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Chen et al. Microbiome Res Rep 2025;4:6 https://dx.doi.org/10.20517/mrr.2024.38 Page 11 of 14

the liver. L. johnsonii CCFM1376 has been shown to reduce the levels of TC and LDL-C in the livers of mice
with hypercholesterolemia. Similarly, L. johnsonii BFE6154 can also reduce the hepatic TC levels in
[21]
hypercholesterolemic mice, but it does not have a considerable influence on the LDL-C levels in the liver .
L. johnsonii CCFM1376 can hydrolyze glycochenodeoxycholic acid (GCDCA) through its BSH activity,
thereby inhibiting GCDCA-induced apoptosis in hepatocytes, and alleviating liver steatosis and bile acid
[23]
dysregulation in parenterally nourished rats .
Strain with BSH activity facilitates the production of various conjugated and unconjugated bile acids, as well
as their metabolic products, secondary bile acids. These bile acids, under the influence of the hepatic-enteric
circulation, alter the composition of bile acids within mice, and the distribution and variation of bile acids
represent the material basis through which gut bacteria regulate cholesterol metabolism via BSH. Compared
to the control group, mice on a high-cholesterol diet exhibited a significant increase in serum total bile acid
concentration, indicating that a high-cholesterol diet leads to an imbalance in bile acid metabolism within
the mice. A similar phenomenon is observed in mouse models where a high-fat diet results in obesity .
[24]
L. johnsonii CCFM1376 has a particularly significant impact on the content of bile acids in the terminal
ileum and feces. The concentrations of several unconjugated bile acids, including β-MCA, CA, CDCA,
UDCA, and HDCA, were notably increased in the terminal ileum of the L. johnsonii CCFM1376 group,
consistent with the action of BSH. Similarly, after gavage administration of Lactobacillus with high BSH
activity to normal mice, changes were observed in the mice’s bile acid composition, particularly in the
[25]
ileum . Prior to reaching the terminal ileum, approximately 95% of bile acids are reabsorbed, with
unconjugated bile acids being less readily absorbed due to their higher hydrophobicity. An increased
proportion of unconjugated bile acids in the feces of the L. johnsonii CCFM1376 group also confirms that
strains with high BSH activity can elevate the content of unconjugated bile acids in the gut, accelerating the
excretion of bile acids with feces. The BSH recombinant strain of L. johnsonii 334 modulated the fecal bile
acid composition in mice on a high-cholesterol diet, with significant increases in the concentrations of
unconjugated bile acid CA, β-MCA, DCA, and LCA . Numerous studies have demonstrated that the
[26]
intervention with Lactobacillus strains can regulate bile acid metabolism. For instance, Lactobacillus
plantarum CCFM8661 can significantly increase bile acid synthesis in the liver and fecal bile acid excretion
[27]
in mice . In contrast, the supplementation with Lactobacillus rhamnosus GG can suppress de novo bile
[28]
acid synthesis, reduce hepatic bile acid content, and increase bile acid excretion .

Alterations in bile acid composition can influence the expression of key genes in the FXR pathway .
[29]
L. johnsonii CCFM1376 significantly downregulated the relative expression levels of FXR and FGF15 in the
ileum of mice with hypercholesterolemia, but did not significantly affect the expression of FXR and SHP in
the liver. Strains with BSH activity have shown varying effects on the ileum and liver; BSH recombinant
strains downregulated the relative expression level of ileal FXR while upregulating hepatic FXR expression,
ultimately demonstrating the ability to upregulate the relative expression of CYP7A1, thus promoting
cholesterol metabolism. Joyce et al. found that the Lactobacillus BSH recombinant strain regulated plasma
cholesterol levels in mice on a high-fat diet, with significant downregulation of hepatic FXR expression and
significant upregulation of intestinal FXR expression . Yao et al., in their study on the effects of BSH gene
[9]
knockout strains on lowering plasma cholesterol in mice on a high-fat diet, found significant
downregulation of hepatic FXR expression with no significant change observed in intestinal FXR . The
[30]
action of gut microbiota BSH leads to an enhanced proportion of unconjugated bile acids in the gut, and the
ileum’s relatively poor absorption of unconjugated bile acids, resulting in reduced reabsorption of bile acids
in the ileum . A decrease in intracellular bile acid levels in intestinal cells downregulates FXR
[31]
transcriptional activity, leading to reduced levels of its downstream target gene FGF15 mRNA, thereby
promoting the expression of CYP7A1. In the FXR regulatory pathway, Tβ-MCA and UDCA act as