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

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

PROVIDER: PRJNA1065397 | ENA |

REPOSITORIES: ENA

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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

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 homoeostasis 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. In addition, 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.

| S-EPMC11196888 | biostudies-literature

Graft versus host disease treatment with mesenchymal stem cells

Project description:graft versus host disease organoids were co-cultured with mesenchymal stem cells

2024-05-22 | PXD034822 | Pride

6-phosphogluconate dehydrogenase blockade in T Cells mitigates acute graft-versus-host disease while preserving graft-versus-tumor activity

Project description:6-phosphogluconate dehydrogenase blockade in T Cells mitigates acute graft-versus-host disease while preserving graft-versus-tumor activity

| PRJNA1225717 | ENA

Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Project description:To predict shared graft versus leukemia minor histocompatibility antigens (mHAs) from the DISCOVeRY-BMT dataset. Via mass spectrometry, we then validated predicted mHAs in cell lines with the corresponding HLA allele and nonzero RNAseq reads corresponding to the source gene of the mHA.

2022-12-06 | GSE212013 | GEO

Host NLRP6 exacerbates graft-versus-host disease independent of microbial diversity

Project description:Host NLRP6 regulates innate immune responses and gastrointestinal (GI) homeostasis. It plays a protective role in pathogenic processes such as intestinal colitis and tumorigenesis in a microbiome dependent manner. Host innate immunity and changes in microbial diversity also play a role in the severity of allo-immune-mediated gastrointestinal pathogenic process, namely graft-versus-host disease (GVHD), the principal toxicity after allogeneic bone marrow transplantation (allo-BMT). Herein, we examined the role of NLRP6 in multiple murine models of allo-BMT. In contrast to its role in intestinal colitis, host NLRP6 aggravated GI GVHD. NLRP6-deficient animals showed improved intestinal barrier function, increased levels of tissue repair associated proteins and preserved Goblet and Paneth cell numbers in the GI tract after allo-BMT. The impact of host NLRP6 deficiency in mitigating GVHD was observed regardless of co-housing, antibiotic treatment, or colonizing littermate germ free wild type (WT) and NLRP6 deficient hosts with fecal microbial transplantation from SPF WT and Nlrp6-/- animals. Chimera studies were performed to assess the role of NLRP6 expression on host hematopoietic and non-hematopoietic cells. The allogeneic [B6Ly5.2→Nlrp6-/-] animals demonstrated significantly improved survival compared to the allogeneic [B6Ly5.2→B6] animals, demonstrating that the absence of NLRP6 in host non-hematopoietic cells is crucial for the protection against GVHD, but did not alter the therapeutic graft-versus-tumor effects after BMT. Our results unveil a novel role for NLRP6 and demonstrate a pathogenic role in GVHD that is independent of variations in its intestinal microbiome in contrast to its well-appreciated microbiome-dependent protective role in intestinal colitis and tumorigenesis.

2018-11-05 | ST001089 | MetabolomicsWorkbench

Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

Project description:Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

| PRJNA873278 | ENA

Transcriptome analysis of acute graft-versus-host disease in children

Project description:Transcriptome analysis of acute graft-versus-host disease in children

| PRJNA706045 | ENA

6-phosphogluconate dehydrogenase blockade in T Cells mitigates acute graft-versus-host disease while preserving graft-versus-tumor activity

Project description:T cells undergo significant metabolic reprogramming after allogeneic hematopoietic cell transplantation (allo-HCT). However, the influence of metabolic pathway reprogramming on altering the severity and mortality of acute graft-versus-host disease (aGvHD), a critical allo-HCT complication, remains unclear. Through single-cell RNA sequencing (scRNA-seq) of allogeneic T cells isolated from the spleen of GvHD mice, we uncovered that 6-phosphogluconate dehydrogenase (6PGD), the second major rate-limiting enzyme in the oxidative pentose phosphate pathway, is upregulated and activated during allo-HCT. Clinical and histopathological analyses revealed that 6PGD deficiency in donor T cells significantly mitigates aGvHD severity and mortality in murine models of acute GvHD. An in vitro assay using murine and human T cells and an in vivo murine GvHD model showed that in the absence of an intact 6PGD pathway, donor T cell proliferation was reduced. Metabolic analyses confirmed that blocking 6PGD activity shifted T cell metabolism from glycolysis to oxidative phosphorylation (OXPHOS), as evidenced by isotope-labeled metabolic tracing and Seahorse assays. Pharmacological inhibition of 6PGD with 6-aminonicotinamide (6AN) demonstrated similar efficacy as the infusion of donor 6PGD deficient T cells in reducing aGvHD severity in allogeneic aGvHD and humanized xenogeneic GvHD models. Importantly, 6PGD inhibition preserved the graft-versus-tumor (GvT) effect by promoting the generation of a small subset of effector T cells with potent anti-tumor activity. From these findings we propose 6PGD as a promising therapeutic target for alleviating aGVHD the beneficial GvT effects.

2025-04-30 | GSE289995 | GEO

Beclomethasone in Treating Patients With Graft-Versus-Host Disease of the Esophagus, Stomach, Small Intestine, or Colon

Project description:RATIONALE: Beclomethasone may be an effective treatment for graft-versus-host disease. PURPOSE: Phase I/II trial to study the effectiveness of beclomethasone in treating patients who have graft-versus-host disease of the esophagus, stomach, small intestine, or colon.

| 2005776 | ecrin-mdr-crc

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