Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents
Xifan Wang, Songtao Yang, Shenghui Li, Liang Zhao, Yanling Hao, Junjie Qin, Lian Zhang, Chengying Zhang, Weijing Bian, Li Zuo, Xiu Kun Gao, Baoli Zhu, Xin Gen Lei, Zhenglong Gu, Wei Cui, Xiping Xu, Zhiming Li, Benzhong Zhu, Yuan Li, Shangwu Chen, Huiyuan Guo, Hao Zhang, Jing Sun, Ming Zhang, Hui Yan, Xiaolin Zhang, Xiaoxue Liu, Bowen Sun, Longjiao Wang, Qinglu Qiu, Yuchan Zhang, Xingqi Li, Weiqian Liu, Rui Xue, Hong Wu, Donghua Shao, Junling Li, Yuanjie Zhou, Shaochuan Li, Rentao Yang, Oluf Pedersen, Zhengquan Yu, S. Dusko Ehrlich, Fazheng Ren
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. Trial registration number This study was registered at ClinicalTrials.gov ( NCT03010696 ).