Description du projet
Mettre à l’épreuve les métabolites des bactéries intestinales
Le microbiote intestinal humain joue un rôle fondamental dans la santé et les altérations de sa composition aboutissent à différentes maladies. Des groupes de gènes biosynthétiques sont potentiellement impliqués dans la structure du microbiome, mais peu d’entre eux ont fait l’objet d’une validation expérimentale concernant leur impact métabolique délétère sur l’hôte humain. Le projet SMs‑Gut, financé par l’UE, a pour objectif d’étendre ces découvertes et d’identifier les métabolites spécialisés de l’intestin ayant un rôle fondamental dans le développement de la maladie inflammatoire de l’intestin et du cancer colorectal. Les scientifiques emploieront une combinaison de technologies de bio‑informatique, de biologie synthétique et d’analyse afin de décrypter les fonctions biologiques des composés découverts.
Objectif
Composition changes of the human gut microbiome has been associated with a series of diseases. However, little is known about the mechanism of this microbiome alteration. Recent in silico studies revealed thousands of biosynthetic gene clusters (BGCs) that encode diverse types of specialized metabolites from human microbiomes. Many of these molecules are potentially involved in shaping microbiome structure or directly affect host cell and contribute to disease development. To date, only colibactin, a hybrid polyketide/non-ribosomal peptide produced by Escherichia coli in human gut, has been experimentally validated for its deleterious metabolic impact on human host and linked to the development of colorectal cancer (CRC). Thus, this project aims to expand the knowledge of specialized metabolites produced by gut microbiome and unravel their role in development of inflammatory bowel disease (IBD) and CRC. State-of-the-art bioinformatic, synthetic biology and chemical-analytic technologies will be used to tackle this challenge. In silico identification of BGCs will be facilitated by sequence homology search and the occurrence of function-related resistant makers. The cloning process will be realized by either capturing native BGCs, adopting polymerase amplification or using synthetic DNA, followed by HiFi DNA assembly, Red/ET recombineering based DNA integration method or combining of both strategies. The chemical diversity of these specialized metabolites will be unlocked by heterologous expression of the cloned BGCs and structure elucidation of the produced molecules. The biological functions of the discovered compounds will be established by probing their genotoxicity and cytotoxicity in vitro with human intestinal cell lines.
Champ scientifique
- natural sciencesbiological sciencessynthetic biology
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health sciencesclinical medicineoncologycolorectal cancer
- natural sciencesbiological sciencesmicrobiology
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
01069 Dresden
Allemagne