Proteome-wide functional interrogation and modulation of gut microbiome species (ProFITGut)
financed by ERC.
This project aims at providing insight into the function of proteins in species of the human gut microbiome, and find drugs to modulate the function of specific proteins to enable rational manipulation of microbiome species composition.
The collection of microbial species that lives in our intestine is known as the human gut microbiome. Imbalances in the composition of the microbiome have been associated with disease. However, we currently do not know the molecular mechanisms that drive these associations. This is partially owed to our lack of knowledge of protein function of a large proportion of the proteome of these organisms. Since these organisms are phylogenetically distinct from current model organisms, inferring protein function based on sequence or structural homology is difficult. Further, the number of species that is amenable to genetic manipulation is limited, which prevents the use of traditional molecular biology approaches.
This project will use systems biology approaches based on proteomics to reveal the function and interactions of proteins of microbiome species. This will be achieved by perturbing the proteome of selected species with commonly used drugs, since proteins of related function change in their levels in a similar way across perturbations. By digging deeper into the mechanisms of action and resistance of these drugs, we will be able to predict which microbiome species are susceptible to specific drugs: those that encode the target, but not the resistance mechanism. These will provide the ability to specifically deplete disease-associated species from microbial communities, a first step towards rational manipulation of microbiome composition.
Overall, this project creates the opportunity for the microbiome field to move from associations towards molecular mechanisms. The overall goal is to design preventive or therapeutic strategies to promote health with reduced side effects.