Dataset Information

Metabolomics analysis of human acute graft-versus-host disease reveals changes in host and microbiota-derived metabolites (Cohort 2)

ABSTRACT:

Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to Graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota.

Here we used high throughput metabolomics (UPLC-MS/MS) in two cohorts of genotypically HLA-identical related recipient and donor pairs. A first monocentric cohort from Saint Louis hospital (Paris, France) was used as an exploratory cohort (n=43) and a second multicentric national cohort from Cryostem biobank was used as a confimatory cohort (n=56).

Metabolomic profile markedly differed between recipients and donors. At the onset of acute GvHD, in addition to host-derived metabolites, we identified significant variation in microbiota-derived metabolites, especially in Aryl hydrocarbon Receptor (AhR) ligands, bile acids and plasmalogens. Altogether, our findings support that the allogeneic immune response during acute GvHD might be influenced by bile acids and by the decreased production of AhR ligands by microbiota that could limit indoleamine 2,3-dioxygenase (IDO) induction and influence allogeneic T-cell reactivity.

MTBLS204 contains study information relating to cohort 1.

MTBLS205 contains study information relating to cohort 2.

INSTRUMENT(S): Q Exactive

SUBMITTER: David Michonneau

PROVIDER: MTBLS205 | MetaboLights | 2019-11-06

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	MTBLS205	Other
	FILES	Other
	a_MTBLS205__NEG_1_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS205__NEG_2_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS205__POS_1_metabolite_profiling_mass_spectrometry.txt	Txt

Items per page:

1 - 5 of 10

Publications

Metabolomics analysis of human acute graft-versus-host disease reveals changes in host and microbiota-derived metabolites.

Michonneau David D Latis Eleonora E Curis Emmanuel E Dubouchet Laetitia L Ramamoorthy Sivapriya S Ingram Brian B de Latour Régis Peffault RP Robin Marie M de Fontbrune Flore Sicre FS Chevret Sylvie S Rogge Lars L Socié Gérard G

Nature communications 20191213 1

Despite improvement in clinical management, allogeneic hematopoietic stem cell transplantation (HSCT) is still hampered by high morbidity and mortality rates, mainly due to graft versus host disease (GvHD). Recently, it has been demonstrated that the allogeneic immune response might be influenced by external factors such as tissues microenvironment or host microbiota. Here we used high throughput metabolomics to analyze two cohorts of genotypically HLA-identical related recipient and donor pairs ...[more]

PMID: 31836702

Similar Datasets

Project description:Background: The etiology of Inflammatory Bowel Disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown. Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3 and Reg3 independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that five weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype. Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or healthy microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for the host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders.

Project description:Neural control of visceral organ function is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence and is often dysregulated in gastrointestinal (GI) disorders. Luminal factors, such as diet and microbiota regulate neurogenic programs of gut motility, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor Aryl hydrocarbon Receptor (AhR) functions as a biosensor in intestinal neural circuits linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons representing distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles controlled by the combined effects of host genetic programmes and microbial colonisation. Microbiota-induced expression of AhR in neurons of the distal gastrointestinal tract enables them to respond to the luminal environment and induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in enteric neurons of antibiotic-treated mice partially restores intestinal motility. Taken together, our experiments identify AhR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits towards gut homeostasis and health. The enteric nervous system (ENS) encompasses the intrinsic neural networks of the gastrointestinal (GI) tract, which regulate most aspects of intestinal physiology, including peristalsis. In addition to host-specific genetic programmes, microbiota and diet have emerged as critical regulators of gut tissue physiology and changes in the microbial composition of the lumen often accompany GI disorders. We found that gut environmental sensor Aryl hydrocarbon receptor (AhR) is induced in colonic neurons in response to microbiota colonisation and regulates intestinal peristalsis in an AhR ligand-dependent manner. In this experiment, we used RNA sequencing to identify genes regulated in mouse colonic neurons by AhR activation.