Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease
- NYU Langone health, United States
- NYU Langone Health, United States
- Litholink Corporation, United States
- Genetech Inc, United States
- Rutgers University, United States
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.
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Author details
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.
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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Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease
eLife 10:e63642.
https://doi.org/10.7554/eLife.63642
