Effects of cholesterol-lowering probiotics on non-alcoholic fatty liver disease in FXR gene knockout mice

Minghua Yang; Haoyang Wang; Ihtisham Bukhari; Ye Zhao; Huang Huang; Yong Yu; Xiangdong Sun; Yang Mi; Lu Mei; Pengyuan Zheng

doi:10.3389/fnut.2023.1121203

Effects of cholesterol-lowering probiotics on non-alcoholic fatty liver disease in FXR gene knockout mice

Front Nutr. 2023 Jul 20:10:1121203. doi: 10.3389/fnut.2023.1121203. eCollection 2023.

Authors

Minghua Yang^#^{1

2}, Haoyang Wang^#^{1

2}, Ihtisham Bukhari^#², Ye Zhao^{1

2}, Huang Huang¹, Yong Yu¹, Xiangdong Sun², Yang Mi^{1

2}, Lu Mei¹, Pengyuan Zheng^{1

2}

Affiliations

¹ Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Henan Key Laboratory for Helicobacter Pylori & Microbiota and GI Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

^# Contributed equally.

Abstract

Background/aims: Some studies showed that probiotics could improve the composition and structure of gut microbiota. Changes in the gut microbiota may alter bile acid (BAs) composition and kinetics, improving non-alcoholic fatty liver disease (NAFLD). However, it still needs to be clarified how probiotics improve both the metabolism of BAs and NAFLD. This study aimed to reveal the regulatory mechanisms of cholesterol-lowering (CL) probiotics on NAFLD from aspects involved in BA metabolism in FXR gene knockout (FXR^-/-) mice.

Methods: FXR^-/- male mice were randomly divided into three groups based on different interventions for 16 weeks, including normal diet (ND), high-fat diet (HFD), and probiotic intervention in the HFD (HFD+P) group. 16s rDNA sequencing and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were utilized to analyze the changes in gut microbiota and fecal bile acids in mice.

Results: We found that the intervention of the CL probiotics improved liver lipid deposition and function in HFD-induced NAFLD mice by decreasing the levels of total cholesterol (TC; p = 0.002) and triglyceride (TG; p = 0.001) in serum, as well as suppressing liver inflammation, such as interleukin-1 beta (IL-1β; p = 0.002) and tumor necrosis factor-alpha (TNF-α; p < 0.0001). 16S rDNA sequencing and metabolomic analyses showed that probiotics effectively reduced the abundance of harmful gut microbiota, such as Firmicutes (p = 0.005), while concomitantly increasing the abundance of beneficial gut microbiota in NAFLD mice, such as Actinobacteriota (p = 0.378), to improve NAFLD. Compared with the ND group, consuming an HFD elevated the levels of total BAs (p = 0.0002), primary BAs (p = 0.017), and secondary BAs (p = 0.0001) in mice feces, while the intervention with probiotics significantly reduced the increase in the levels of fecal total bile acids (p = 0.013) and secondary bile acids (p = 0.017) induced by HFD.

Conclusion: The CL probiotics were found to improve liver function, restore microbiota balance, correct an abnormal change in the composition and content of fecal bile acids, and repair the damaged intestinal mucosal barrier in mice with NAFLD, ultimately ameliorating the condition. These results suggested that CL probiotics may be a promising and health-friendly treatment option for NAFLD.

Keywords: FXR; NAFLD; bile acids; gut microbiota; probiotics.

Grants and funding

This work was supported by the Medical Service Capacity Improvement Project of Henan Province in China [Grant number Yu Wei Medicine (2017) No. 66]; the Key projects of discipline construction in Zhengzhou University (No. XKZDJC202001); the National Natural Science Foundation of China (No. 81870408).