1. Computational and Systems Biology
  2. Microbiology and Infectious Disease
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Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

  1. Menghan Liu
  2. Joseph C Devlin
  3. Jiyuan Hu
  4. Angelina Volkova
  5. Thomas W Battaglia
  6. Melody Ho
  7. John R Asplin
  8. Allyson Byrd
  9. P'ng Loke
  10. Huilin Li
  11. Kelly V Ruggles
  12. Aristotelis Tsirigos
  13. Martin J Blaser  Is a corresponding author
  14. Lama Nazzal  Is a corresponding author
  1. NYU Langone health, United States
  2. NYU Langone Health, United States
  3. Litholink Corporation, United States
  4. Genetech Inc, United States
  5. Rutgers University, United States
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Cite this article as: eLife 2021;10:e63642 doi: 10.7554/eLife.63642

Abstract

Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbes can degrade oxalate using multiple ODPs and protect against its absorption. The exact oxalate-degrading taxa in the human microbiota and their ODP have not been described. We leverage multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota primarily uses the type II ODP, rather than type I. Further, among the diverse ODP-encoding microbes, an oxalate autotroph, Oxalobacter formigenes, dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) frequently suffer from disrupted oxalate homeostasis and calcium oxalate nephrolithiasis. We show that the enteric oxalate level is elevated in IBD patients, with highest levels in Crohn's disease patients with both ileal and colonic involvement consistent with known nephrolithiasis risk. We show that the microbiota ODP expression is reduced in IBD patients, which may contribute to the disrupted oxalate homeostasis. The specific changes in ODP expression by several important taxa suggest that they play distinct roles in IBD-induced nephrolithiasis risk. Lastly, we colonize mice that are maintained in the gnotobiotic facility with O. formigenes, using either a laboratory isolate or an isolate we cultured from human stools, and observed a significant reduction in host fecal and urine oxalate levels, supporting our in silico prediction of the importance of the microbiome, particularly O. formigenes in host oxalate homeostasis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2-5.

The following previously published data sets were used

Article and author information

Author details

  1. Menghan Liu

    Sackler Institute of Graduate Biomedical Sciences, NYU Langone health, New York, United States
    Competing interests
    No competing interests declared.
  2. Joseph C Devlin

    Sackler Institute of Graduate Biomedical Sciences, NYU Langone health, New York, United States
    Competing interests
    No competing interests declared.
  3. Jiyuan Hu

    Department of Public Health, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  4. Angelina Volkova

    Sackler Institute of Graduate Biomedical Sciences, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  5. Thomas W Battaglia

    Department of Medicine, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  6. Melody Ho

    Department of Medicine, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  7. John R Asplin

    Litholink Corporation, Chicago, United States
    Competing interests
    John R Asplin, is an employee of Litholink.
  8. Allyson Byrd

    Department of Cancer Immunology, Genetech Inc, South San Francisco, United States
    Competing interests
    Allyson Byrd, is an employee of Genentech.
  9. P'ng Loke

    Department of Microbiology and Immunology, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6211-3292
  10. Huilin Li

    Department of Public Health, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  11. Kelly V Ruggles

    Department of Medicine, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0152-0863
  12. Aristotelis Tsirigos

    Applied Bioinformatics Laboratories, NYU Langone Health, New York, United States
    Competing interests
    No competing interests declared.
  13. Martin J Blaser

    Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United States
    For correspondence
    martin.blaser@cabm.rutgers.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2447-2443
  14. Lama Nazzal

    Department of Medicine, NYU Langone Health, New York, United States
    For correspondence
    Lama.Nazzal@nyulangone.org
    Competing interests
    No competing interests declared.

Funding

National Institute of Allergy and Infectious Diseases (U01AI22285)

  • Martin J Blaser

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110014)

  • Huilin Li

Rare Kidney Stone Consortium (U54 DK083908)

  • Lama Nazzal

The C & D and Zlinkoff Funds

  • Martin J Blaser

Oxalosis and Hyperoxaluria Foundation-American Society of Nephrology (career development grant)

  • Lama Nazzal

TransAtlantic Partnership of the Fondation LeDucq

  • Martin J Blaser

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IA16-00822) of the New York University Langone Medical Center.

Reviewing Editor

  1. Peter Turnbaugh, University of California, San Francisco, United States

Publication history

  1. Received: October 1, 2020
  2. Accepted: March 23, 2021
  3. Accepted Manuscript published: March 26, 2021 (version 1)

Copyright

© 2021, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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