to microbiota transplantation by oral gavage of cecum content obtained from donor CTRL‐ or HFD‐treated mice. Fibrosis, intestinal permeability, bacterial translocation, and serum endotoxemia were measured. Inflammasome components were evaluated in gut and liver. Microbiota composition (dysbiosis) was evaluated by Pyrosequencing. Fibrosis degree was increased in HFD+BDL versus CTRL+BDL mice, whereas no differences were observed between CTRL+CCl4 and HFD+CCl4 mice. Culture of mesenteric lymph nodes showed higher density of infection in HFD+BDL mice versus CTRL+BDL mice, suggesting higher bacterial translocation rate. Pyrosequencing revealed an increase in percentage of Gram‐negative versus Gram‐postive bacteria, a reduced ratio between Bacteroidetes and Firmicutes, as well as a dramatic increase of Gram‐negative Proteobacteria in HFD+BDL versus CTRL+BDL mice. Inflammasome expression was increased in liver of fibrotic mice, but significantly reduced in gut. Furthermore, microbiota transplantation revealed more liver damage in chimeric mice fed CTRL diet, but receiving the microbiota of HFD‐treated mice; liver damage was further enhanced by transplantation of selected Gram‐negative bacteria obtained from cecum content of HFD+BDL‐treated mice. Conclusions: Dietary habits, by increasing the percentage of intestinal Gram‐negative endotoxin producers, may accelerate liver fibrogenesis, introducing dysbiosis as a cofactor contributing to chronic liver injury in NAFLD. (Hepatology 2014;59:1738–1749)

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…As expected, in our murine model of NAFLD metagenomic studies revealed differences at phylum, class and genus levels between HFD-fed mice and controls, leading to dysbiosis. As previously described, HFD-induced dysbiosis was characterized by an increase in Gram-negative bacteria and, most important, by a general decrease of total bacteria concentration [40]. In turn, it has been described that differences in gut microbial composition can determine response to HFD in mice [29,41], which would explain the wide spectrum of NAFLD observed in our study in accordance with the individual metabolic phenotype, as corroborated by results obtained from correlation analysis.…”

Dietary Milk Sphingomyelin Reduces Systemic Inflammation in Diet-Induced Obese Mice and Inhibits LPS Activity in Macrophages

“…Gut dysbiosis has been linked with endotoxin-mediated chronic disease in mouse models [51,52]. Sphingosine, a hydrolytic product of dietary SM, is known to have bactericidal effects [53].…”

Intestinal transport and metabolism of bile acids

“…For example, microbiota effects upon body weight, adiposity, lipid metabolism, liver disease, intestinal mucosal function, colon carcinogenesis, and cardiovascular function have recently been linked to luminal bile acid metabolism and modulation of bile acid signaling ( 26, 213-218 ). Of note, these studies are at the forefront of a new fi eld, and make innovative use of mouse models with altered microbiomes, including models that are germ-free or colonized with specifi c organisms, including microbiota from humans with select clinical characteristics ( 214,216,(219)(220)(221)(222)(223)(224). Compared with mice raised conventionally, the pool of bile acids in germ-free mice is less "FXR agonistic," because the bile and luminal contents include an increased proportion of tauro-␤ -murocholic acid, an endogenous mouse bile acid species that functions as an FXR antagonist ( 26, 223 ).…”