Dataset Information

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents

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.

INSTRUMENT(S): Liquid Chromatography MS - Negative (LC-MS (Negative)), Gas Chromatography MS - Positive (GC-MS (Positive)), Liquid Chromatography MS - Positive (LC-MS (Positive))

SUBMITTER: Fazheng Ren

PROVIDER: MTBLS700 | MetaboLights | 2020-10-20

REPOSITORIES: MetaboLights

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Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

Wang Xifan X Yang Songtao S Li Shenghui S Zhao Liang L Hao Yanling Y Qin Junjie J Zhang Lian L Zhang Chengying C Bian Weijing W Zuo Li L Gao Xiu X Zhu Baoli B Lei Xin Gen XG Gu Zhenglong Z Cui Wei W Xu Xiping X Li Zhiming Z Zhu Benzhong B Li Yuan Y Chen Shangwu S Guo Huiyuan H Zhang Hao H Sun Jing J Zhang Ming M Hui Yan Y Zhang Xiaolin X Liu Xiaoxue X Sun Bowen B Wang Longjiao L Qiu Qinglu Q Zhang Yuchan Y Li Xingqi X Liu Weiqian W Xue Rui R Wu Hong H Shao DongHua D Li Junling J Zhou Yuanjie Y Li Shaochuan S Yang Rentao R Pedersen Oluf Borbye OB Yu Zhengquan Z Ehrlich Stanislav Dusko SD Ren Fazheng F

Gut 20200402 12

<h4>Objective</h4>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).<h4>Design</h4>Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy c ...[more]

PMID: 32241904

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Project description:Background: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. Methods: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Results: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Conclusions: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

			Action	DRS
	MTBLS700	Other
	FILES	Other
	a_MTBLS700_FecBA_Targ_Neg_LC_MS.txt	Txt
	a_MTBLS700_Fec_GC_MS.txt	Txt
	a_MTBLS700_Ser_Targ_LC_MS.txt	Txt