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Human gut metagenome

ABSTRACT: Fecal microbiota transplantation for the gastrointestinal steroid-refractory graft-versus host disease using frozen capsule.

PROVIDER: PRJDB7070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	DRR138494_1.fastq.gz	Fastqsanger.gz
	DRR138494_2.fastq.gz	Fastqsanger.gz
	DRR138495_1.fastq.gz	Fastqsanger.gz
	DRR138495_2.fastq.gz	Fastqsanger.gz
	DRR138496_1.fastq.gz	Fastqsanger.gz

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Inhibition of Bromodomain and Extra Terminal (BET) domain activity modulates the IL-23R/IL17 axis and suppresses acute Graft-Versus-Host Disease [ChIP-seq]

Project description:Acute graft-versus-host disease (GVHD) is the major cause of non-relapse mortality post-allogeneic stem cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Treatment options for steroid-refractory acute GVHD are limited. Bromodomain and Extraterminal Domain (BET) inhibitors PLX51107 and PLX2853, deemed safe in human clinical trials in high risk malignancies, significantly downregulate pro-inflammatory Th1 and Th17 responses without impacting T regulatory cells, improving survival in murine models of acute GVHD while retaining beneficial graft-versus-leukemia effects. Modulation of the IL23/STAT3 axis via BET inhibition resulted in a reduction of pathogenic Th1/Th17 cells in the spleen and acute GVHD target organs such as the gastrointestinal tract. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.

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Inhibition of Bromodomain and Extra Terminal (BET) domain activity modulates the IL-23R/IL17 axis and suppresses acute Graft-Versus-Host Disease [RNA-Seq]

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Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD). The hypothesis of this study is that allogeneic FMT may improve outcomes of these patients.

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Project description:Allogeneic hematopoietic stem cell transplantation remains the most efficacious treatment for many hematological malignancies. However, its therapeutic potential is affected by the most prominent side effect graft versus host disease. Despite advances in the treatment of graft versus host disease in recent years, morbidity and mortality remains high, which requires the development of new treatment approaches. We therefore implemented mouse models to assess potential treatment options for graft versus host disease. In in vivo experiments, we had observed a protective effect of LCN2 on graft versus host disease of the gastrointestinal tract. We also observed higher numbers of anti-inflammatory macrophages in the intestinal tissues of these animals. Therefore, we aimed to determine potentially regulated genes in these cells by using an in vitro approach of LCN2-treated macrophages.

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Project description:Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease

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Project description:Acute graft-versus-host disease (aGvHD) is a significant complication after allogeneic hematopoietic stem cell transplantation (aHSCT), but major factors determining disease severity are not well defined yet. By combining multiplexed tissue imaging and single-cell RNA sequencing on gastrointestinal biopsies from aHSCT patients with fecal microbiome analysis, we could link high microbiome diversity and the abundance of short-chain fatty acid-producing bacteria to the sustenance of suppressive regulatory T cells. Furthermore, aGvHD severity was strongly associated with the clonal expansion of mainly CD8 T cells, which we found distributed over anatomically distant regions of the gut, persistent over time, and inversely correlated with the presence of suppressive Tregs. Overall, our study highlights the pathophysiological importance of expanded CD8 T cell clones in the progression of aGvHD towards more severe clinical manifestations and strongly supports the further development of microbiome interventions as GvHD treatment via repopulation of the gut Treg niche to suppress inflammation.

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