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Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

ABSTRACT: Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the conserved microbial functions that influence host energy metabolism and adiposity have not been determined. Here we show that bacterial bile salt hydrolase (BSH) controls a microbe-host dialogue which functionally regulates host lipid metabolism and weight gain. Expression of cloned BSH enzymes in the GI tract of gnotobiotic or conventional mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (PPARgamma angptl4), cholesterol metabolism (abcg5/8), gastrointestinal homeostasis (regIIIgamma) and circadian rhythm (dbp, per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in significant reduction of host weight-gain, plasma cholesterol and liver triglycerides. We demonstrate that bacterial BSH activity significantly impacts systemic metabolic processes and adiposity in the host, and represents a key mechanistic target for the control of obesity and hypercholesterolaemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE46952 | GEO | 2014/05/09

SECONDARY ACCESSION(S): PRJNA203148

REPOSITORIES: GEO

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Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

Project description:Alterations in the gastrointestinal microbiota have been implicated in obesity in mice and humans, but the conserved microbial functions that influence host energy metabolism and adiposity have not been determined. Here we show that bacterial bile salt hydrolase (BSH) controls a microbe-host dialogue which functionally regulates host lipid metabolism and weight gain. Expression of cloned BSH enzymes in the GI tract of gnotobiotic or conventional mice significantly altered plasma bile acid signatures and regulated transcription of key genes involved in lipid metabolism (PPARgamma angptl4), cholesterol metabolism (abcg5/8), gastrointestinal homeostasis (regIIIgamma) and circadian rhythm (dbp, per1/2) in the liver or small intestine. High-level expression of BSH in conventionally raised mice resulted in significant reduction of host weight-gain, plasma cholesterol and liver triglycerides. We demonstrate that bacterial BSH activity significantly impacts systemic metabolic processes and adiposity in the host, and represents a key mechanistic target for the control of obesity and hypercholesterolaemia. Germ free Swiss Webster mice were monocolonised with EC containing the bacterial gene, Bile salt hydroalse. The treatment groups and relevant controls were; 1. Germ Free(GF) n=4 , 2. GF and EC n=4, 3. GF and EC +BSH1 n=4, 4. GF and EC+ BSH2 n=4, 5. GF re-conventionalised (CONV-D) n= 5. The Ileum and Liver were removed and the RNA extracted (RNAeasy plus universal kit (Qiagen), quantified and Microarrays were carried out using mouse Exon ST1.0 arrays (Affymetrix) by Almac Group, Craigavon, Northern Ireland. Analysis and pathway mapping was carried out by ALMAC and using Subio Platform software (Subio Inc) and Genesis Software.

2014-05-09 | E-GEOD-46952 | biostudies-arrayexpress

A selective gut bacterial bile salt hydrolase alters host metabolism

Project description:The human gut microbiota impacts host metabolism and has been implicated in the pathophysiology of obesity and metabolic syndromes. However, defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging due to the complexity of the microbiome-host ecosystem. Here, we identify strains from the abundant gut bacterial phylum Bacteroidetes that display selective bile salt hydrolase (BSH) activity. Using isogenic strains of wild-type and BSH-deleted Bacteroides thetaiotaomicron, we selectively modulated the levels of the bile acid tauro-b-muricholic acid in monocolonized gnotobiotic mice. B. thetaiotaomicron BSH mutant-colonized mice displayed altered metabolism, including reduced weight gain and respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales.

2018-07-19 | GSE112571 | GEO

Bile acid-induced inflammatory signaling in mice lacking Foxa2 in the liver leads to activation of mTOR and age-onset obesity

Project description:Cytokine signaling has been connected to regulation of metabolism and energy balance. Numerous cytokine gene expression changes are stimulated by accumulation of bile acids in livers of young Foxa2 liver-conditional null mice. We hypothesized that bile acid-induced inflammation in young Foxa2 mutants, once chronic, affects metabolic homeostasis. We found that loss of Foxa2 in the liver results in a premature aging phenotype, including significant weight gain, reduced food intake, and decreased energy expenditure. We show that Foxa2 antagonizes the mammalian target of rapamycin (mTOR) pathway, resulting in increased hepatic lipogenesis and adiposity. While much prior work has focused on adipose tissue in obesity, we discovered a novel age-onset obesity phenotype in a model where genetic deletion occurs only in the liver, underscoring the importance of the role hepatic lipogenesis plays in the development of obesity.

2013-08-19 | E-MTAB-1825 | biostudies-arrayexpress

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

Project description:Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity mouse model and compared metabolic remission when bile flow was diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We found that only bile diversion to the ileum results in physiologic changes similar to RYGB including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-b-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 axis was reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB. Total RNA from n = 5 DIO, n = 4 GB-IL, n = 5 RYGB mice livers was extracted of total RNA and submitted fro RNAseq

2015-05-13 | E-GEOD-68812 | biostudies-arrayexpress

Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis

Project description:miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.

2021-02-11 | PXD023471 | Pride

The Microbial Metabolite Deoxycholic Acid Modulates Cholesterol Metabolism in the Germ-Free Mouse

Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways. two mouse strains, three diets, one time point

2015-01-08 | E-GEOD-34730 | biostudies-arrayexpress

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

2015-05-13 | GSE68812 | GEO

Transintestinal cholesterol transport is important in mice and humans and controls ezetimibe induced fecal neutral sterol excretion

Project description:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of these pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4-weeks treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile-derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a fourfold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

2016-11-04 | GSE77236 | GEO

E-GEOD-46952

Project description:Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut

2015-07-13 | E-GEOD-46952 | ExpressionAtlas

Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis

Project description:miR-33 is an intronic miRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve HDL biogenesis in the liver and increase circulating HDL-C levels in both rodents and non-human primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole body miR-33 knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver, and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardio-metabolic diseases.

2021-01-31 | GSE164517 | GEO

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