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Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway

Lan Lia,1, Shengye Yanga,b,1, Xinyu Liangc,1, Yameng Liud, Hualing Xuc, Xiaozhen Guod(), Cen Xiec,d(), Xiaojun Xua,b()
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210029, China
Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210029, China
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

1 These authors share joint first authorship.

Peer review under responsibility of Tsinghua University Press.

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Highlights

• SSD can regulate hepatic lipid metabolism and improve liver steatosis.

• SSD modulated levels of conjugated and unconjugated bile acids in serum and ileal, thereby inhibiting the intestinal FXR signaling pathway.

• SSD influenced the function of gut microbiota involved in bile acid metabolism.

• SSD reduced the content of 7-oxo-CA by decreasing the expression of 7α-HSDH, which exerted potent activation effect of FXR.

• SSD induced the accumulation of conjugated bile acids in serum and ileum by reducing BSH activity.

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide. Bupleurum is widely used in the treatment of non-alcoholic fatty liver, and saikosaponin D (SSD) is one of the main active components of Bupleurum. The purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on “gut-liver axis”. Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice, improved insulin sensitivity, and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor (Fxr), small heterodimer partner (Shp), recombinant fibroblast growth factor 15 (Fgf15) and apical sodium dependent bile acid transporter (Asbt) in the intestine, suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR signaling. SSD can significantly reduce the gut microbiota associated with bile salt hydrolase (BSH) expression, such as Clostridium. Decreased BSH expression reduced the ratio of unconjugated to conjugated bile acids, thereby inhibiting the intestinal FXR. These data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.

Keywords

Saikosaponin D (SSD)Non-alcoholic fatty liver diseaseBile acidsGut microbiotaFarnesoid X receptor

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Food Science and Human Wellness
Volume 13 Issue 5,
September 2024
Pages 2703-2717
DOI: 10.26599/FSHW.2022.9250218
Cite this article:
Li L, Yang S, Liang X, et al. Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway. Food Science and Human Wellness, 2024, 13(5): 2703-2717. https://doi.org/10.26599/FSHW.2022.9250218
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