Abstract
Bile salt hydrolase (BSH) activity against the bile acid tauro-beta-muricholic acid (T-β-MCA) was recently reported to mediate host bile acid, glucose, and lipid homeostasis via the farnesoid X receptor (FXR) signaling pathway. An earlier study correlated decreased Lactobacillus abundance in the cecum with increased concentrations of intestinal T-β-MCA, an FXR antagonist. While several studies have characterized BSHs in lactobacilli, deconjugation of T-β-MCA remains poorly characterized among members of this genus, and therefore it was unclear what strain(s) were responsible for this activity. Here, a strain of L. johnsonii with robust BSH activity against T-β-MCA in vitro was isolated from the cecum of a C57BL/6J mouse. A screening assay performed on a collection of 14 Lactobacillus strains from nine different species identified BSH substrate specificity for T-β-MCA only in two of three L. johnsonii strains. Genomic analysis of the two strains with this BSH activity revealed the presence of three bsh genes that are homologous to bsh genes in the previously sequenced human-associated strain L. johnsonii NCC533. Heterologous expression of several bsh genes in E. coli followed by enzymatic assays revealed broad differences in substrate specificity even among closely related bsh homologs, and suggests that the phylogeny of these enzymes does not closely correlate with substrate specificity. Predictive modeling allowed us to propose a potential mechanism driving differences in BSH activity for T-β-MCA in these homologs. Our data suggests that L. johnsonii regulates T-β-MCA levels in the mouse intestinal environment, and that this species may play a central role in FXR signaling in the mouse.
Highlights
The gut microbiota has received increasing attention throughout the last decade for its role in human and animal health [1,2]
Cultures and cell lysates of LB1 spiked with tauro-beta-muricholic acid (T-β-MCA) were analyzed by ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and found to have undergone nearly complete reductions in the peak area associated with T-β-MCA (m/z 514.2844) with corresponding increases in the peak area associated with β-MCA (m/z 407.2803) (Figure A in S1 File) These results indicate that LB1 exhibits Bile salt hydrolase (BSH) activity towards T-β-MCA (Table 1) and suggest that changes in intestinal LB1 populations have the potential to mediate farnesoid X receptor (FXR) signaling
Li et al.[7] reported that the antioxidant tempol decreased Lactobacillus populations in the cecum which was proposed to be responsible for increases in intestinal T-β-MCA concentrations and decreases in FXR signaling
Summary
The gut microbiota has received increasing attention throughout the last decade for its role in human and animal health [1,2]. L. johnsonii candidates for metabolic control collection and analysis, decision to publish, or preparation of the manuscript
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