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Original research
Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents
  1. Xifan Wang1,
  2. Songtao Yang2,
  3. Shenghui Li3,
  4. Liang Zhao4,
  5. Yanling Hao1,
  6. Junjie Qin3,
  7. Lian Zhang5,
  8. Chengying Zhang6,
  9. Weijing Bian7,
  10. Li Zuo8,
  11. Xiu Gao9,
  12. Baoli Zhu10,
  13. Xin Gen Lei11,
  14. Zhenglong Gu12,
  15. Wei Cui13,
  16. Xiping Xu1,14,
  17. Zhiming Li3,
  18. Benzhong Zhu15,
  19. Yuan Li1,
  20. Shangwu Chen4,
  21. Huiyuan Guo4,
  22. Hao Zhang15,
  23. Jing Sun16,
  24. Ming Zhang17,
  25. Yan Hui1,
  26. Xiaolin Zhang1,
  27. Xiaoxue Liu1,
  28. Bowen Sun1,
  29. Longjiao Wang1,
  30. Qinglu Qiu1,
  31. Yuchan Zhang1,
  32. Xingqi Li4,
  33. Weiqian Liu15,
  34. Rui Xue18,
  35. Hong Wu2,
  36. DongHua Shao2,
  37. Junling Li9,
  38. Yuanjie Zhou3,
  39. Shaochuan Li3,
  40. Rentao Yang3,
  41. Oluf Borbye Pedersen19,
  42. Zhengquan Yu1,20,
  43. Stanislav Dusko Ehrlich21,22,
  44. Fazheng Ren1
  1. 1Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
  2. 2Department of Nephrology, Aerospace Center Hospital, Beijing, China
  3. 3Promegene Institute, Shenzhen, China
  4. 4Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
  5. 5Department of Epidemiology, School of Oncology, Beijing University, Beijing, China
  6. 6Department of Nephrology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China
  7. 7Renal Division, Beijing AnZhen Hospital, Capital Medical University, Beijing, China
  8. 8Department of Nephrology, Peking University People's Hospital, Beijing, China
  9. 9Department of Nephrology, Peking University Shougang Hospital, Beijing, China
  10. 10Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
  11. 11Department of Animal Science, Cornell University, Ithaca, New York, USA
  12. 12Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA
  13. 13Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
  14. 14Renal Division, Nanfang Hospital, National Clinical Research Center for Kidney Disease, Southern Medical University, State Key Laboratory for Organ Failure Research, Guangzhou, Guangdong, China
  15. 15Beijing Laboratory of Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
  16. 16Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
  17. 17School of Food and Chemical Engineering, Beijing Technology and Business University, Beijing, China
  18. 18Shanghai SLAC Laboratory Animal Co., Ltd, Shanghai Laboratory Animal Center, Shanghai, China
  19. 19Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, Kobenhavns Universitet, Kobenhavn, Denmark
  20. 20State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
  21. 21Metagenopolis, Université Paris-Saclay, INRAE, MGP, 78350, Jouy-en-Josas, France
  22. 22Dental Institute, King's College London, London, London, UK
  1. Correspondence to Professor Stanislav Dusko Ehrlich, Metagenopolis, INRA, Jouy enn Josas, France; stanislav.ehrlich{at}inra.fr; Professor Fazheng Ren, China Agricultural University, Beijing, China; renfazheng{at}cau.edu.cn; Professor Zhengquan Yu, China Agricultural University, Beijing, China; zyu{at}cau.edu.cn

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).

  • enteric bacterial microflora
  • bile acid
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Footnotes

  • 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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