Many reports described that most studied BSHs are encoded by lactic acid bacteria and are used as probiotics to prevent mainly metabolic disorders in humans [30,31,32]. Recently, it was demonstrated that the human gut microbiota plays key a role in contributing to host health [33]. Among these microbial functions, the deconjugation of BAs by BSH enzymes comprises an imperative gateway reaction in the metabolism of BAs [6]. Considering the importance of BAs as biomolecules, gaps in our knowledge of these enzymes need to be filled. To uncover BSH gene abundance and their activity distribution in the gut microbiota, different approaches such as biochemical assays and metagenomic analysis are currently used; however, both approaches have inherent limitations. Indeed, standard biochemical assays that measure substrate consumption or product generation are unsuitable for defining and characterizing BSH enzymatic activities from complex biological samples. Through functional and comparative metagenomic analysis, Jones et al. highlighted the presence of BSH activity in all major bacterial divisions and the enrichment of BSHs in the human gut metagenomes of healthy subjects. Indeed, most metagenomic BSH-active clones were found to belong to Firmicutes, Bacteroidetes, and Actinobacteria [34]. Recently, taxonomic analyses among 11 different worldwide healthy populations have revealed 591 BSH enzymes, which are distributed over 117 genera and 447 bacterial strains [26]. The majority of the identified BSHs in the study belong to five genera, namely Bacteroides, Blautia, Eubacterium, Clostridium, and Roseburia. Around 27% of BSH-encoding bacteria behave as paralogs and are mainly assigned to Bacteroides. Given that the presence of paralogs introduces significant BSH sequence dissimilarity, Song et al. proposed an eight phylotype classification based on a phylogenetic tree as a more rational alternative than the classification by genera. A multivariable regression analysis showed that the relative abundance of BSHs does not significantly correlate with gender, age, and body mass index (BMI), while BSH distribution varies among populations from different geographical regions. At the biochemical level, enzyme activity assays highlighted different deconjugation selectivity between the phylotypes, in agreement with previous reports [26,35]. For example, while the T0 (Clostridium, Intestinibacter, Lactobacillus, Enterococcus), T1 (Eubacterium, Blautia, Clostridium, Roseburia, Ruminococcus), T3 (Lactobacillus), T4 (Bifidobacterium and Collinsella), and T7 (mainly Blautia) groups have significant specific activity for most bile salts, the T5 and T6 groups (assigned to Bacteroides) exhibit lower specificity towards GCA and both GCA/TCA, respectively. In contrast, the T1, T3, and T4 groups display the highest specific activities with GCA. When GCDCA and TCDCA are used as substrates, the highest specific activity is observed for group T2. Using a chemoproteomic approach to target BSH activities in the gut, Parasar et al. (2019) showed that this activity increases during intestinal inflammation, which results in higher deconjugated BAs [36]. Further studies are required to understand the relevance of gut BSH activities in host diseases.

Several studies have investigated BSH-active bacteria for their clinical efficacy in lowering hypercholesterolemia [15,37,38]. These bacteria have been shown to increase BA deconjugation, which in turn decreases cholesterol absorption by enterocytes and enhances its fecal excretion [14]. Increased BSH activity was suggested to affect bile acid composition and to influence farnesoid X receptor (FXR) signaling. It has been demonstrated that reduced FXR activity promotes the downregulation of the small heterodimer partner (SHP) and increases the synthesis of BAs from cholesterol through the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1) [39] (Figure 1). The downregulation of the SHP elicits the activation of the liver X receptor (LXR), which in turn upregulates the adenosine triphosphate-binding cassette transporters G5 and G8 (ABCG5/G8) and promotes cholesterol transport into the bile [40,41] (Figure 1). The effect of BSH activity may be extended to weight gain through FXR signaling and the membrane receptor TGR-5. Previous studies demonstrated that the use of Tempol, an anti-oxidant, prevents obesity in mice through the reduction of BSH activity, resulting in FXR inhibition via the accumulation of tauro-β-muricholic acid. Furthermore, high-fat diet-fed FXR null mice showed reduced diet-induced obesity [12,42]. On the other hand, the activation of TGR-5 by BAs induced a significant weight reduction in mice on a high-fat diet. [43]. Obesity may also be associated with several liver-related diseases, including steatosis, hepatic cancer, and non-alcoholic fatty liver disease (NAFLD), which are linked to altered gut microbiota communities. NAFLD is a chronic liver disease with inflammation, hepatocyte injury, steatosis, and fibrosis as pathological features. Strategies for NAFLD treatment target the gut microbiota based on its ability to modulate insulin sensitivity and metabolism related to host energy, choline, and BAs. Of note, a clinical trial showed that VSL#3, a combination of eight probiotics, improves NAFLD through the increase in glucagon-like peptide-1 (GLP-1) [44]. Other probiotics, tested either in combination or isolated, also showed beneficial effects on NAFLD improvement [45,46]. Recently, Huang et al. demonstrated that Lactobacillus plantarum AR113 and L. casei pWQH0, which both display high BSH activity, decrease hepatic lipid accumulation in NAFLD cell models, which is potentially mediated by the BSH activity [47]. Besides cholesterol and lipid metabolism, BSH activity may be linked to inflammatory disorders. Gut metagenomic analysis revealed a reduced abundance in the BSH gene in patients suffering from inflammatory bowel diseases (IBD) and type 2 diabetes [48,49]. In the IBD context, the induced modification of the BA profile was suggested to alter the protective effect on the intestinal barrier mediated by FXR [49]. Repression of secondary BA metabolism via the modulation of BSH activity may represent a new therapeutic method for hepatic cancer treatment. In fact, primary BAs have been shown to stimulate the liver’s accumulation of hepatic NKT cells and antitumor immunity, thus inhibiting tumorigenesis in a mice model [50]. Besides host–microbiome crosstalk, BSHs are suggested to protect commensal bacteria from BA toxicity and to contribute to bacterial survival and gut colonization [51,52,53]. They are also believed to confer a nutritional advantage since released amino acids might be used as sources of nitrogen, carbon, and energy [14]. Altogether, these data stress the importance of BSH activity and BA receptors as therapeutic targets in numerous diseases.

This global overview leads us to focus on the analysis of the relevant roles of BSHs on human health and their potential as therapeutic alternatives to treat human diseases.