Cholesterol-lowering effect of bile salt hydrolase from a Lactobacillus johnsonii strain mediated by FXR pathway regulation.

Hypercholesterolemia is a major risk factor for cardiovascular diseases worldwide. Healthy intestinal microbiota can contribute to reducing the high cholesterol symptoms by producing bile salt hydrolase (BSH). In this study, recombinant BSH from the strain L. johnsonii 334 with high cholesterol reduction ability was selected to study the cholesterol-lowering mechanism mediated by farnesoid X receptor (FXR) regulation in mice. In the presence of recombinant BSH, mice had a larger bile acid pool. Analysis of individual bile acids revealed that bile acid composition was affected not only by recombinant BSH but also by the modulated gut microbiota. We confirmed a marked reduction in the transcription of FXR and its molecular targets in the ileum and a significant increase in the transcription of cholesterol 7a-hydroxylase (CYP7A1), which resulted in the increased bile acid synthesis and cholesterol-lowering effects. Notably, our work reveals the importance of BSH substrate specificity.

Bacteroides thetaiotaomicron and Lactobacillus johnsonii modulate intestinal inflammation and eliminate fungi via enzymatic hydrolysis of the fungal cell wall.

Alterations to the gut microbiota can cause an amplification of the inflammatory response to intestinal pathogens. We assessed the effect of Bacteroides thetaiotaomicron and Lactobacillus johnsonii on the elimination of Candida species and whether restoration of these two anaerobic bacteria could attenuate the development of colitis in mice. In this study, L. johnsonii and B. thetaiotaomicron interacted directly with Candida species and induced a degradation of the fungal cell wall, mediated via chitinase-like and mannosidase-like activities, which promoted the inhibition of Candida species growth. In the DSS-induced colitis model, oral administration of L. johnsonii and B. thetaiotaomicron to mice reduced the overgrowth of Escherichia coli, Enterococcus faecalis and Candida glabrata populations and resulted in a significant reduction in inflammatory parameters. L. johnsonii and B. thetaiotaomicron decreased pro-inflammatory mediators and enhanced the anti-inflammatory cytokine response with high TLR9 expression and chitinase-like protein-1 activation, which promoted the elimination of C. glabrata from the gut. Overall, these findings provide evidence that L. johnsonii and B. thetaiotaomicron decrease the development of colitis mediated by TLR9 and promote the elimination of C. glabrata from the gut via chitinase-like and mannosidase-like activities.

Microencapsulated feruloyl esterase-producing lactobacilli ameliorate lipid profile and glycaemia in high fat diet-induced obese mice.

The effect of oral administration of spray-dried microcapsules of feruloyl esterase (FE) producing Lactobacillus fermentum CRL1446 (Lf) and Lactobacillus johnsonii CRL1231 (Lj) on high fat diet-induced obese mice was investigated to evaluate whether these strains could be used as a biotherapeutic for obesity. Swiss albino mice were divided into a normal diet fed group receiving empty microcapsules (control), a high fat diet plus empty microcapsules (HFD group), HFD plus microcapsules with Lf (HFD-Lf group) and HDF plus microcapsules with Lj (HFD-Lj group). Microcapsules containing Lf or Lj at a dose of ~107 cells/day/mouse were given orally for 7 weeks. Body weight gain, adiposity index, plasma leptin, lipid profiles, glycaemia, insulinemia, oral glucose tolerance, intestinal FE, glutathione peroxidase and glutathione reductase (GR) activities were determined. Administration of lactobacilli (HFD-Lf and HFD-Lj groups) improved metabolic parameters (triglyceride, total cholesterol, low-density lipoprotein cholesterol levels) and cardiovascular risk indicators (37-46% decrease of atherogenic index), and reduced body weight gain (29-38%), adiposity index (42-62%), plasma leptin levels, liver weight and fat deposition in liver. Intestinal FE activities significantly increased in HFD-Lf (62%) and HFD-Lj group (48%), thus improving hepatic GR activity (42% increment) compared to HFD group. Moreover, L. johnsonii increased HDL-cholesterol and L. fermentum reduced blood glucose to levels similar to the control. These FE-producing lactobacilli have the potential to improve biomarkers involved in obesity by increasing intestinal FE activity.

Identification of a mouse Lactobacillus johnsonii strain with deconjugase activity against the FXR antagonist T-ß-MCA.

Bile salt hydrolase (BSH) activity against the bile acid tauro-beta-muricholic acid (T-ß-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-ß-MCA, an FXR antagonist. While several studies have characterized BSHs in lactobacilli, deconjugation of T-ß-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-ß-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-ß-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-ß-MCA in these homologs. Our data suggests that L. johnsonii regulates T-ß-MCA levels in the mouse intestinal environment, and that this species may play a central role in FXR signaling in the mouse.