Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents
Top Cited Papers
Open Access
- 30 November 2020
- Vol. 69 (12), 2131-+
- https://doi.org/10.1136/gutjnl-2019-319766
Abstract
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.Funding Information
- Beijing Municipal Commission of Education Co-constructed Program, the Beijing Science and Technology Project (Z181100009318005)
- Agence Nationale de la Recherche (Metagenopolis grant ANR-11-DPBS-0001)
- National Natural Science Foundation of China (NSFC31570116)
- 111 Project from the Education Ministry of China (B18053)
This publication has 55 references indexed in Scilit:
- p -Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidaseKidney International, 2013
- Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κBBMC Nephrology, 2013
- Prevalence of chronic kidney disease in China: a cross-sectional surveyThe Lancet, 2012
- Colonic Contribution to Uremic SolutesJournal of the American Society of Nephrology, 2011
- Protein-Bound Uremic Toxins: New Insight from Clinical StudiesToxins, 2011
- Gut flora metabolism of phosphatidylcholine promotes cardiovascular diseaseNature, 2011
- p-Cresol and Cardiovascular Risk in Mild-to-Moderate Kidney DiseaseClinical Journal of the American Society of Nephrology, 2010
- Metabolite Profiling Identifies Markers of UremiaJournal of the American Society of Nephrology, 2010
- Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease PatientsClinical Journal of the American Society of Nephrology, 2009
- Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolitesProceedings of the National Academy of Sciences of the United States of America, 2009