The study of American and Chinese researchers investigated whether the Western-type diet contributes to the pathogenesis of nonalcoholic steatohepatitis in clinically relevant mouse model.
Non-alcoholic fatty liver disease is rapidly becoming the leading cause of chronic liver disease, affecting 25% of the world’s population. The development of non-alcoholic fatty liver disease ranges from simple steatosis to the advanced form, non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis is characterized by hepatocyte injury and ballooning, inflammation, and hepatic fibrosis. The progression of nonalcoholic steatohepatitis can lead to subsequent cirrhotic liver disease and hepatocellular carcinoma.
The gut and liver have close anatomical and functional communication through their connection via the portal vein. This gut-liver axis enables the transport of dietary and microbial components from the gut into the liver, whereas the liver secretes factors like primary bile acids that have an impact on gut homeostasis.
Human and animal studies have shown that gut microbiota plays an important role in non-alcoholic fatty liver disease. It affects hepatic carbohydrate and lipid metabolism, as well as the balance between pro-inflammatory and anti-inflammatory effectors. The interaction between diet and gut microbiota results in a wide range of bioactive metabolites that affect the pathogenesis of nonalcoholic steatohepatitis.
Increasing evidence suggests that the interaction between the Western-type diet, which is rich in fructose, sucrose, and saturated fats, and gut microbiota results in the production of metabolites that contribute to the development and further progression of non-alcoholic fatty liver disease. However, the specific bacteria and metabolites that promote non-alcoholic fatty liver disease, as well as the underlying mechanisms, are not understood.
About the study
The authors have successfully developed a clinically relevant mouse model of non-alcoholic steatohepatitis by feeding wild-type mice with choline-low, high-fat, and high-sugar diet, representing a typical Western-type diet, named CL-HFS. CL-HFS more closely recapitulates the typical Western-type diet than a choline deficient HFD (CD-HFD). Because the prevalence of non-alcoholic fatty liver disease is higher in males than in females of all ages, the authors selected male mice.
A CL-HFS diet successfully induced nonalcoholic steatohepatitis in male mice with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Staining revealed a significant increase in the infiltration of inflammatory cells, accumulation of lipid droplets, and hepatocyte ballooning. This resulted in an increase in non-alcoholic fatty liver disease Activity Score.
Sirius red staining detected a significant increase in collagen production, forming pericellular and bridging hepatic fibrosis. qPCR detected a significant increase in mRNA expression of extracellular matrix genes and inflammatory cytokine genes. These changes were consistent with human non-alcoholic steatohepatitis.
The authors noted that Blautia producta, a genus of Lachnospiraceae family, has been reported to increase in human patients with non-alcoholic fatty liver disease and to decrease in rodents after treatment of non-alcoholic fatty liver disease. In addition, cellular mechanistic studies demonstrated that 2-oleoylglycerol is a microbial metabolite that activates hepatic stellate cells to produce extracellular matrix proteins in a macrophage-dependent manner. Previous in vitro and in vivo studies have shown that Blautia producta is able to produce and accumulate 2-oleoylglycerol in the liver.
In the present study, the authors have identified Blautia producta and its metabolite, 2-oleoylglycerol, as clinically relevant bacterial and metabolic mediators that promote the onset and development of non-alcoholic fatty liver disease. The reduction of Blautia producta was associated with suppression of the pathogenesis of nonalcoholic steatohepatitis. In contrast, repopulation with Blautia producta significantly promoted hepatic inflammation and fibrosis and further progression of nonalcoholic steatohepatitis in CL-HFS-fed mice.
The scientists concluded that these cellular and molecular findings significantly advance the understanding of the diet/gut/liver/ immune axis in the pathogenesis of nonalcoholic steatohepatitis. This study should also advance the development of dietary and microbiome/metabolite based therapeutic strategies.
This article was published in the scientific journal Nature Communication. Yang M. Western diet contributes to the pathogenesis of nonalcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol Nature Communications 2023; 14: 228. (Open Access) https://doi.org/10.1038/s41467-023-35861-1
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