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Understanding the gut–kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers
  1. Andrea Ticinesi1,2,3,
  2. Christian Milani4,
  3. Angela Guerra2,3,
  4. Franca Allegri2,3,
  5. Fulvio Lauretani2,3,
  6. Antonio Nouvenne1,2,3,
  7. Leonardo Mancabelli4,
  8. Gabriele Andrea Lugli4,
  9. Francesca Turroni1,4,
  10. Sabrina Duranti4,
  11. Marta Mangifesta4,5,
  12. Alice Viappiani5,
  13. Chiara Ferrario4,
  14. Rossella Dodi6,
  15. Margherita Dall’Asta6,
  16. Daniele Del Rio1,7,
  17. Marco Ventura1,4,
  18. Tiziana Meschi1,2,3
  1. 1 Microbiome Research Hub, University of Parma, Parma, Italy
  2. 2 Department of Medicine and Surgery, University of Parma, Parma, Italy
  3. 3 Dipartimento Medico-Geriatrico-Riabilitativo, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy
  4. 4 Laboratory of Probiogenomics, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy
  5. 5 GenProbio S.r.l., Parma, Italy
  6. 6 Department of Food and Drugs, University of Parma, Parma, Italy
  7. 7 Department of Veterinary Science, University of Parma, Parma, Italy
  1. Correspondence to Dr Andrea Ticinesi, Department of Medicine and Surgery, University of Parma, Parma 43126, Italy; andrea.ticinesi{at}


Objectives The involvement of the gut microbiota in the pathogenesis of calcium nephrolithiasis has been hypothesised since the discovery of the oxalate-degrading activity of Oxalobacter formigenes, but never comprehensively studied with metagenomics. The aim of this case–control study was to compare the faecal microbiota composition and functionality between recurrent idiopathic calcium stone formers (SFs) and controls.

Design Faecal samples were collected from 52 SFs and 48 controls (mean age 48±11). The microbiota composition was analysed through 16S rRNA microbial profiling approach. Ten samples (five SFs, five controls) were also analysed with deep shotgun metagenomics sequencing, with focus on oxalate-degrading microbial metabolic pathways. Dietary habits, assessed through a food-frequency questionnaire, and 24-hour urinary excretion of prolithogenic and antilithogenic factors, including calcium and oxalate, were compared between SFs and controls, and considered as covariates in the comparison of microbiota profiles.

Results SFs exhibited lower faecal microbial diversity than controls (Chao1 index 1460±363vs 1658±297, fully adjusted p=0.02 with stepwise backward regression analysis). At multivariate analyses, three taxa (Faecalibacterium, Enterobacter, Dorea) were significantly less represented in faecal samples of SFs. The Oxalobacter abundance was not different between groups. Faecal samples from SFs exhibited a significantly lower bacterial representation of genes involved in oxalate degradation, with inverse correlation with 24-hour oxalate excretion (r=−0.87, p=0.002). The oxalate-degrading genes were represented in several bacterial species, whose cumulative abundance was inversely correlated with oxaluria (r=−0.85, p=0.02).

Conclusions Idiopathic calcium SFs exhibited altered gut microbiota composition and functionality that could contribute to nephrolithiasis physiopathology.

  • urolithiasis
  • metagenomics
  • diet
  • microbiome
  • oxalate
  • kidney stones

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  • AT and CM contributed equally.

  • Contributors Conception and design of the study: AT, AN, TM. Data collection: AT, FA, AN, TM. Data preparation: CM, AG, LM, GAL, FT, SD, MM, AV, CF, MDA, RD, MV. Data analysis and interpretation: AT, CM, FL, MDA, DDR, MV, TM. Manuscript drafting: AT, CM. Critical revision for important intellectual content: FL, DDR, MV. All the authors approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests TM received an unconditioned grant for research in the field of nephrolithiasis by Fiuggi Acqua & Terme S.p.A. (Fiuggi, Frosinone, Italy). All the other authors have no conflict of interest to declare.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by the local ethics committee (Comitato Etico per Parma).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The 16S rRNA profiling data and shotgun metagenomics data sequenced in this study were deposited in SRA database under the following study accession numbers: SRP125171 and SRP125191.

  • Presented at The results of this study have been presented as AT’s PhD dissertation at the Department of Medicine and Surgery of Parma University in October 2017.

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