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Zhao et al. Microbiome Res Rep. 2025;4:28 https://dx.doi.org/10.20517/mrr.2025.12 Page 9 of 13

TGR5 also plays an important role in glucose and lipid metabolism and in mitigating inflammation in
MASLD. Bariatric surgery, known for its metabolic benefits, increases levels of intestinal and circulating
taurine-conjugated BAs, which in turn activate FXR and TGR5 signaling, thereby stimulating adaptive
[51]
thermogenesis . Salidroside has been found to alleviate lipid accumulation and inflammatory injury in
MASH mice by increasing the abundance of BSH-expressing bacteria and decreasing conjugated BA levels,
[52]
thereby enhancing downstream FXR and TGR5 activation . Interestingly, oral administration of live
Parabacteroides distasonis has been shown to alleviate inflammatory arthritis. This effect was attributed to
its BSH-derived metabolites, 3-oxoLCA and isoLCA, which act as TGR5 agonists and promote M2
macrophage polarization .
[53]

Inhibiting NLRP3 to alleviate inflammation
The NLR family pyrin domain containing 3 (NLRP3) inflammasome is an intracellular sensor implicated in
the pathogenesis of various metabolic diseases, including MASLD. BAs can dose-dependently activate the
NLRP3 inflammasome, leading to IL-1β secretion and liver fibrosis . This activation occurs through
[54]
mechanisms such as potassium efflux and ROS generation. In mouse models, reduced BSH activity lowers
levels of secondary BAs like nor-deoxycholic acid (NorDCA), which in turn suppresses NLRP3 activation
and mitigates liver inflammation . Sun et al. found that Bacteroides dorei BDX-01 enhanced BSH protein
[55]
expression in the intestines of mice, increasing the β-MCA to T-β-MCA ratio and decreasing NLRP3 and
IL-1β expression in the colon . These changes significantly alleviated intestinal inflammation. Notably,
[56]
T-β-MCA antagonized the inhibitory effect of BDX-01 on NLRP3 inflammasome activity in vitro. Thus,
modulating BSH activity alters the composition of secondary BAs, which can impact NLRP3 inflammasome
activation and inflammation. Among these, T-β-MCA appears to be a particularly noteworthy target
molecule.

CHALLENGES AND FUTURE DIRECTIONS
As the “gatekeeper” responsible for initiating secondary modifications of BAs in the gut, BSH plays a pivotal
role in linking the gut microbiome with BA metabolism. Although no consensus has been reached
regarding the precise pattern of BSH changes in individuals with MASLD, it is evident that such changes are
closely related to disease progression. Most studies have demonstrated that intestinal BSH expression or
activity tends to decline in more advanced stages of MASLD, such as the onset of hepatitis or fibrosis. These
changes primarily affect the ratio of conjugated to unconjugated BAs, thereby disrupting the dynamic
balance of the BA metabolic network. This, in turn, influences enterohepatic circulation and various
metabolic signaling pathways.

Challenges in evaluating BSH activity in MASLD
Several factors contribute to the current uncertainties regarding the role of BSH in MASLD progression.
First, the degree of disease severity varies among individuals, leading to differences in gut microbiome
composition and BA profiles. Clinical studies have shown that MASLD patients with steatohepatitis exhibit
significantly elevated serum levels of taurocholic acid (TCA), glycocholic acid (GCA), and taurolithocholic
[57]
acid (TLCA) compared to those with simple steatosis . The worsening of hepatic steatosis, inflammation,
and ballooning degeneration is closely linked to the increase in these conBAs. Second, because BAs serve
diverse biological functions, microbial BSH directly influences the levels of both beneficial and harmful
secondary BAs. Consequently, studies focusing on specific BAs may yield varying conclusions regarding the
relationship between BSH activity and disease progression. Third, the BA pool in mice contains a higher
proportion of primary BAs and a broader range of secondary BAs than in humans , leading to potential
[5]
discrepancies in BSH-related findings across species. Lastly, different methodologies have been employed to
measure BSH expression and activity, with varying levels of sensitivity and accuracy, making direct
comparison across studies challenging.