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

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.

Risk factors for developing hyperoxaluria in children with Crohn’s disease

“…In addition to the aforementioned pathogenetic mechanism, we found a significant proportion of CD patients with less O. formigenes colonization compared with controls, and the majority of the hyperoxaluria group (91%) had undetected O. formigenes in their stools. This is in accordance with a recent 2021 study analyzing large-scale data demonstrating that in comparison with the general population, patients with oxalate stones have low levels of intestinal colonization with O. formigenes [23].…”

An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria

“…The role of OF in human oxalate metabolism has been extensively characterized (Liu et al , 2021 ). OF expresses an oxalate degradation pathway comprised of genes encoding the oxalate/formate antiporter (OxlT), oxalyl‐CoA decarboxylase (OxdC), and formyl‐CoA transferase (Frc).…”

Probiotic Oxalate-Degrading Bacteria: New Insight of Environmental Variables and Expression of the oxc and frc Genes on Oxalate Degradation Activity

“…The potential for replacement therapy with probiotic preparations of O. formigenes should be excellent in such a niche [ 47 ]. In these investigations, molecular quantitative methods can be used since Oxalobacter’s loss correlates with other diseases, in addition to the potential link between antibiotic use and its loss [ 48 ] will be helpful. Other than LAB and O. formigenes , it seems unclear what bacteria are responsible for oxalate degradation in the gut [ 9 , 27 ].…”