Page 12 - Read Online

Zhao et al. Microbiome Res Rep. 2025;4:28 https://dx.doi.org/10.20517/mrr.2025.12 Page 7 of 13

and related signaling pathways, which may lead to novel targeted strategies for early diagnosis and
treatment of liver fibrosis.

Causes of contradictory changes in BSH
The inconsistent findings regarding BSH activity in MASLD may be attributed to several factors. First,
clinical and animal studies differ in sample sources, detection methods, and disease modeling approaches.
Second, the heterogeneity of MASLD itself may lead to dynamic changes in BSH activity among different
populations. Third, BSH-expressing bacteria may exhibit strain-specific functional differences; for example,
[8]
Lactobacillus and Bacteroides strains may behave differently in the context of MASLD . Song et al. reported
that while atherosclerotic patients exhibited reduced total BSH abundance in the gut microbiota, the relative
abundance of high-activity BSH subtypes was significantly increased, whereas low-activity subtypes were
decreased . Lastly, structural variations and substrate specificity among microbial BSH enzymes may
[16]
produce divergent effects on BA metabolism (i.e., the relative composition and absolute concentration of
both conBAs and unconBAs). For example, several studies have reported an increase in pro-inflammatory
DCA and a decrease in hepatoprotective UDCA in MASLD. To summarize, these contradictory findings
underscore the complexity of microbial BSH’s role in MASLD development and the need for further
mechanistic research to clarify its function and therapeutic potential.

BIOLOGICAL MECHANISMS UNDERLYING BACTERIAL BSH-DRIVEN THERAPEUTIC
INTERVENTIONS
This section summarizes three main biological mechanisms through which targeting microbial BSH may
contribute to the prevention and treatment of MASLD [Figure 1].

Microbial BSH-mediated modulation of BA metabolism
Regulating BA deconjugation through BSH represents a promising therapeutic approach for managing
MASLD. Probiotics, prebiotics, and BA sequestrants have shown potential in modulating BA metabolism
and thereby improving liver health in MASLD patients . Compared to conBAs, unconBAs are more
[39]
[40]
hydrophobic and less soluble, facilitating their excretion or utilization by gut bacteria . This process
triggers a feedback mechanism that stimulates the synthesis of primary BAs, thereby enhancing cholesterol
utilization . Probiotics offer unique advantages in MASLD management, with BSH activity playing a
[41]
crucial role in their colonization and growth in the gastrointestinal tract . Several well-characterized
[42]
BSH-active probiotic strains, primarily lactobacilli derived from both human and non-human origins,
exhibit cholesterol-lowering effects and show promise for clinical application . Notably, Lactobacillus
[43]
plantarum strains Lp91 and Lp21 demonstrate strong BSH activity, with a substrate preference for
glycocholate over other amino acid conjugates . Moreover, colonization by BSH-positive bacteria is
[44]
essential for BA hydrolysis and subsequent re-amidation . Genetic manipulation of these strains - either
[15]
via BSH gene deletion or overexpression - can influence BA synthesis and conversion, offering therapeutic
potential for modulating inflammation and liver diseases . BSH hydrolyzes conjugated BAs, thereby
[14]
reducing their toxicity to bacterial cell membranes, while the released taurine or glycine can be utilized as an
energy source, conferring a nutritional advantage to the bacteria . Finally, diet interventions or bioactive
[45]
compounds may benefit MASLD through their influence on microbiota-BA interactions. For instance, Zhao
et al. reported that administration of ilexsaponin A1 (IsA) significantly improved insulin resistance and
hepatic steatosis in MASLD mice . This improvement was linked to increased BSH activity in the gut
[28]
microbiome, which promoted conjugated BA hydrolysis and reduced hepatic BA accumulation.

Modulation of FXR and TGR5 signaling pathways to improve glucose and lipid metabolism
FXR and TGR5 are two key BA receptors involved in regulating energy expenditure, reducing
inflammation, and maintaining gut barrier integrity, making them attractive therapeutic targets for