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[32]
antagonists of the FXR receptor, while unconjugated bile acids such as CDCA are agonists . Previous
research has shown that compared to conjugated bile acids, unconjugated bile acids are less efficient in
[33]
activating the FXR transcriptional mechanism in the ileum . This also explains the significant increase in
the concentration of the FXR agonist CDCA, the significant rise in the concentrations of the antagonists
UDCA and Tβ-MCA, and the significant decrease in Tβ-MCA concentration in the ileum of the L. johnsonii
CCFM1376 group, which collectively contribute to the suppression of ileal FXR. Unconjugated bile acid
CDCA is less readily absorbed by intestinal cells and has a lower efficiency in activating FXR within these
cells, allowing the antagonists Tβ-MCA and UDCA to predominate.

This study measured the levels of bile acids at various locations in the enterohepatic circulation of mice and
detailed the direct link between the reduction of cholesterol and changes in bile acid composition. However,
this study has its limitations, such as the lack of conclusive evidence to demonstrate the colonization of
L. johnsonii CCFM1376 in the gut. Additionally, the fact that this study did not include more strains for
comparison is also one of its limitations.

In summary, L. johnsonii CCFM1376 with high BSH activity can directly influence the composition of bile
acids in the enterohepatic circulation of hypercholesterolemic conditions, promoting the conversion of
conjugated bile acids to unconjugated bile acids. It also suppresses the expression of genes related to the
FXR pathway in the mouse ileum, facilitating bile acid synthesis. Through the alteration of bile acid
composition, L. johnsonii CCFM1376 exerts a mitigating effect on hypercholesterolemia in mice. This study
provides a reference for the regulation of cholesterol metabolism by probiotic strategy.

DECLARATIONS
Authors’ contributions
Performed conceptualization: Yang B, Ross RP, Chen W
Supplied the method: Chen K, Dang D, Li H
Validated the method and software: Yang B
Contributed to formal analysis, investigation, and original draft preparation: Chen K
Contributed to review and editing: Yang B, Ross RP, Stanton C
Contributed to supervision: Chen W
Contributed to funding acquisition: Yang B, Chen W
All authors have read and agreed to the published version of the manuscript.

Availability of data and materials
All data are available in the main text. For other raw data, please contact the corresponding author.

Financial support and sponsorship
This research was supported by the National Natural Science Foundation of China (Nos. 32021005), and the
Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province.

Conflicts of interest
Yang B, Stanton C, and Ross RP are Editorial Board members of the journal Microbiome Research Reports,
with Yang B serving as the Guest Editor of the Special Issue Lactic Acid Bacteria: Functional
Characterization and Applications. While the other authors have declared that they have no conflicts of
interest.