Human gut Microbiome, gene Expression and Colorectal Cancer: Assigning causal roles from a novel Mendelian randomization perspective.

Informations projet

MECoCaM

N° de convention de subvention: 796216

DOI

10.3030/796216

Projet clôturé

Date de signature de la CE 5 Avril 2018

Date de début 3 Septembre 2018

Date de fin 2 Septembre 2020

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 158 121,60

Contribution de l’UE

€ 158 121,60

Coordonné par

FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE BELLVITGE
Spain

Periodic Reporting for period 1 - MECoCaM (Human gut Microbiome, gene Expression and Colorectal Cancer: Assigning causal roles from a novel Mendelian randomization perspective.)

Période du rapport: 2018-09-03 au 2020-09-02

Résumé du contexte et des objectifs généraux du projet

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths in the world and its burden is expected to increase by 60% to more than 1.1 million cancer deaths by 2030. Among CRC risk factors, the contribution of the microbial ecosystem in the gut (gut microbiome) to CRC is not well understood. Some correlations between a microbe and cancer stages have been observed, but only Fusobacterium has shown consistent evidence as risk factor. Additionally, the enrichment of a microbe at a tumour site does not directly assume causation. Rather, microbes may find a carcinogenic ambient as underused nutritional niche (reverse causation) or external exposures can be independently influencing both microbial and host cell proliferation (confounding).
In order to reveal causal associations between microbiota and CRC risk and its biological mechanism, in this project, we assessed the potential causal effect of microbiota on host colon gene expression and on CRC risk, using genetic instruments under a Mendelian randomization approach.
The results did not clarify the role of microbiota to CRC risk; however, their reflected the effect of the gut microbiota composition in the gene expression of a healthy colon tissue. This can be used as a reference dataset for microbiome-based therapies in colon diseases, such as CRC and inflammatory bowel diseases.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Initially, using genetic instruments for gut microbiota from The Flemish Gut Flora Project (FGFP), we identified weak association between microbiome taxa and CRC risk, and we could not appraise the role of microbiota to CRC risk. This was done in collaboration with Prof. Nicholas Timpson from the School of Social and Community Medicine of the University of Bristol in UK.
Analysing 350 gut healthy tissue samples we identified 15,542 genes expressed in the gut that clustered in 22 modules of gene co-expression (correlated gene expression). Then, during the secondment performed at the APC Microbiome Institute at the University of Cork under the supervision of Prof. Paul O’Toole, we distinguished 245 different bacterial taxa, most of them clustered in 28 modules of co-abundance (correlated taxa), and 14 of these clusters influenced the gene expression of 17 modules of gene co-expression.
The methodology and results were disseminated in international conferences as poster or oral presentations for the scientific audience, and as videos at the IDIBELL Youtube channel for the general audience. Scientific publications will be ready by 2021.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We described for first time the effect of the gut microbiota composition in the gene expression of a healthy colon tissue, and generated a reference dataset for microbiome-based therapies in colon diseases, such as CRC and inflammatory bowel diseases. These results are paving the way to guide a state-of-art multidisciplinary approach to the microbiome-based therapies, a research field with great success in the following decade.

Reddish and bluish colours represent that bacterial module increase or decrease, respectively.