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Page 2 of 14 Chen et al. Microbiome Res Rep 2025;4:6 https://dx.doi.org/10.20517/mrr.2024.38

Results: Compared to the model group, the group treated with L. johnsonii CCFM1376 exhibited significantly
reduced levels of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), along with a
significant increase in high density lipoproteins cholesterol (HDL-C) level. Moreover, hepatic levels of TC and LDL-
C in the CCFM1376 group also decreased significantly. Furthermore, the content and amount of unconjugated bile
acids in the hepatic-enteric circulation of the L. johnsonii CCFM1376 group significantly increased, and the total bile
acid content in the feces also significantly increased. In the L. johnsonii CCFM1376 group, the relative expression
levels of ileal farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were downregulated, while the
relative expression level of CYP7A1 was upregulated.

Conclusion: These results indicated L. johnsonii CCFM1376 improves hypercholesterolemia in mice by regulating
the composition of bile acids. This provides a reference for probiotic strategy to regulate cholesterol metabolism.

Keywords: Lactobacillus johnsonii, bile salt hydrolase, bile acids, FXR

INTRODUCTION
It is widely acknowledged that disorders impacting the cardiovascular and cerebrovascular systems are
significant in terms of global death rates, resulting in millions of fatalities each year. With economic
development and improved living conditions, dietary habits have gradually shifted toward high-fat, high-
cholesterol, and high-calorie foods, leading to a substantial rise in the number of people with
dyslipidemia . Hypercholesterolemia is distinguished by increased amounts of cholesterol in the blood
[1]
plasma, particularly low-density lipoprotein cholesterol (LDL-C), and epidemiological studies consistently
indicate that this is a major risk factor for a range of cardiovascular diseases, including atherosclerosis .
[2]

Probiotics with high bile salt hydrolase (BSH) activity can significantly reduce serum cholesterol levels in
humans and animals . High BSH activity is also a key criterion for screening probiotics with cholesterol-
[3]
[4]
lowering functions in many current research studies . BSH is an enzyme widely present in the gut
microbiota of humans and other mammals, facilitating the hydrolysis of conjugated bile acids into
unconjugated bile acids and amino acids (glycine or taurine), thereby regulating the metabolism of bile acid.
BSH is predominantly produced by microbes such as Lactobacillus, Bifidobacterium, Enterococcus, and
Clostridium in the intestine. Lactobacillus and Bifidobacterium are the main sources for the in vitro
[5]
screening of high-activity BSH strains .
Hepatocytes in the liver synthesize primary bile acids from cholesterol through two interconnected
pathways, the classic and alternative pathways. These bile acids are then conjugated by combining with
[4]
glycine or taurine . When these conjugated bile acids are excreted into the ileum or upper colon, they
undergo hydrolysis due to the effect of BSH enzymes generated by intestinal flora, releasing unconjugated
bile acids and amino acids. Subsequently, unconjugated bile acids are subject to additional metabolic
changes, yielding secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid (LCA),
[6]
under the action of a series of microbial enzymes, such as 7α-dehydroxylase . In the terminal part of the
small intestine, most conjugated bile acids are ingested by intestinal epithelial cells through sodium-
dependent bile acid transport proteins and transported to the portal vein system, while unconjugated bile
acids are less readily reabsorbed. These bile acids circulate back to the liver with the blood and are
subsequently embraced by hepatocytes through specific transport proteins, such as the polypeptide
responsible for sodium and taurocholate cotransport, along with polypeptides that transport organic anions,
with some bile acids participating in the synthesis of cholesterol through the de novo synthesis pathway .
[7]
[8]
This forms the hepatic-enteric circulation of cholesterol and bile acids in the human body . When BSH
activity in the gut increases, more conjugated bile acids are altered into unconjugated bile acids, raising the