Descrizione del progetto
Svelare la relazione tra microbiota intestinale e ospite
I microrganismi che risiedono nell’intestino (conosciuti collettivamente come microbiota intestinale) hanno un ruolo importante nella salute umana. Producono, infatti, molecole bioattive e metaboliti che influenzano il metabolismo dell’ospite e la sua espressione genica. Per delineare con precisione le interazioni metaboliche tra il microbiota e l’ospite sono necessari metodi in grado di discriminare tra i metaboliti generati dall’ospite e dal microrganismo. Per superare queste limitazioni, il progetto GutTransForm, finanziato dal CER, propone di sviluppare un approccio sistematico che utilizza molecole farmacologiche per sondare la capacità del microbiota intestinale di modificare le sostanze chimiche. Questo approccio contribuirà a svelare gli aspetti chiave della relazione microbiota-ospite che possono essere utili nella progettazione di interventi medici.
Obiettivo
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.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
69117 Heidelberg
Germania