Description du projet
Mieux comprendre la relation entre le microbiote de l’intestin et l’hôte
Les micro-organismes qui résident dans l’intestin (collectivement appelés microbiote intestinal) jouent un rôle important dans la santé humaine. Ils produisent des molécules bioactives et des métabolites qui influencent le métabolisme de l’hôte et son expression génétique. La délimitation complète des interactions métaboliques précises entre le microbiote et l’hôte nécessite des méthodes permettant de distinguer les métabolites générés par l’hôte de ceux générés par le micro-organisme. Pour surmonter cet obstacle, le projet GutTransForm, financé par le CER, propose d’élaborer une approche systématique qui utilise des molécules médicamenteuses pour sonder la capacité du microbiote intestinal à modifier les substances chimiques. Cette approche permettra de dévoiler des aspects clés de la relation entre le microbiote et l’hôte, qui pourraient être utiles à la conception d’interventions médicales.
Objectif
The variability of the human gut microbiome (entirety of microorganisms inhabiting the intestine) far exceeds human genome variability, and has been connected to various aspects of human health. Although microbiome differences are often linked to altered metabolism, the current view on metabolic interactions between the microbiota and the host remain mostly descriptive due to several limiting factors. First, most sequencing-based human microbiome studies rely on correlative analyses between microbiome composition and human phenotypes, depend on largely incomplete microbial genome annotations, and are not targeted to identify community-mediated functional traits. Second, many metabolites can be both of microbial and human origin, which makes it conceptually and methodologically challenging to disentangle metabolic microbiota-host interactions.
To overcome these limitations, I propose a systematic bottom-up strategy to mechanistically study metabolic microbiota-host interactions by harnessing gut microbiota’s capacity to biotransform (chemically modify) drug molecules. The large chemical diversity and exogenous origin makes medical drugs ideally suited for experimental in vitro and in vivo approaches to probe microbiota-host interactions in a controlled way. We will combine high-throughput culturing protocols, genetics, metabolomics measurements, genomics analyses, gnotobiotic mouse work, and computational modeling to connect interpersonal differences in microbiome composition to differences in metabolic functions of individuals’ gut microbiota, and ultimately link them to molecular host phenotypes. Generating these mechanistic insights and transformational resources is essential to understand the fundamental principles of the microbiota-host relationship. In addition, this project has direct medical relevance, as it provides actionable microbiome-based links to interpersonal differences in medical drug response, which remain a widespread problem in clinical practice.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
69117 Heidelberg
Allemagne