Decreased Fat Storage by Lactobacillus Paracasei Is Associated with Increased Levels of Angiopoietin-Like 4 Protein (ANGPTL4)

Background: Intervention strategies for obesity are global issues that require immediate attention. One approach is to exploit the growing consensus that beneficial gut microbiota could be of use in intervention regimes. Our objective was to determine the mechanism by which the probiotic bacteria Lactobacillus paracasei ssp paracasei F19 (F19) could alter fat storage. Angiopoietin-like 4 (ANGPTL4) is a circulating lipoprotein lipase (LPL) inhibitor that controls triglyceride deposition into adipocytes and has been reported to be regulated by gut microbes. Methodology/Principal Findings: A diet intervention study of mice fed high-fat chow supplemented with F19 was carried out to study potential mechanistic effects on fat storage. Mice given F19 displayed significantly less body fat, as assessed by magnetic resonance imaging, and a changed lipoprotein profile. Given that previous studies on fat storage have identified ANGPTL4 as an effector, we also investigated circulating levels of ANGPTL4, which proved to be higher in the F19-treated group. This increase, together with total body fat and triglyceride levels told a story of inhibited LPL action through ANGPTL4 leading to decreased fat storage. Co-culture experiments of colonic cell lines and F19 were set up in order to monitor any ensuing alterations in ANGPTL4 expression by qPCR. We observed that potentially secreted factors from F19 can induce ANGPTL4 gene expression, acting in part through the peroxisome proliferator activated receptors alpha and gamma. To prove validity of in vitro findings, germ-free mice were monocolonized with F19. Here we again found change

Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11\u2005326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 710(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver

BACKGROUND: The liver is the central organ for xenobiotic metabolism (XM) and is regulated by nuclear receptors such as CAR and PXR, which control the metabolism of drugs. Here we report that gut microbiota influences liver gene expression and alters xenobiotic metabolism in animals exposed to barbiturates. PRINCIPAL FINDINGS: By comparing hepatic gene expression on microarrays from germfree (GF) and conventionally-raised mice (SPF), we identified a cluster of 112 differentially expressed target genes predominantly connected to xenobiotic metabolism and pathways inhibiting RXR function. These findings were functionally validated by exposing GF and SPF mice to pentobarbital which confirmed that xenobiotic metabolism in GF mice is significantly more efficient (shorter time of anesthesia) when compared to the SPF group. CONCLUSION: Our data demonstrate that gut microbiota modulates hepatic gene expression and function by altering its xenobiotic response to drugs without direct contact with the liver