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Page 2 of 13 Zhao et al. Microbiome Res Rep. 2025;4:28 https://dx.doi.org/10.20517/mrr.2025.12

INTRODUCTION
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease
globally, characterized by hepatic fat accumulation that can progress from simple steatosis [metabolic
dysfunction-associated steatosis (MASL)] to steatohepatitis [metabolic dysfunction-associated
[1]
steatohepatitis (MASH)], fibrosis, and even cirrhosis and hepatocellular carcinoma . MASLD is linked not
only to liver-related complications but also to extrahepatic manifestations such as cardiovascular disease,
[2]
chronic kidney disease, and certain cancers . With a global prevalence of approximately 38.77%, MASLD
[3]
has become a major global public health concern, imposing a heavy burden on individuals and society .
Therefore, the development of effective strategies for the prevention, screening, and treatment of MASLD is
[4]
of great importance .
Bile acid (BA) metabolism and its interaction with the gut microbiota play important roles in modulating
[5,6]
host immunity and influencing the pathogenesis of MASLD . Primary bile acids (PBAs) are synthesized
from cholesterol in the liver via both classical and alternative pathways. These PBAs are conjugated with
taurine or glycine to form conjugated bile acids (conBAs), which are stored in the gallbladder and released
into the intestine upon food intake to facilitate lipid digestion. In the intestine, the gut microbiota converts
PBAs into secondary bile acids (secBAs), primarily deoxycholic acid (DCA) and lithocholic acid (LCA).
Both PBAs and secBAs can activate receptors such as the farnesol X receptor (FXR) and G protein-coupled
bile acid receptor 1 (TGR5), which regulate glucose and lipid metabolism as well as immune responses .
[7]
During the microbial transformation of BAs, certain gut bacteria that express bile salt hydrolase (BSH)
enzymes can deconjugate conBAs into unconjugated bile acids (unconBAs), initiating further modifications
such as dehydroxylation and epimerization . As such, BSH is often regarded as the “gatekeeper” of BA
[5]
modifications in the gut , with significant influence on host metabolic processes including lipid digestion
[8]
and cholesterol metabolism. Recent studies have highlighted close correlations between BSH activity and
metabolic diseases, suggesting that BSH could serve as a therapeutic target in MASLD [9-11] . This review
provides an overview of the structural features and functions of BSH, its distribution among gut bacteria,
and current evaluation methods. It also examines changes in microbial BSH activity during the progression
of MASLD, offering insights into the complex relationship between BSH, BA metabolic balance, and
MASLD pathogenesis, with the goal of identifying novel therapeutic strategies for this widespread disease.

BILE SALT HYDROLASE
Molecular structure of BSH
BSH, classified as EC 3.5.1.24 in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, is an
enzyme that hydrolyzes the amide bond in conjugated bile acids, converting them into free bile acids and
amino acids. It belongs to the N-terminal nucleophile (Ntn) hydrolase family and typically consists of
314-338 amino acids, with a monomeric molecular weight of approximately 34-42 kDa. The enzyme’s active
sites include Cys2, Arg18, Asp21, Asn175, and Arg228, with the cysteine residue being highly conserved .
[12]
BSH generally exists as a homotetramer, although other homooligomeric forms such as hexamers or
octamers have also been observed. Notably, structural variations can occur even within the same organism,
suggesting that different BSH isoforms may exhibit distinct substrate specificities . For instance, recent
[13]
research has shown that BSH enzymes from Lactobacillus species possess two different substrate selectivity
loops: those with G-V/T-G motifs demonstrate a higher affinity for taurine-conjugated BAs, while those
with S-R-G/S motifs are more selective for glycine-conjugated BAs . This structural diversity highlights the
[8]
important role of BSH in regulating BA modification based on substrate specificity.