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Page 6 of 13 Zhao et al. Microbiome Res Rep. 2025;4:28 https://dx.doi.org/10.20517/mrr.2025.12

[11]
along with increased expression of dehydratase and HSDH . These enzymes are essential for the
production of DCA, which has been positively associated with MASLD severity. Conversely, reducing BSH
expression may elevate the proportion of certain conBAs, such as tauro-β-muricholic acid (T-β-MCA),
which inhibits intestinal FXR signaling, thereby enhancing the hepatic BA synthesis and reducing
cholesterol levels [17,30] . Li et al. further observed that conBAs can form micelles with unconBAs, thereby
sequestering unconBAs away from intestinal epithelial cells, reducing intestinal permeability damage, and
mitigating hepatic inflammation .
[31]

MASH
MASH represents a more severe and progressive form of MASLD, characterized by liver inflammation and
hepatocellular damage, and is closely associated with an increased risk of liver fibrosis. Although research
on changes in BSH activity in MASH is limited, existing studies suggest that BSH expression is closely
related to the metabolic functions of specific bacterial taxa. These bacteria utilize BSH to modulate the
composition and concentration of the BA pool, particularly unconBAs. For example, reduced BSH
expression in MASH mice has been associated with a decreased abundance of Lactobacillus in the gut
microbiome. Supplementation with Lactobacillus has been shown to promote the formation of LCA, which
can activate the FXR signaling pathway, thereby improving liver inflammation and fat accumulation .
[32]
Conversely, other studies have reported a significant increase in BSH-expressing bacteria, such as
Bacteroides, Clostridium, and Lactobacillus, in MASH mice fed a high-fat, high-cholesterol diet. This
increase was positively correlated with elevated levels of unconBAs in the liver. Among these, excessive
levels of DCA and chenodeoxycholic acid (CDCA) were found to significantly upregulate the expression of
pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β),
[33]
exacerbating inflammation and hepatic steatosis . Furthermore, the enrichment of Bacteroides has been
linked to enhanced hydrolysis of TconBAs, resulting in the overproduction of CDCA in mice fed a Western
diet. This, in turn, induces mitochondrial reactive oxygen species (ROS) accumulation and lipid
peroxidation in the liver in a dose-dependent manner .
[34]
Liver fibrosis and cirrhosis
As the disease progresses, excessive extracellular matrix accumulation can drive the progression of MASH
to advanced liver fibrosis and ultimately cirrhosis. Existing studies have consistently reported decreased
microbial BSH gene expressions in liver fibrosis, leading to a significant accumulation of conBAs in the
intestine. This accumulation may inhibit the FXR/FGF-15 signaling pathway, thereby aggravating liver
damage . Notably, the enrichment of BSH-expressing genera such as Erysipelotrichaceae, Lactobacillus,
[19]
Clostridium, and Bifidobacterium [35,36] , as well as probiotic interventions with BSH-active strains [18,37] , has
shown beneficial effects in reversing liver fibrosis. For example, one study reported that the fecal CDCA/
taurochenodeoxycholic acid (TCDCA) ratio was significantly lower in patients with liver fibrosis compared
to healthy individuals, suggesting reduced microbial BSH activity . The study also observed a marked
[18]
decrease in Parabacteroides distasonis, a bacterium known for high BSH expression. Supplementation with
P. distasonis alleviated liver fibrosis by enhancing BSH activity and promoting TCDCA hydrolysis, thereby
reducing hepatotoxicity. Similarly, probiotic treatment with Lactobacillus rhamnosus GG (LGG)
demonstrated therapeutic effects in murine models of liver fibrosis . LGG supplementation increased
[37]
microbial BSH activity, facilitating BA deconjugation and promoting BA excretion via feces and urine,
finally preventing BA-induced liver fibrosis by enhancing intestinal FXR-FGF-15 signaling. Additionally,
LGG promoted the deconjugation of T-βMCA, mitigating its antagonistic effect on FXR and FGF-19
pathways. A large-scale cohort study further confirmed that BSH gene expression in the gut microbiota was
significantly reduced in patients with cirrhosis . These findings highlight the therapeutic potential of BSH-
[38]
active probiotics in advanced liver diseases. Future studies should explore how BSH modulates the BA pool