Chronic kidney disease (CKD) affects 10 to 15% of the adult population and is associated with high risks of progression to end-stage kidney disease (ESKD), cardiovascular disease and mortality. Few treatments are currently available to slow CKD progression and reduce its complications. The composition of gut microbiota in CKD has attracted particular interest, because of its role in colon-derived uremic solutes. Food protein fermentation by the gut microbiota leads to the generation of waste metabolites, known as uremic toxins that are normally cleared by the kidneys. These toxins promote CKD progression, insulin resistance and inflammation. Nevertheless, the relations between features of the gut microbiota, uremic toxin production and CKD progression have not been explored prospectively in humans. The overall goal of the CKD_Microbiome project is to investigate the role and mechanisms of gut microbiota-related toxicity in the progression of CKD and the potential impact of diet on that relation. It includes an observational and an experimental component.
The observational component of the project is an ancillary study based on the on-going CKD-REIN study, a large prospective cohort that included 3033 adult patients with non-dialysis CKD stages 3-5 (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m²), from 40 nationally representative nephrology outpatient facilities, recruited from 01/2014 to 03/2016. Patient follow-up is on-going and will last 5 years, with an annual clinical and biological data collection. The CKD_Microbiome study is based on a subsample of 240 patients with simultaneous blood and stool samples collected twice, 3 years apart, at the 2-year (completed) and 5-year (to be completed) follow-up examinations, together with data on food intake. Highly standardized protocols will be used throughout to extract total DNA from stools, shotgun sequence the DNA, and deduce the presence and abundance of each microbial species and functionalities for all samples. In parallel, protein-bound and unbound uremic toxins will be measured in blood. Availability of these unique samples and the expertise in metagenomic profiling of INRA-MetaGenoPolis will allow us to assess both cross-sectional and longitudinal associations of gut microbiome composition and functionalities with kidney function and its decline over 3 years, and to test the hypothesis (primary objective) that some microbiota compositions worsen CKD progression through production of uremic toxin precursors. This observational component will also evaluate the potential modulating effect of dietary patterns on these associations (secondary objective).
In the experimental component of the project, we will investigate the causality of the relation between microbial species, identified by metagenomics, and uremic toxin production. We will study the impact of faecal microbiota transplantation (FMT) from CKD patients with high vs low levels of uremic toxins, into antibiotic-treated mice and investigate their uremic toxin production.
The CKD_Microbiome consortium is composed of 5 complementary teams providing the expertise required in metagenomics and bioinformatics (SD Ehrlich, INRA U1367), uremic toxin analyses (JC Alvarez, ZA Massy, UVSQ), epidemiology and biostatistics (B Stengel, INSERM U1018, S Wagner, CIC1433, SD Ehrlich, INRA U1367), nutrition (S Wagner, CIC1433, D Fouque, INSERM U1060), nephrology and basic sciences (L Koppe, D Fouque, INSERM U1060) as well as operational capacity, which form the pillars of the project.
The CKD_Microbiome project will provide new conceptual and mechanistic leads, based on 'toxic' microbiome tests performed in animal models and will improve our understanding of gut microbiota-related toxicity in CKD. This may identify new prognostic biomarkers of CKD progression in humans and provide the basic data to design interventions by food modulation, to change the microbiota, in order to diminish its toxicity.
Madame Bénédicte Stengel (CENTRE DE RECHERCHE EN ÉPIDÉMIOLOGIE ET SANTÉ DES POPULATIONS)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CESP CENTRE DE RECHERCHE EN ÉPIDÉMIOLOGIE ET SANTÉ DES POPULATIONS
UMR_S1060 LABORATOIRE DE RECHERCHE EN CARDIOVASCULAIRE, METABOLISME, DIABETOLOGIE (CARMEN)
2IC Infection et Inflammation chronique
Help of the ANR 461,332 euros
Beginning and duration of the scientific project: December 2019 - 48 Months