Microbial genetic and transcriptional contributions to oxalate degradation by the gut microbiota in health and disease

• 27 June 2024

Microbial genetic and transcriptional
contributions to oxalate degradation by
the gut microbiota in health and disease
Menghan Liu1,2†, Joseph C Devlin1,2, Jiyuan Hu1, Angelina Volkova1,2,
Thomas W Battaglia1, Melody Ho1, John R Asplin3, Allyson Byrd4, P’ng Loke1,
Huilin Li1, Kelly V Ruggles1, Aristotelis Tsirigos1, Martin J Blaser5*, Lama Nazzal1*
1NYU Langone Health, New York, United States; 2Vilcek Institute of Graduate
Biomedical Sciences, New York, United States; 3Litholink Corporation, Laboratory
Corporation of America Holdings, Chicago, United States; 4Department of Cancer
Immunology, Genentech Inc, South San Francisco, United States; 5Center for
Advanced Biotechnology and Medicine, Rutgers University, New York, 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. Furthermore, 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 (CD) 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.

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