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Functional characterization of specialized metabolites from gut microbiomes

Project description

Putting gut bacteria metabolites to the test

The human gut microbiome plays a fundamental role in health, and alterations in its composition lead to various diseases. Biosynthetic gene clusters (BGCs) are potentially implicated in microbiome structure, but very few have been experimentally validated for their deleterious metabolic impact on the human host. The scope of the EU-funded SMs-Gut project is to extend these findings and identify specialised metabolites in the gut with a fundamental role in the development of inflammatory bowel disease and colorectal cancer. Scientists will employ a combination of bioinformatics, synthetic biology and analytical technologies to decipher the biological functions of the discovered compounds.

Objective

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.

Coordinator

TECHNISCHE UNIVERSITAET DRESDEN
Net EU contribution
€ 174 806,40
Address
HELMHOLTZSTRASSE 10
01069 Dresden
Germany

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Region
Sachsen Dresden Dresden, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 174 806,40