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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Yan Guo

PROVIDER: E-GEOD-68812 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2015-05-13 | GSE68812 | GEO

Microarray analysis of FXR-regulated genes in murine small intestine.

Project description:Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier. These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow. In this report we have examined the role of FXR in the ileum. We demonstrate that it plays a crucial role in preventing bacterial overgrowth and maintaining the integrity of the intestinal epithelium

2012-07-19 | GSE39507 | GEO

Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

Project description:Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis causes changes in the small intestine, including bacterial overgrowth and translocation across the mucosal barrier. Oral administration of bile acids inhibits these effects. The genes regulated by FXR in ileum suggested that it might contribute to the enteroprotective actions of bile acids. To test this hypothesis, mice were administered either GW4064 or vehicle for 2 days and then subjected to bile duct ligation (BDL) or sham operation. After 5 days, during which GW4064 or vehicle treatment was continued, the mice were killed and their intestines were analyzed for FXR target gene expression. Mice were treated with or without FXR ligand GW4064 for 2 days prior to bile duct ligation surgery and for 5 days after surgery. After 5 days the mice were sacrificed and the ileum collected and processed for gene expression analysis. Gene expression in the ilium from each sample group was assayed in duplicate using Affymetrix Mouse Genome 430A 2.0 Gene Chips.

2012-09-12 | E-GEOD-40821 | biostudies-arrayexpress

Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

2012-09-12 | GSE40821 | GEO

Intestinal microbiota after RYGB

Project description:Objective: Roux-Y gastric bypass (RYGB) surgery is a last treatment resort to induce substantial and sustained weight loss in severe obesity. The anatomical rearrangement affects the intestinal microbiota but so far, little information is available how it interferes with microbial functionality and microbial-host interaction independent from weight loss. Design: A RYGB rat model was utilized and compared to sham-operated controls which were kept at matched body weight as RYGB animals by food restriction. We assessed microbial taxonomy by 16S rRNA gene sequencing and functional activity by metaproteomics and metabolomics on microbiota samples collected separately from the ileum, the cecum as well as the colon and separately analysed the lumen and mucus associated microbiota. Results: Altered gut architecture in RYGB strongly affected the occurrence of Actinobacteria, especially Bifidobacteriaceae and Proteobacteria which were increased, whereas Firmicutes were decreased, although Streptococcaceae and Clostridium perfringens were observed at higher abundances. A decrease of conjugated as well as secondary bile acids was observed in the RYGB-gut lumen. In addition the arginine biosynthesis pathway in the microbiota was altered, indicated by the changes in abundance of upstream metabolites and enzymes, resulting in lower levels of arginine and higher levels of aspartate in the colon after RYGB. Conclusion: The anatomical rearrangement in RYGB affects microbiota composition and functionality by changes in amino acid and bile acid metabolism, independent of weight loss. The shift in microbiota taxonomic structure after RYGB may be mediated by the resulting change in composition of the bile acid pool in the gut lumen.

2020-03-17 | PXD013337 | Pride

MAFG is a transcriptional repressor of bile acid synthesis and metabolism (ChIP-seq)

Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.

2016-02-04 | GSE77529 | GEO

Differential gene expression following MafG overexpression

2016-02-04 | GSE77507 | GEO

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease

Project description:Microbial transformation of bile acids affects intestinal immune homeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. Additionally, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

2024-02-09 | GSE253360 | GEO

Hepatic glucose sensing is required to preserve beta-cell glucose competence

Project description:We assessed the impact of glucose transporter Glut2 gene inactivation in adult mouse liver (LG2KO mice). This suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was normal early after Glut2 inactivation but intolerance developed at later time. This was caused by progressive impairment of glucose-stimulated insulin secretion even though beta-cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinate down-regulation of cholesterol biosynthesis genes in LG2KO mice. This was associated with reduced hepatic cholesterol in fasted mice and a 30 percent reduction in bile acid production. We showed that chronic bile acids or FXR agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls beta-cell glucose competence, through a mechanism that likely depends on bile acid production and action on beta-cells. three replicates each of ps_ctrl_refed, ps_tamox_refed, ps_ctrl_fasted, ps_tamox_fasted

2013-01-18 | E-GEOD-43581 | biostudies-arrayexpress

Hepatic Farnesoid X-Receptor Isoforms α2 and α4 Differentially Modulate Bile Salt and Lipoprotein Metabolism in Mice

Project description:The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8B1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.

2014-11-11 | GSE51805 | GEO

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