Objective Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD).
Design Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity.
Results A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats.
Conclusion Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients.
Trial registration number This study was registered at ClinicalTrials.gov (NCT03010696).
- enteric bacterial microflora
- bile acid
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XW, SY, SL and LZ contributed equally.
Correction notice This article has been corrected since it published Online First. The author names and affiliations have been updated.
Contributors All authors included on a paper fulfil the criteria of authorship.
Funding This work was financially supported by Beijing Municipal Commission of Education Co-constructed Program, the Beijing Science and Technology Project (Z181100009318005), the 111 Project from the Education Ministry of China (No. B18053). Part of this work was also supported by the Metagenopolis grant ANR-11- DPBS-0001 and National Natural Science Foundation of China (NSFC31570116). ZY is supported by the National Natural Science Foundation of China (No. 81772984, 81572614); the Major Project for Cultivation Technology (2016ZX08008001); Basic Research Program (2015QC0104, 2015TC041, 2016SY001, 2016QC086); SKLB Open Grant (2020SKLAB6-18).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval The study protocol was approved by the Ethics Committees of China Agricultural University (No. 2015035) and Beijing Aerospace Center Hospital (No. 20151230-YW-01).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. The shotgun sequencing data for all metagenomic samples have been deposited into the European Bioinformatic Institute (EBI) database under the BioProject accession code PRJNA449784. The serum and faecal metabolomes datasets reported in this article are available at the MetaboLights database (http://www.ebi.ac.uk/metabolights/) with accession number MTBLS700. The authors declare that all other data supporting the ﬁndings of the study are available in the paper and supplementary materials, or from the corresponding authors on request.
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