Advanced liver steatosis accompanies an increase in hepatic inflammation, colonic secondary bile acids and Lactobacillaceae/Lachnospiraceae bacteria in C57BL/6 mice fed a high-fat diet

Authors: Zeng, Huawei; Larson, Kate; CHENG, WEN-HSING - Mississippi State University; Bukowski, Michael; Safratowich, Bryan; LIU, ZHENHUA - University Of Massachusetts; HAKKAK, REZA - University Of Arkansas

Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/20/2019
Publication Date: 1/8/2020
Citation: Zeng, H., Larson, K.J., Cheng, W., Bukowski, M.R., Safratowich, B.D., Liu, Z., Hakkak, R. 2020. Advanced liver steatosis accompanies an increase in hepatic inflammation, colonic secondary bile acids and lactobacillaceae/lachnospiraceae bacteria in C57BL/6 mice fed a high-fat diet. Journal of Nutritional Biochemistry. https://doi.org/10.1016/j.jnutbio.2019.108336.
DOI: https://doi.org/10.1016/j.jnutbio.2019.108336

Interpretive Summary: The abundance of food and the spread of a Western diet that is high in saturated fat and added sugars have been implicated in the rise of the obesity epidemic. Obesity is a major cause of metabolic syndrome and is associated with an increased risk of non-alcoholic fatty liver disease. This liver disease affects approximately 75% of obese individuals and is the most common cause of liver diseases in the Western population. To understand the diet-induced fatty liver development, it is important to identify and characterize the link between diet, bile acids (in the gut) and fatty liver development. However, at the molecular level, few studies examine the connection between liver inflammation, colonic bile acids, and their associated bacteria in the context of obesity and liver diseases. In this study, we found that non-alcoholic fatty liver disease accompanies an increase in liver inflammation, colonic bile acids and their associated bacteria in an animal model of obesity, mice fed a high-fat diet. This information will be useful for scientists and health-care professionals who are interested in obesity-related liver disease prevention.

Technical Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, and the gut-liver axis is implicated in liver disease pathogenesis. We hypothesize that advanced liver steatosis accompanies an increase in hepatic inflammation, colonic secondary bile acids (BAs)and secondary BA-producing bacteria in mice fed a high-fat (HF) diet model of obesity. Four-week old male C57BL/6 mice were fed an HF (45% energy) or a low-fat (LF) (10% energy) diet for 21 weeks. At the end of the study, body weight and body fat percentage in the HF group were 0.23- and 0.41- fold greater than those in the LF group, respectively. Similarly, the HF group exhibited an increase in hepatic lipid droplets, inflammatory cell infiltration, inducible nitric oxide synthase, and hepatocellular ballooning (but without hepatic Mallory bodies) which are key histological features of advanced hepatic steatosis. Furthermore, RNA sequencing, qPCR and immunohistological methods found that nicotinamide n-methyltransferase and selenoprotein P, two inflammation-related hepatic genes, were upregulated in the HF group. Consistent with the hepatic inflammation, the levels of colonic secondary bile acids (LCA, DCA) and their producing bacteria (e, g., lactobacillaceae/Lachnospiraceae) were at least 0.5-fold greater in the HF group compared with the LF group. It is known that pro-inflammatory LCA and DCA cause the production of proinflammatory cytokines (TNF-''and IL6''in the colon and exacerbate hepatic inflammation via portal venous circulation. This potential gut-liver cross-talk is consistent with increased plasma concentrations of TNF-''and IL6, 0.5-fold greater in the HF group compared with the LF group. Taken together, the data demonstrate that advanced liver-steatosis is concurrent with an elevated level of hepatic inflammation, colonic secondary bile acids and their associated bacteria.