The role of Oxalobacter formigenes in calcium oxalate stone disease
1 University Stone Centre, Department of Urology, University of Bonn, Bonn, Germany
Calcium oxalate is the major component of about 75% of all urinary stones. Hyperoxaluria is a primary risk factor for calcium oxalate stone formation. The bioavailability of ingested oxalate and the extent of intestinal absorption of dietary oxalate are considered to be important factors in hyperoxaluria. Oxalobacter formigenes is a Gram-negative anaerobic bacterium that colonizes the intestinal tract. It is unique in that it requires oxalate both as an energy and carbon source. The only known factor which reduces colonization with O. formigenes is the treatment with antibiotics to which the bacterium has been reported to be sensitive. A deficiency of oxalate degradation by O. formigenes may increase urinary oxalate excretion, attributed to decreased intestinal oxalate degradation, leaving more oxalate available for absorption at a constant intestinal absorption rate. A lack of colonization with O. formigenes increases the risk of recurrent calcium oxalate stone formation. While evidence is emerging that orally administered O. formigenes can reduce urinary and plasma oxalate, the possible treatment with a probiotic still remains a challenge.
Summary of recommendations
- Colonization with O. formigenes is associated with a reduced risk of calcium oxalate stone formation probably resulting from a decreased excretion of urinary oxalate (GoR B)
- Several studies have suggested that colonization with O. formigenes is markedly affected by use of antibiotics to which the bacterium is sensitive (GoR B).
- Long-term controlled studies on the treatment of idiopathic calcium oxalate stone formers with O. formigenes are lacking so far.
Calcium oxalate is the most common stone constituent, and is suggested to be the major mineral in about 75% of all urinary stones . Hyperoxaluria is a primary risk factor for calcium oxalate stone formation. Since the molar oxalate-to-calcium ratio is normally at 1:10, even slight changes in urinary oxalate concentration exert much larger effects on crystallization and stone formation than comparable changes in the calcium concentration .
Hyperoxaluria can result from a high dietary oxalate intake, intestinal hyperabsorption of oxalate from the diet, or an increased endogenous production of oxalate from ingested or metabolically-generated precursors. The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and stone formation. It has been suggested that dietary oxalate contributes up to 50% to urinary oxalate excretion . The bioavailability of ingested oxalate and the extent of absorption of dietary oxalate may be important factors in hyperoxaluria.
A high dietary oxalate intake plays a key role in idiopathic hyperoxaluria. Some foods, particularly vegetables, cereals and nuts such as sesame, almonds, wheat bran, mangold, rhubarb, sorrel and spinach, are known to contain high oxalate concentrations , , . Among beverages, green and black teas as well as various vegetable juices were found to contain considerable amounts of highly bioavailable, soluble oxalate , , . A high dietary intake of oxalate can significantly increase urinary oxalate excretion even in healthy individuals without disturbances in oxalate metabolism .
Intestinal hyperabsorption of oxalate can considerably contribute to urinary oxalate, even in the absence of gastrointestinal disorders. A study using the standardized [13C2] oxalate absorption test revealed a significantly higher mean intestinal oxalate absorption in idiopathic calcium oxalate stone formers (10.2%) compared to healthy controls (8.0%) . However, the reason for this difference is unclear. Intestinal oxalate absorption greater than 10% was found in only 28% of healthy subjects, but in 46% of patients. Oxalate absorption greater than 20% only occurred in stone formers.
A systematic literature search was performed in PubMed over the last 40 years using the following key word: Oxalobacter/formigenes. Search results were limited to studies written in the English language. A total of 176 publications were identified, which were screened by title and, when appropriate, abstract. After exclusion of duplicates, a total of twenty-two were included in the analysis. It should be stated that there are no meta-analyses for Oxalobacter formigenes published in the literature. The studies were rated according to the level of evidence (LoE) and the grade of recommendation (GoR) using ICUD standards.
3.1 Oxalobacter formigenes
Oxalobacter formigenes is a Gram-negative anaerobic bacterium that colonizes the intestinal tract of humans . It is unique in that it requires oxalate both as an energy and carbon source. There is very little known about the biology of the organism, particularly on how it establishes and maintains gut colonization.
The only known factor which reduces colonization with Oxalobacter formigenes is the treatment with antibiotics. Several studies have suggested that colonization with O. formigenes is markedly affected by use of antibiotics , , , , , , . In a study of 37 idiopathic calcium oxalate stone formers, only 11 (30%) tested positive for O. formigenes, whereas 26 (70%) tested negative . Analysis of a history of use of antibiotics revealed that only 13% of O. formigenes-positive patients had taken antibiotics, whereas 81% of O. formigenes-negative patients had received antibiotic treatment before the start of the study. O. formigenes has been reported to be sensitive to a variety of antibiotics commonly used in clinical practice for the treatment of a broad range of infections , , . These antibiotics include macrolides, such as erythromycin and clarithromycin, metronidazole, and doxycycline.
A prospective study in patients who where undergoing upper endoscopy and biopsy revealed that antibiotics for Helicobacter pylori infection leads to persistently reduced intestinal colonization rates with O. formigenes . The absence of O. formigenes colonization in women could be attributed to frequent use of antibiotics owing to recurrent urinary tract infections, which have been found to be associated with increased oxalate excretion . According to a recent study, the relatively lower rate of O. formigenes detection in relation to other populations outside the United States provides further evidence to support a general trend of the disappearance of this organism with socioeconomic development, likely due to higher general use of antibiotics within these populations . A lack of colonization with O. formigenes increases the risk of recurrent calcium oxalate stone formation , , , , , , .
3.2 Oxalobacter formigenes and urinary oxalate excretion
The lasting elimination of O. formigenes could lead to a reduced rate or deficiency of oxalate degradation in the colon . Oxalate degradation by O. formigenes might be expected to reduce the extent of urinary oxalate excretion. Whereas several studies have linked the absence of O. formigenes to higher urinary oxalate excretion , , , , others revealed no significant difference in urinary oxalate excretion between patients who tested positive or negative for O. formigenes , . However, a major limitation is that none of these studies in stone formers were conducted under controlled conditions. A study in calcium oxalate stone formers on two days under controlled, standardized diet revealed that mean urinary oxalate excretion was significantly lower in O. formigenes-positive patients (0.318 and 0.367 mmol/24h, respectively) than in those who were O. formigenes-negative (0.454 and 0.474 mmol/24h, respectively) (p=0.003 and p=0.043, respectively) .
3.3 Oxalobacter formigenes and intestinal oxalate absorption
The understanding of the role of O. formigenes in oxalate metabolism is still limited. It has been hypothesized that the absence of this bacterium could be associated with higher intestinal oxalate absorption , , . In our study in 37 idiopathic calcium oxalate stone formers, no difference in mean oxalate absorption, measured by [13C2]oxalate absorption test, was observed between O. formigenes colonized and noncolonized patients . Intestinal oxalate absorption was 11.5±4.6% in O. formigenes-positive patients and 11.3±5.9% in O. formigenes-negative patients, which is consistent with mean intestinal absorption of 10.2±5.2% in 120 recurrent idiopathic calcium oxalate stone formers , . Similarly, Knight et al. (2011) reported in 38 calcium oxalate stone formers that absorption was not significantly different in colonized and noncolonized subjects . Overall, these findings suggest that intestinal oxalate absorption is not modulated by O. formigenes.
3.4 Oxalobacter formigenes and enteric oxalate secretion
There is still a significant lack of knowledge on the mechanism of action of O. formigenes colonization in patients with idiopathic calcium oxalate stone disease. The only study investigating the effect of colonization with O. formigenes on plasma oxalate concentration in idiopathic stone patients revealed that mean plasma oxalate concentration was more than threefold higher in patients without O. formigenes (5.79 µmol/l) than in colonized stone formers (1.70 µmol/l) . While glomerular filtration rate was similar in both groups, the results of the study suggest that differences in urinary oxalate excretion were not apparently associated with either changes in glomerular filtration or tubular secretion of oxalate.
A hypothetical explanation for the higher plasma oxalate concentration in noncolonized stone formers is that the absence of O. formigenes is attributable to altered intestinal oxalate transport. Rat models have suggested that Oxalobacter, in addition to degrading dietary sources of oxalate, interacts physiologically with colonic mucosa by inducing active secretion of endogenously produced oxalate . Hatch et al. (2006) demonstrated that this bacterial-enterocyte interaction results in a significant reduction in urinary oxalate excretion owing to this enteric oxalate shunt . The latter study was also the first to demonstrate that endogenously derived oxalate can sustain O. formigenes colonization. In patients with primary hyperoxaluria, oral administration of O. formigenes has been shown to significantly induce enteric oxalate secretion, possibly by contributing to a transepithelial gradient favoring intestinal secretion of endogenous oxalate , .
3.5 Treatment with Oxalobacter formigenes
Results of clinical trials on the use of O. formigenes as a probiotic to reduce urinary oxalate excretion are inconsistent. Despite favorable results in a pilot study , the efficacy of orally administered O. formigenes for reducing urinary oxalate excretion could not be confirmed in a multicenter trial in 42 patients with primary hyperoxaluria . In contrast, a recent study in 80 calcium oxalate stone formers randomized to receive either KMgCit or O. formigenes preparation revealed that the incidence of hyperoxaluria decreased at 1 month compared to baseline in both groups, while other urinary metabolic abnormalities remained similar . However, the possible use of O. formigenes as a probiotic therapy remains a challenge with several hurdles to overcome before reaching clinical practice . The main limitation of the use of O. formigenes is that its effect remains as long as the preparation is taken, indicating only transient gut colonization , .
4 Further research
Further studies with larger sample sizes are needed to define the exact role of O. formigenes colonization in calcium oxalate stone disease and to evaluate the efficacy of O. formigenes during long-term treatment.
Colonization with O. formigenes is associated with a reduced risk of calcium oxalate stone formation. Recent findings revealed that colonization with O. formigenes may reduce urinary oxalate excretion, attributed to increased intestinal oxalate degradation, leaving less oxalate available for absorption at a constant intestinal absorption rate. The observation that active enteric secretion of endogenously produced oxalate may be induced or enhanced by O. formigenes, thereby decreasing plasma oxalate concentration, may have important consequences for future hyperoxalemia treatment strategies. However, colonization with O. formigenes may be markedly affected by use of antibiotics to which the bacterium is sensitive. While evidence is emerging that orally administered O. formigenes can reduce urinary and plasma oxalate, the possible treatment with a probiotic still remains a challenge. Because only transient gut colonization with O. formigenes has been achieved so far, attention should be focused also on additional oxalate-degrading microorganisms such as Lactobacillus and Bifidobacterium strains and oxalate-degrading enzymes.
References Hesse A, Siener R. Current aspects of epidemiology and nutrition in urinary stone disease. World J Urol. 1997;15(3):165-71. DOI: 10.1007/BF02201853
 Siener R, Schade N, Nicolay C, von Unruh GE, Hesse A. The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients. J Urol. 2005 May;173(5):1601-5. DOI: 10.1097/01.ju.0000154626.16349.d3
 Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney Int. 2001 Jan;59(1):270-6. DOI: 10.1046/j.1523-1755.2001.00488.x
 Hönow R, Hesse A. Comparison of extraction methods for the determination of soluble and total oxalate in foods by HPLC-enzyme-reactor. Food Chem. 2002;78(4):511-21. DOI: 10.1016/S0308-8146(02)00212-1
 Siener R, Hönow R, Seidler A, Voss S, Hesse A. Oxalate contents of species of the Polygonaceae, Amaranthaceae and Chenopodiaceae families. Food Chem. 2006;98: 220-4. DOI: 10.1016/j.foodchem.2005.05.059
 Siener R, Hönow R, Voss S, Seidler A, Hesse A. Oxalate content of cereals and cereal products. J Agric Food Chem. 2006 Apr;54(8):3008-11. DOI: 10.1021/jf052776v
 Hönow R, Gu KL, Hesse A, Siener R. Oxalate content of green tea of different origin, quality, preparation and time of harvest. Urol Res. 2010 Oct;38(5):377-81. DOI: 10.1007/s00240-009-0245-x
 Siener R, Seidler A, Voss S, Hesse A. The oxalate content of fruit and vegetable juices, nectars and drinks. J Food Compos Anal. 2016;45:108-12. DOI: 10.1016/j.jfca.2015.10.004
 Siener R, Bade DJ, Hesse A, Hoppe B. Dietary hyperoxaluria is not reduced by treatment with lactic acid bacteria. J Transl Med. 2013;11:306. DOI: 10.1186/1479-5876-11-306
 Voss S, Hesse A, Zimmermann DJ, Sauerbruch T, von Unruh GE. Intestinal oxalate absorption is higher in idiopathic calcium oxalate stone formers than in healthy controls: measurements with the [13C2]oxalate absorption test. J Urol. 2006;175:1711-5. DOI: 10.1016/S0022-5347(05)01001-3
 Allison MJ, Dawson KA, Mayberry WR, Foss JG. Oxalobacter formigenes gen. nov., sp. nov.: oxalate-degrading anaerobes that inhabit the gastrointestinal tract. Arch Microbiol. 1985 Feb;141(1):1-7. DOI: 10.1007/BF00446731
 Sidhu H, Hoppe B, Hesse A, Tenbrock K, Brömme S, Rietschel E, Peck AB. Absence of Oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria. Lancet. 1998 Sep 26;352(9133):1026-9.DOI: 10.1016/S0140-6736(98)03038-4
 Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS. Oxalobacter formigenes and its potential role in human health. Appl Environ Microbiol. 2002 Aug;68(8):3841-7. DOI: 10.1128/AEM.68.8.3841-3847.2002
 Kelly JP, Curhan GC, Cave DR, Anderson TE, Kaufman DW. Factors related to colonization with Oxalobacter formigenes in U.S. adults. J Endourol. 2011 Apr;25(4):673-9. DOI: 10.1089/end.2010.0462
 Kharlamb V, Schelker J, Francois F, Jiang J, Holmes RP, Goldfarb DS. Oral antibiotic treatment of Helicobacter pylori leads to persistently reduced intestinal colonization rates with Oxalobacter formigenes. J Endourol. 2011 Nov;25(11):1781-5. DOI: 10.1089/end.2011.0243
 Sidhu H, Schmidt ME, Cornelius JG, Thamilselvan S, Khan SR, Hesse A, Peck AB. Direct correlation between hyperoxaluria/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: possible prevention by gut recolonization or enzyme replacement therapy. J Am Soc Nephrol. 1999 Nov;10 Suppl 14:S334-40.
 Kaufman DW, Kelly JP, Curhan GC, Anderson TE, Dretler SP, Preminger GM, Cave DR. Oxalobacter formigenes may reduce the risk of calcium oxalate kidney stones. J Am Soc Nephrol. 2008 Jun;19(6):1197-203. DOI: 10.1681/ASN.2007101058
 Lange JN, Wood KD, Wong H, Otto R, Mufarrij PW, Knight J, Akpinar H, Holmes RP, Assimos DG. Sensitivity of human strains of Oxalobacter formigenes to commonly prescribed antibiotics. Urology. 2012 Jun;79(6):1286-9. DOI: 10.1016/j.urology.2011.11.017
 Siener R, Bangen U, Sidhu H, Hönow R, von Unruh G, Hesse A. The role of Oxalobacter formigenes colonization in calcium oxalate stone disease. Kidney Int. 2013 Jun;83(6):1144-9. DOI: 10.1038/ki.2013.104
 Siener R, Ebert D, Hesse A. Urinary oxalate excretion in female calcium oxalate stone formers with and without a history of recurrent urinary tract infections. Urol Res. 2001 Aug;29(4):245-8. DOI: 10.1007/s002400100198
 Barnett C, Nazzal L, Goldfarb DS, Blaser MJ. The presence of Oxalobacter formigenes in the microbiome of healthy young adults. J Urol. 2016 Feb;195(2):499-506. DOI: 10.1016/j.juro.2015.08.070
 Kumar R, Mukherjee M, Bhandari M, Kumar A, Sidhu H, Mittal RD. Role of Oxalobacter formigenes in calcium oxalate stone disease: a study from North India. Eur Urol. 2002 Mar;41(3):318-22. DOI: 10.1016/S0302-2838(02)00040-4
 Troxel SA, Sidhu H, Kaul P, Low RK. Intestinal Oxalobacter formigenes colonization in calcium oxalate stone formers and its relation to urinary oxalate. J Endourol. 2003 Apr;17(3):173-6. DOI: 10.1089/089277903321618743
 Kwak C, Kim HK, Kim EC, Choi MS, Kim HH. Urinary oxalate levels and the enteric bacterium Oxalobacter formigenes in patients with calcium oxalate urolithiasis. Eur Urol. 2003 Oct;44(4):475-81. DOI: 10.1016/S0302-2838(03)00318-X
 Mittal RD, Kumar R, Mittal B, Prasad R, Bhandari M. Stone composition, metabolic profile and the presence of the gut-inhabiting bacterium Oxalobacter formigenes as risk factors for renal stone formation. Med Princ Pract. 2003 Oct-Dec;12(4):208-13. DOI: 10.1159/000072285
 Mikami K, Akakura K, Takei K, Ueda T, Mizoguchi K, Noda M, Miyake M, Ito H. Association of absence of intestinal oxalate degrading bacteria with urinary calcium oxalate stone formation. Int J Urol. 2003 Jun;10(6):293-6. DOI: 10.1046/j.1442-2042.2003.00634.x
 Knight J, Jiang J, Wood KD, Holmes RP, Assimos DG. Oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. Urology. 2011 Aug;78(2):475.e9-475.e13. DOI: 10.1016/j.urology.2011.04.008
 Liebman M, Al-Wahsh IA. Probiotics and other key determinants of dietary oxalate absorption. Adv Nutr. 2011 May;2(3):254-60. DOI: 10.3945/an.111.000414
 Argenzio RA, Liacos JA, Allison MJ. Intestinal oxalate-degrading bacteria reduce oxalate absorption and toxicity in guinea pigs. J Nutr. 1988 Jun;118(6):787-92.
 Hatch M, Cornelius J, Allison M, Sidhu H, Peck A, Freel RW. Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion. Kidney Int. 2006 Feb;69(4):691-8. DOI: 10.1038/sj.ki.5000162
 Hoppe B, Beck B, Gatter N, von Unruh G, Tischer A, Hesse A, Laube N, Kaul P, Sidhu H. Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney Int. 2006 Oct;70(7):1305-11. DOI: 10.1038/sj.ki.5001707
 Hoppe B, Dittlich K, Fehrenbach H, Plum G, Beck BB. Reduction of plasma oxalate levels by oral application of Oxalobacter formigenes in 2 patients with infantile oxalosis. Am J Kidney Dis. 2011 Sep;58(3):453-5. DOI: 10.1053/j.ajkd.2011.05.012
 Hoppe B, Groothoff JW, Hulton SA, Cochat P, Niaudet P, Kemper MJ, Deschênes G, Unwin R, Milliner D. Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria. Nephrol Dial Transplant. 2011 Nov;26(11):3609-15. DOI: 10.1093/ndt/gfr107
 Jairath A, Parekh N, Otano N, Mishra S, Ganpule A, Sabnis R, Desai M. Oxalobacter formigenes: Opening the door to probiotic therapy for the treatment of hyperoxaluria. Scand J Urol. 2015;49(4):334-7. DOI: 10.3109/21681805.2014.996251
 Peck AB, Canales BK, Nguyen CQ. Oxalate-degrading microorganisms or oxalate-degrading enzymes: which is the future therapy for enzymatic dissolution of calcium-oxalate uroliths in recurrent stone disease? Urolithiasis. 2016 Feb;44(1):45-50. DOI: 10.1007/s00240-015-0845-6