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T cell regulation by fed state bacterial metabolites

Intestinal microbial communities expand the functional capabilities of the host via their metabolic attributes. From energy harvest to the production of vitamins, the gut microbiota shapes mammalian physiology and is often conside... ver más

31/12/2028

CEMM FORSCHUNGSZE...

1M€

Presupuesto del proyecto: 1M€

Líder del proyecto

CEMM FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZ... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-09-12

ERC-2023-STG: ERC STARTING GRANTS Scope:Objectives

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Duración del proyecto: 63 meses Fecha Inicio: 2023-09-12
Fecha Fin: 2028-12-31

Líder del proyecto

CEMM FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZ... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 1M€

Descripción del proyecto Intestinal microbial communities expand the functional capabilities of the host via their metabolic attributes. From energy harvest to the production of vitamins, the gut microbiota shapes mammalian physiology and is often considered a postnatally developed organ. Yet, the microbiome poses a formidable challenge to the immune system: How can we host trillions of bacteria without mounting an inflammatory response? Gut immune homeostasis relies on the balanced action of suppressive and inflammatory T cell subsets. I discovered that bacterial metabolism of bile acids and dietary fibers promotes the differentiation of suppressive T cells. Given the complexity of the microbiome, finding other immunoregulatory cues deployed by gut bacteria and their mechanisms of action remains a major challenge, and the logic behind these tolerance mechanisms is not understood. I will use a novel conceptual framework to bridge this gap: based on my previous findings, I postulate that immunoregulatory bacterial molecules are produced in response to food intake. Within this emerging paradigm, I selected two new groups of bacterial molecules for immediate investigation and developed a strategy to identify novel putative immunoregulatory candidates based on a careful examination of microbial metabolism after food intake. I will find the molecular targets of active molecules using chemical screening and chemoproteomic methods and test metabolites in vivo by colonizing germ-free mice with genetically manipulated bacterial strains. The proposed work is grounded on my strong expertise in host-microbe interactions and takes advantage of the state-of-the-art biochemistry facilities at my hosting institution and of the complementary skillsets of my collaboration network. This synergistic combination will allow for a comprehensive interrogation of immunological tolerance to gut commensals: from metabolites and their molecular targets to their functional relevance for intestinal health.

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