Abstract
Gut microbiota dysbiosis plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD), and no approved drugs are available for NAFLD treatment. In this study, we aimed to explore the dynamic changes of gut microbiota at the different stages of NAFLD and determine whether ursodeoxycholic acid (UDCA) could improve liver histopathological features of non-alcoholic steatohepatitis (NASH) mice induced by a high-fat high-cholesterol (HFHC) diet and its impact on gut microbiota. 6-week-old male C57BL/6 mice were fed with a HFHC or normal diet for 12, 18, and 24 weeks, respectively, to simulate the different stages of NAFLD. 16s ribosomal RNA genes from mice fecal samples at the different time points were sequenced to evaluate the dynamic changes of the gut microbiota. Then, C57BL/6 mice were fed with a HFHC diet for 24 weeks to establish the NASH model. Different doses of UDCA were administered intragastrically for additional 4 weeks. Normal diet–fed mice were taken as control. Serum samples, liver, and intestine tissues were harvested for biochemical tests and histopathological examinations. 16s ribosomal RNA genes from mice fecal samples were sequenced to assess the structural changes of gut microbiota. HFHC diet–fed mice developed simple steatosis, steatohepatitis, and fibrosis at 12, 18, and 24 weeks, respectively. The profile of gut microbiota dynamically changed with the different stages of NAFLD. NASH mice had significantly higher abundance of Fecalibaculum, Coriobacteriaceae_UCG-002, and Enterorhabdus, and lower abundance of norank_f_Muribaculaceae, Bacteroides, and Alistipes, which were partially restored by UDCA treatment. UDCA treatment significantly attenuated hepatic inflammation of NASH mice as indicated by the sum of ballooning and lobular inflammation of the NALFD activity score (3.2 ± 0.8 vs 1.8 ± 0.8, p = 0.029), and partially restored gut microbiota dysbiosis, and increased the expression of Claudin-1 and ZO-1 in the intestine, but did not activate the suppressed Farnesoid X receptor signal pathway. Conclusions: The gut microbiota dynamically changes with the different stages of NAFLD. UDCA treatment (120 mg/kg) could partially restore gut microbiota, repair gut barrier integrity, and attenuate hepatic inflammation in the NASH mouse model.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis without secondary causes of hepatic fat accumulation, ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) with or without liver fibrosis (Chalasani et al, 2018)
We aimed to explore the dynamic changes of gut microbiota at the different stages of NAFLD and determine whether ursodeoxycholic acid (UDCA) could improve liver histopathological features of non-alcoholic steatohepatitis (NASH) mice induced by a high-fat high-cholesterol (HFHC) diet and its impact on gut microbiota. 6-week-old male C57BL/6 mice were fed with a HFHC or normal diet for 12, 18, and 24 weeks, respectively, to simulate the different stages of NAFLD. 16s ribosomal RNA genes from mice fecal samples at the different time points were sequenced to evaluate the dynamic changes of the gut microbiota
The serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) were significantly elevated in HFHC diet–fed mice compared to ND diet–fed mice, and the differences reached a statistical significance from the 12th week onward (p < 0.05)
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic steatosis without secondary causes of hepatic fat accumulation, ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) with or without liver fibrosis (Chalasani et al, 2018). NASH is the active subtype of NAFLD and can potentially progress to liver cirrhosis or hepatocellular carcinoma over time (Sheka et al, 2020). Epidemiology studies and meta-analysis showed that the global prevalence of NAFLD is approximately 25%, with the highest rates in the South America and the Middle East, and the lowest in Africa (Younossi et al, 2016; Fan et al, 2017; Sheka et al, 2020). Data regarding the gut microbiota dysbiosis in NAFLD are discordant across studies due to the variability of patients, NAFLD diagnostic methods, and sequencing tools (Aron-Wisnewsky et al, 2020). Demonstrating the causality of gut microbiota in the development and progression of NAFLD will help identify novel therapeutic targets for treating it
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