Oxalates, Kidney Stones, and the Microbiome

Oxalates are naturally occurring compounds found in many foods, formed as end products of metabolism in plants and animals. Chemically, oxalates are salts or esters of oxalic acid that can bind with minerals like calcium to form insoluble crystals like calcium oxalate. Dietary sources of oxalates include leafy greens (e.g., sorrel, spinach, moringa), chia seeds, nuts, beets, sweet potatoes, certain fruits like kiwi, and even chocolate.^1-5 These so-called “toxic superfoods” can contribute to excessive oxalate intake if consumed in large quantities, potentially increasing the risk of health issues in susceptible individuals. Endogenous oxalate is also produced in the liver through glyoxylate metabolism.⁶

In humans, excessive oxalate can lead to oxalosis, a condition characterized by the systemic deposition of calcium oxalate crystals in tissues.^5-8 This is particularly common in primary hyperoxaluria type 1 (PH1), a genetic disorder caused by mutations in the AGXT gene that results in the overproduction of oxalate.^6,9 This often results in nephrocalcinosis (calcium oxalate deposits in the kidneys), nephrolithiasis (kidney stones), and progression to end-stage renal disease (ESRD).¹⁰ Calcium oxalate stones are the most common type of kidney stones, with hyperoxaluria (elevated urinary oxalate) being a key risk factor. High oxalate levels in the urine can result from dietary intake, increased intestinal absorption (e.g., in malabsorptive conditions like Roux-en-Y gastric bypass), or genetic conditions like PH1.^11-14 Systemic oxalosis can damage organs such as the kidneys, heart, and retina, particularly in severe cases like infantile oxalosis, which often leads to ESRD early in life.¹⁰

Role of Oxalobacter in degrading oxalates

Oxalobacter formigenes is a gram-negative, obligate anaerobic bacterium that colonizes the human colon and specializes in degrading dietary and endogenous oxalate.^1,15 It uses oxalate as its sole carbon and energy source, metabolizing it into formate and carbon dioxide via two key enzymes: formyl-CoA transferase (encoded by the frc gene) and oxalyl-CoA decarboxylase (encoded by the oxc gene). The process involves the uptake of oxalate through the OxlT transporter, an oxalate-formate antiporter, which facilitates oxalate influx and formate efflux, generating a proton gradient for ATP production. By degrading oxalate in the gut, O. formigenes reduces intestinal oxalate absorption and promotes enteric oxalate secretion, lowering plasma and urinary oxalate levels.¹⁶

The presence of O. formigenes in the gut is associated with reduced risk of calcium oxalate kidney stones.^17-22 Some retrospective studies indicate that stone formers have lower or absent O. formigenes colonization rates compared to healthy controls, potentially due to antibiotic exposure, which can eradicate this fastidious anaerobe.^18,23 O. formigenes colonization is typically established in early childhood but can be lost due to antibiotics or dietary factors like high calcium intake, which binds oxalate and reduces its availability.^23-25

Why do herbivores have fewer kidney stones

Herbivores, such as sheep, cattle, and rodents, rarely develop kidney stones despite their oxalate-rich diets. This is primarily attributed to their robust gut microbiome, particularly the presence of oxalate-degrading bacteria like O. formigenes. In herbivores, these bacteria efficiently metabolize dietary oxalate in the rumen or large intestine, reducing its absorption and subsequent urinary excretion.¹ For instance, the type strain O. formigenes OxB (ATCC® 35274™; Table 1), which was first isolated from the sheep rumen, degrades oxalate before it can be absorbed systemically. Additionally, herbivores have adapted physiological mechanisms, such as efficient oxalate secretion in the gut and urine, and their diets often contain higher levels of calcium, which binds oxalate in the gut, forming insoluble complexes that are excreted in feces rather than absorbed. These factors collectively minimize the risk of calcium oxalate stone formation in herbivores as compared to humans, who rely more on renal excretion of oxalate.

Role of Oxalobacter in the microbiome 

In the human gut microbiome, O. formigenes is thought to play a critical role in oxalate homeostasis.^21,26-30 It reduces the intestinal oxalate load by degrading dietary oxalate and stimulating active transcellular oxalate secretion from blood to the gut lumen, likely via interaction with transporter proteins like those in the SLC26 family. This dual action decreases oxalate absorption and promotes its elimination, lowering plasma oxalate and urinary oxalate levels. 

Oxalobacter prevalence rates among healthy adults vary; in the United States, it ranges from 30–40%, but in other countries, such as Korea, Japan, India, or native ethnic groups in Venezuela and Tanzania, the prevalence can be as high as 80%.^31,32,24 These differences could be attributed to several factors, including variations in medical practices, dietary habits, environmental exposure, and even the methodologies used for detection. Various studies have highlighted the potential impact of modern lifestyles and antibiotic use on the prevalence of O. formigenes colonization.

The Human Microbiome Project has also shed light on the genetic diversity of O. formigenes within the human gut, revealing the presence of different strains.^22,31,33-35 Specifically, Group 1 strains like OXCC13 and Group 2 strains like HOxBLS have been identified. Research indicates that co-colonization with both Group 1 and Group 2 strains is common, and Group 2 strains are often detected in conjunction with Group 1 strains. These strains exhibit genetic and phenotypic differences in factors such as oxalate-degrading capacity and antibiotic susceptibility. For instance, OXCC13 possesses a gene encoding for 5-nitroimidazole antibiotic resistance, whereas HOxBLS lacks this gene and is sensitive to the antibiotic nitrofurantoin.

Co-colonization with multiple strains is common, but their clinical significance remains unclear.³² Other oxalate-degrading bacteria, such as Bifidobacterium and Lactobacillus species, may also contribute to oxalate metabolism, though O. formigenes is the most effective. ^{21,29,30,35-39} Its absence, often due to antibiotics, is associated with hyperoxaluria and increased kidney stone risk, highlighting its protective role in the microbiome.

Some recent metagenomic studies, however, highlight the role of oxalate-degrading genes in the context of microbiome “enterotypes” (distinct bacterial communities).  As previously mentioned, the stone formers are characterized by a lower abundance of O. formigenes and reduced representation of genes associated with oxalate metabolism.^6,21,22 At the same time, the comparison of other known oxalate-degrading bacteria did not show any significant differences in terms of abundance.^6,22,40

Several microbiome studies have found that individuals who develop kidney stones show reduced biodiversity and lower levels of genes involved in oxalate metabolism.^8,22,21,31 Notably, taxa such as Faecalibacterium, Enterobacter, and Dorea are significantly decreased in stone formers, while Oxalobacter levels remain stable. These findings agree with meta-analyses indicating that colonization by O. formigenes does not consistently predict stone risk or urinary oxalate excretion. A wide variety of bacteria, including Bacteroides, Ruminococcus, Bifidobacterium, Coprococcus, Lactobacillus, Oscillospira, and Parabacteroides, are also linked to oxalate metabolism in healthy people, emphasizing the complexity beyond just single-species probiotics.^{15,21,22,31,36,40} Additionally, some studies report lower O. formigenes abundance and decreased oxalate metabolism gene presence in recurrent stone formers, suggesting dysbiosis and altered microbial populations in this condition. 

The microbiome research field has been expanding rapidly, producing a wealth of insightful discoveries. To guarantee consistency, convergence, and, most importantly, reliability, the scientific community emphasizes the importance of standardizing protocols. This standardization will facilitate a more confident translation of research findings into successful applications.^30,35,41

Clinical trials and observational studies

Recent research highlights the complex relationship between gut microbiota and urinary stone disease (USD), particularly the role of oxalate-degrading bacteria such as O. formigenes.^21,22,42 While O. formigenes is associated with lower urinary oxalate levels in just over half of the reported studies, its presence alone does not consistently predict reduced kidney stone risk. Clinical trials using O. formigenes as a probiotic have had mixed results; some show reduced urinary oxalate, while others find no effect, even when colonization is confirmed.^6,10,35 This suggests that a network of bacteria, rather than a single strain or even species (Table 1), is crucial for oxalate homeostasis. Another confounding and challenging factor is manufacturability.^21,22,40,42

Dysbiosis—characterized by reduced biodiversity and altered gut composition—is consistently observed in stone formers.^22,23,29 Probiotic candidates, particularly strains of Lactobacillus and Bifidobacterium, have shown oxalate-degrading potential and are common in human diets, often added to dairy products for their health benefits.^40,43 Studies indicate that these bacteria, along with O. formigenes, may help manage urinary oxalate, but results vary and often depend on individual microbiome makeup.

Recent analyses reveal that genera, such as Prevotella, are enriched in healthy individuals and correlate with lower urinary oxalate, while Bacteroides are more common in those with USD. Additional bacteria, like Eubacterium, are inversely related to urine oxalate, further supporting the idea that oxalate metabolism relies on a complex microbial community rather than a single probiotic intervention.^21,22

In summary, while manipulating the gut microbiota holds promise for reducing kidney stone risk, consistent clinical benefit likely requires a holistic approach targeting microbial diversity and function, rather than focusing solely on one oxalate-degrading species.

How ATCC resources can aid research and clinical investigations to discover microbiome-based therapeutics against oxalosis

ATCC is instrumental in advancing research on microbiome-based treatments for oxalosis. ATCC does not develop therapies directly but supports researchers by providing high-quality, authenticated microbial strains that are essential for reproducible scientific studies.

Key ATCC contributions include:

• Reference strains: ATCC supplies crucial oxalate-degrading microbes, enabling studies on oxalate metabolism, the development of probiotics, and the identification of new therapeutic candidates (Table 1).

• Metagenomic analytical reference materials: Through mock or synthetic microbial communities and DNA controls, ATCC ensures reproducible and accurate metagenomic research, crucial for identifying and monitoring oxalate-metabolizing bacteria in the gut.

• Probiotic development: Researchers can use ATCC strains to validate next-generation probiotics and study their safety, efficacy, and ability to reduce oxalate levels (Table 2 and Table 3).

• Cell models & genomic tools: The collection offers human renal and gut epithelial cell lines, along with microbial DNA and RNA standards, facilitating research on host–microbe interactions and disease modeling.

By maintaining strict quality control and authentication, ATCC provides materials that meet regulatory standards and facilitate the transition of laboratory research to clinical applications. These resources are widely used to construct disease models, validate sequencing workflows, and support the development of microbiome-based therapeutics for oxalosis.

Conclusions

Oxalates are common in food and can cause kidney stones, especially in people with certain genetic or digestive conditions. The gut bacterium O. formigenes helps break down oxalates, lowering stone risk, but its presence varies widely and can be reduced by antibiotics. Research shows that a diverse microbiome, not just O. formigenes, is essential for oxalate management. ATCC supports studies and probiotic development by providing reference strains and research tools for advancing microbiome-based therapies against oxalosis.

Table 1: Oxalobacter species and strains at ATCC.  

Table 2: Lactobacillus and Bifidobacterium strains and nucleic acids at ATCC.

Table 3: Species that could be associated with oxalate metabolism.

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References 

1. Daniel SL, et al. Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist. Appl Environ Microbiol 87(18): e0054421, 2021. PubMed: 34190610
2. Oxalosis and Hyperoxaluria Foundation. https://ohf.org/.
3. Norton, SK. Toxic Superfoods, 2023. https://sallyknorton.com/toxic_superfoods/
4. Barman AK, et al. Acute Kidney Injury Associated with Ingestion of Star Fruit: Acute Oxalate Nephropathy. Indian J Nephrol 26(6): 446-448, 2026. PubMed: 27942177
5. Asplin JR. Hyperoxaluric Calcium Nephrolithiasis. Endocrinol Metab Clin North Am 31(4); 927–949, 2002. PubMed: 12474639
6. Cellini B, et al. Opportunities in Primary and Enteric Hyperoxaluria at the Cross-Roads Between the Clinic and Laboratory. Kidney Int Rep 9(11): 3083–3096, 2024. PubMed: 39534212
7. Hoppe B, et al. Urolithiasis and Nephrocalcinosis in Childhood. In Comprehensive Pediatric Nephrology; Elsevier, 2008; pp 499–525.
8. Robijn S, et al. Hyperoxaluria: A Gut–Kidney Axis? Kidney Int 80(11): 1146–1158, 2011. PubMed: 21866092
9. Devresse A, et al. Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives. Kidney Int Rep 5(12): 2136–2145, 2020. PubMed: 33305106
10. Pape L, et al. Oxalobacter Formigenes Treatment Combined with Intensive Dialysis Lowers Plasma Oxalate and Halts Disease Progression in a Patient with Severe Infantile Oxalosis. Pediatr Nephrol 35(6): 1121–1124, 2020. PubMed: 32107618
11. Witting C, et al. Pathophysiology and Treatment of Enteric Hyperoxaluria. Clin J Am Soc Nephrol 16(3): 487–495, 2021. PubMed: 32900691
12. Prochaska M, Worcester E. Risk Factors for Kidney Stone Formation Following Bariatric Surgery. Kidney360 1(12): 1456–1461, 2020. PubMed: 34085046
13. Canales BK, Hatch M. Kidney Stone Incidence and Metabolic Urinary Changes after Modern Bariatric Surgery: Review of Clinical Studies, Experimental Models, and Prevention Strategies. Surg Obes Relat Dis 10(4): 734–742, 2014. PubMed: 24969092
14. Bhatti U, et al. Nephrolithiasis after Bariatric Surgery: A Review of Pathophysiologic Mechanisms and Procedural Risk. Int J Surg 36: 618–623, 2016. PubMed: 27847289
15. Mehta M, et al. The Role of the Microbiome in Kidney Stone Formation. Int J Surg 36: 607–612, 2016. PubMed: 27847292
16. Arvans D, et al. Oxalobacter Formigenes–Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells. J Am Soc Nephrol 28(3): 876–887, 2017. PubMed: 27738124
17. Fargue S, et al. Inducing Oxalobacter Formigenes Colonization Reduces Urinary Oxalate in Healthy Adults. Kidney Int Rep 10(5): 1518–1528, 2025. PubMed: 40485679
18. Kaufman DW, et al. Oxalobacter Formigenes May Reduce the Risk of Calcium Oxalate Kidney Stones. J Am Soc Nephrol 19(6): 1197–1203, 2008. PubMed: 18322162
19. Li X, et al. Oxalobacter Formigenes Colonization and Oxalate Dynamics in a Mouse Model. Appl Environ Microbiol 81(15): 5048–5054, 2015. PubMed: 25979889
20. Siener R, et al. The Role of Oxalobacter Formigenes Colonization in Calcium Oxalate Stone Disease. Kidney Int 83(6): 1144–1149, 2013. PubMed: 23536130
21. Ticinesi A, et al. Gut Microbiome and Kidney Stone Disease: Not Just an Oxalobacter Story. Kidney Int 96(1): 25–27. 2019. PubMed: 31229040
22. Ticinesi A, et al. Calcium Oxalate Nephrolithiasis and Gut Microbiota: Not Just a Gut-Kidney Axis. A Nutritional Perspective. Nutrients 12(2): 548, 2020. PubMed: 32093202
23. Zampini A, et al. Defining Dysbiosis in Patients with Urolithiasis. Sci Rep 9(1): 5425, 2019. PubMed: 30932002
24. PeBenito A, et al. Comparative Prevalence of Oxalobacter Formigenes in Three Human Populations. Sci Rep 9(1): 574, 2019. PubMed: 30679485
25. Barnett C, et al. The Presence of Oxalobacter Formigenes in the Microbiome of Healthy Young Adults. J Urol 195(2): 499–506, 2016. PubMed: 26292041
26. Hiremath S, Viswanathan P. Oxalobacter Formigenes: A New Hope as a Live Biotherapeutic Agent in the Management of Calcium Oxalate Renal Stones. Anaerobe 75: 102572, 2022. PubMed: 35443224
27. Siva S, et al. A Critical Analysis of the Role of Gut Oxalobacter Formigenes in Oxalate Stone Disease. BJU Int 103(1): 18–21, 2009. PubMed: 19021605
28. Liu M, et al. Oxalobacter Formigenes-Associated Host Features and Microbial Community Structures Examined Using the American Gut Project. Microbiome 5(1): 108, 2017. PubMed: 28841836
29. Yuan T, et al. Gut Microbiota in Patients with Kidney Stones: A Systematic Review and Meta-Analysis. BMC Microbiol. 23(1): 143, 2023. PubMed: 37208622
30. Federici F, et al. Characterization and Heterologous Expression of the Oxalyl Coenzyme A Decarboxylase Gene from Bifidobacterium Lactis. Appl Environ Microbiol 70(9): 5066–5073, 2004. PubMed: 15345383
31. Jung HD, Lee JY. Impact of the Human Microbiome on Nephrolithiasis. Urogenit Tract Infect 16 (2): 25–31, 2021.
32. Kelly JP, et al. Factors Related to Colonization with Oxalobacter Formigenes in U.S. Adults. J Endourol 25(4): 673–679, 2011. PubMed: 21381959
33. Knight J, et al. The Genetic Composition of Oxalobacter Formigenes and Its Relationship to Colonization and Calcium Oxalate Stone Disease. Urolithiasis 41(3): 187–196, 2013. PubMed: 23632911
34. Liu M, et al. Microbial Genetic and Transcriptional Contributions to Oxalate Degradation by the Gut Microbiota in Health and Disease. eLife 10: e63642, 2021. PubMed: 33769280
35. Sidhu H, et al. Identification and Classification of Oxalobacter Formigenes Strains by Using Oligonucleotide Probes and Primers. J Clin Microbiol 35(2): 350–353, 1997. PubMed: 9003594
36. Hoesl CE, Altwein JE. The Probiotic Approach: An Alternative Treatment Option in Urology. Eur Urol 47(3): 288–296, 2005. PubMed: 15716188
37. Klimesova K, et al. Bifidobacterium Animalis Subsp. Lactis Decreases Urinary Oxalate Excretion in a Mouse Model of Primary Hyperoxaluria. Urolithiasis 43(2): 107–117, 2015. PubMed: 25269440
38. Noonin C, et al. The Direct Inhibitory Effects of Lactobacillus Acidophilus, a Commensal Urinary Bacterium, on Calcium Oxalate Stone Development. Microbiome 12(1): 175, 2024. PubMed: 39289694
39. Turroni S, et al. Oxalate-Degrading Activity in Bifidobacterium Animalis Subsp. Lactis : Impact of Acidic Conditions on the Transcriptional Levels of the Oxalyl Coenzyme A (CoA) Decarboxylase and Formyl-CoA Transferase Genes. Appl Environ Microbiol 76(16): 5609–5620, 2010. PubMed: 20601517
40. Wigner P. Probiotics in the Prevention of the Calcium Oxalate Urolithiasis. Cells 11(2): 284, 2022. PubMed: 35053400
41. Kachroo N, et al. Standardization of Microbiome Studies for Urolithiasis: An International Consensus Agreement. Nat Rev Urol 18(5): 303–311, 2021. PubMed: 33782583
42. Hiremath S, Viswanathan P. Oxalobacter Formigenes: A New Hope as a Live Biotherapeutic Agent in the Management of Calcium Oxalate Renal Stones. Anaerobe 75: 102572, 2022. PubMed: 35443224
43. Hoesl CE, Altwein JE. The Probiotic Approach: An Alternative Treatment Option in Urology. Eur Urol 47(3); 288–296, 2005. PubMed: 15716188