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Gut microbiota-dependent tryptophan metabolism: role in disease pathogenesis and therapeutic target

Objective

Tryptophan (Trp) is an essential amino acid required for protein biosynthesis and is also a biochemical precursor of metabolites which have major effects on mammalian physiology. In the gastrointestinal tract, Trp metabolism can follow three major pathways, all of which are under the control of the gut microbiota: (i) the kynurenin pathway in immune and epithelial cells via indoleamine 2,3-Dioxygenase 1, (ii) the serotonin production pathway in enterochromaffin cells via Trp hydroxylase 1 and (iii) the direct use of Trp by the microorganisms of the gut microbiota into several molecules including ligands of the Aryl Hydrocarbon Receptor. The end products of these pathways play key roles in modulating the immune response, intestinal and metabolic functions and behaviour. Several diseases which involve the gut microbiota in their pathogenesis are also impacted by Trp metabolite. This suggests that the effect of the microbiota in these diseases could be at least partially mediated by impaired Trp metabolism. We recently observed that impaired Trp metabolism by the gut microbiota is involved in inflammatory bowel disease pathogenesis and preliminary data suggest a potential role in other major human diseases.
The aims of the current proposal are (i) to identify the components of the gut microbiota, including both bacteria and fungi, involved in the control of the 3 Trp metabolism pathways in the gut, (ii) to decipher the reciprocal equilibrium between the pathways and to evaluate the potential of its modulation as a therapeutic target, and finally (iii) to assess the relevance of these phenomena in human patients.
This challenging project will involve multi-disciplinary aspects, from microbiology to metabolism, inflammation and medicine, the use of multiple cutting edge technologies and translational analysis from mice to human. Beside scientific importance, it will have societal impact by identifying new therapeutic strategies in several human diseases with unmet needs.

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Keywords

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Programme(s)

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Topic(s)

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ERC-STG - Starting Grant

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Call for proposal

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(opens in new window) ERC-2016-STG

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Host institution

SORBONNE UNIVERSITE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 533 816,25
Address
21 RUE DE L'ECOLE DE MEDECINE
75006 PARIS
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 533 816,25

Beneficiaries (2)

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