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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253360 | GEO | 2024/02/09

REPOSITORIES: GEO

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Microbial Bile Acid Metabolism Shapes T Cell Responses During Inflammation

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

2023-06-28 | MSV000092300 | MassIVE

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

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Next Generation Sequencing Analysis of colon transcriptomes in BF638R bsh- and bF638R bsh+ colonized Cdx2Apcf/w mice.

Project description:Bacteroides, that expresses bile salt hydrolase (BSH), is considered as a potential drug target for metabolic diseases. In the present study, BSH-expressing Bacteroides was found to be enriched in two different CRC mouse models and colonization of nonenterotoxigenic Bacteroides species, such as B. fragilis 9343 or B. vulgatus , enhanced CRC growth. Expression of the 9343 bsh gene in B. fragilis 638R, a bsh - lacking strain, enabled more bile acids to escape into the colon and accelerated CRC progression . The presence of BSH activated WNT signaling and upregulated CCL28 expression dependent on b-catenin in colon tumors. The activated b-catenin/CCL28 axis elevated intra-tumororal immunosuppressive CD25+ FOXP3+ T reg cells. Anti-CCL28 antibody reversed microbial BSH amplificationinduced immunosuppression. Inhibition of BSH reduced CRC progression, coincident with suppression of WNT signaling and CCL28 expression. These findings provide a novel insight into the pro-carcinogenetic role of NTBF in CRC and characterize BSH as a potential target for CRC treatment.

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

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

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

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2014-05-09 | GSE46952 | GEO

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

Dietary fiber is a critical determinant of pathologic ILC2 responses and intestinal inflammation - Bulk RNA-Seq

Project description:Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared to controls, suggesting relevance of this diet-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.

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