Functional analysis of pre-selected MetaGenomic Species likely predictive of NAFLD progression for an improved quality of care of the patients – FunAMetaGen

Benign steatohepatitis (Non Alcoholic Fatty Liver Disease / NAFLD) represents a spectrum of liver diseases encompassing simple fatty infiltration (steatosis), fat and inflammation (non-alcoholic steatohepatitis - NASH), and cirrhosis in the absence of excessive alcohol consumption, viral diseases or other identified etiologies. Due to the high prevalence and to the fact that NAFLD is a common condition that has significant adverse health consequences for those who are afflicted, NAFLD is considered a major public health problem throughout the world. Liver disease has been associated with changes in the intestinal microbiota and specific pathways in which microbiota is involved have been demonstrated to play a role in exacerbation of liver disease. Taking advantage of recently available high throughput sequencing technologies, the three partners involved in the project are currently working in close collaboration to develop a clinically validated biomarker platform to establish quantitative description of gut microbiota and correlations with disease phenotypes. In this context, MetaGenomic Species (MGS, sets of genes predicted to belong to the same microorganism, likely bacterial species) that are associated with NAFLD but are significantly less abundant in advanced liver disease (NASH) were identified. A biomarker is under development based on these results. This project aims at better understanding the biology beyond the biomarkers, i.e. identify which biological functions associated to the biomarkers could explain their potential beneficial effect, as described recently for Faecalibacterium prausnitzii. Since most gut bacterial species cannot easily be cultivated, an innovative strategy will be used. Briefly, specific probes targeting MGS of interest will be used to enrich stool fractions. DNA will then be extracted from these enriched fractions. A high throughput functional screening method of metagenomic libraries will be used to characterize the putative protective effect of molecules that could be encoded by genes belonging to these MGS. Mice will also be colonized with microbiota derived from patients and known to contain low or high proportions of “protective” MGS, then challenged with high fat/fructose diet to explore the effect of these selected microbiota on the onset of steatohepatitis. This project will make it possible for Enterome to validate the technological concept on which its overall activity is based. Indeed, if a functional link is demonstrated between the selected MGS species identified using Enterome’s technology and the development and/or maintenance of the disease, this would fully validate the relevance of the quantitative metagenomic analysis to accurately identify robust biomarkers. In addition the project will generate new IP such as new clones and new molecules of interest that will potentially be further developed in future projects. New technical tools and animal models colonized with MGS of interest will also be useful in future research projects aiming for example at isolating bacterial species corresponding to beneficial MGS. This will be an important asset in a very competitive field of research that has generated lot of interest from big pharmaceutical companies these last few years, thus supporting the international development of the company in a close partnership with its academic partners INRA-Micalis and INRA-Metagenopolis.