Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion.

The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.

Oxalobacter formigenes reduce the risk of kidney stones in patients exposed to oral antibiotics: a case-control study.

This is the first prospective study to investigate the association between kidney stones, bone mineral density, serum testosterone, colon cancer and O. formigenes colonization. 40 kidney stone patients and 85 controls were enrolled. O. formigenes colonization was established. BMD was examined from T- and Z-scores using dual energy absorptiometry. O. formigenes was found in 28 of 40 cases and 80 of 85 controls. BMD was significantly reduced in patients (p < 0.05). The evaluation revealed a significant association between lowered O. formigenes colonization and low testosterone. Urinary calcium and oxalates levels were greater in patient. Serum testosterone and urinary citrate concentrations was reduced in patients with a significant difference. Also an association between O. formigenes and colon cancer was noted. Absence of O. formigenes might stand for a pathogenic factor in calcium oxalate stone, low bone mineral density, low testosterone levels and also colon cancer, when antibiotics are prescribed generously.

The use of antibiotics and risk of kidney stones.

PURPOSE OF REVIEW: The effect of the intestinal microbiome on urine chemistry and lithogenicity has been a popular topic. Here we review the evidence for exposure to antibiotics increasing the risk of nephrolithiasis. RECENT FINDINGS: Studies of the intestinal microbiome have focused on Oxalobacter formigenes, an anaerobe that frequently colonizes the human colon. As a degrader of fecal oxalate its presence is associated with lower urinary oxalate, which would be protective against calcium oxalate stone formation. It also appears capable of stimulating colonic oxalate secretion. A recent study showed that antibiotics can eliminate colonization with O. formigenes. In a case-control study, exposure to sulfa drugs, cephalosporins, fluoroquinolones, nitrofurantoin/methenamine, and broad spectrum penicillins prospectively increased the odds of nephrolithiasis. The effect was greatest for those exposed at younger ages and 3-6 months before being diagnosed with nephrolithiasis. SUMMARY: Recent evidence suggests a possible, causal role of antibiotics in the development of kidney stones. A possible explanation for this finding includes alterations in the microbiome, especially effects on oxalate-degrading bacteria like O. formigenes. Ample reasons to encourage antibiotic stewardship already exist, but the possible role of antibiotic exposure in contributing to the increasing prevalence of kidney stones in children and adults is another rationale.

The role of the microbiome in kidney stone formation.

Nephrolithiasis is a complex disease of worldwide prevalence that is influenced by both genetic and environmental factors. About 75% of kidney stones are predominantly composed of calcium oxalate and urinary oxalate is considered a crucial risk factor. Microorganisms may have a role in the pathogenesis and prevention of kidney stones and the involvement of the intestinal microbiome in this renal disease has been a recent area of interest. Oxalobacter formigenes is a gram negative bacteria that degrades oxalate in the gut decreasing urinary oxalate excretion. In this review, we examine the data studying the role of Oxalobacter formigenes in kidney stone disease in humans and animals, the effect of antibiotics on its colonization, and the potential role of probiotics and whole microbial communities as therapeutic interventions.

Effect of Dietary Oxalate on the Gut Microbiota of the Mammalian Herbivore Neotoma albigula.

Diet is one of the primary drivers that sculpts the form and function of the mammalian gut microbiota. However, the enormous taxonomic and metabolic diversity held within the gut microbiota makes it difficult to isolate specific diet-microbe interactions. The objective of the current study was to elucidate interactions between the gut microbiota of the mammalian herbivore Neotoma albigula and dietary oxalate, a plant secondary compound (PSC) degraded exclusively by the gut microbiota. We quantified oxalate degradation in N. albigula fed increasing amounts of oxalate over time and tracked the response of the fecal microbiota using high-throughput sequencing. The amount of oxalate degraded in vivo was linearly correlated with the amount of oxalate consumed. The addition of dietary oxalate was found to impact microbial species diversity by increasing the representation of certain taxa, some of which are known to be capable of degrading oxalate (e.g., Oxalobacter spp.). Furthermore, the relative abundances of 117 operational taxonomic units (OTU) exhibited a significant correlation with oxalate consumption. The results of this study indicate that dietary oxalate induces complex interactions within the gut microbiota that include an increase in the relative abundance of a community of bacteria that may contribute either directly or indirectly to oxalate degradation in mammalian herbivores.

The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease.

Oxalobacter formigenes is a unique intestinal organism that relies on oxalate degradation to meet most of its energy and carbon needs. A lack of colonization is a risk factor for calcium oxalate stone disease. Protection against calcium oxalate stone disease appears to be due to the oxalate degradation that occurs in the gut on low calcium diets with a possible further contribution from intestinal oxalate secretion. Much remains to be learned about how the organism establishes and maintains gut colonization and the precise mechanisms by which it modifies stone risk. The sequencing and annotation of the genomes of a Group 1 and a Group 2 strain of O. formigenes should provide the informatic tools required for the identification of the genes and pathways associated with colonization and survival. In this review we have identified genes that may be involved and where appropriate suggested how they may be important in calcium oxalate stone disease. Elaborating the functional roles of these genes should accelerate our understanding of the organism and clarify its role in preventing stone formation.

Sensitivity of human strains of Oxalobacter formigenes to commonly prescribed antibiotics.

OBJECTIVE: To determine the sensitivity of 4 strains of Oxalobacter formigenes (Oxf) found in humans--HC1, Va3, CC13, and OxK--to varying concentrations of commonly prescribed antibiotics. Oxf gut colonization has been associated with a decreased risk of forming recurrent calcium oxalate kidney stones. METHODS: For each strain and each antibiotic concentration, 100 µL of an overnight culture and 100 µL of the appropriate antibiotic were added to a 7-mL vial of oxalate culture medium containing 20 mM oxalate. On the fourth day, vials were visually examined for growth, and a calcium oxalate precipitation test was performed to determine whether Oxf grew in the presence of the antibiotic. RESULTS: All 4 Oxf strains were resistant to amoxicillin, amoxicillin/clavulanate, ceftriaxone, cephalexin, and vancomycin, and they were all sensitive to azithromycin, ciprofloxacin, clarithromycin, clindamycin, doxycycline, gentamicin, levofloxacin, metronidazole, and tetracycline. One strain, CC13, was resistant to nitrofurantoin, and the others were sensitive. Differences in minimum inhibitory concentration between strains were demonstrated. CONCLUSION: Four human strains of Oxf are sensitive to a number of antibiotics commonly used in clinical practice; however, minimum inhibitory concentrations differ between strains.

Acute irreversible oxalate nephropathy in a lung transplant recipient treated successfully with a renal transplant.

We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically-mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional basiliximab. Calcium carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended.

Oral antibiotic treatment of Helicobacter pylori leads to persistently reduced intestinal colonization rates with Oxalobacter formigenes.

BACKGROUND AND PURPOSE: Oxalobacter formigenes (OF) may play a protective role in preventing calcium oxalate stones. This is the first prospective study to evaluate the effect of antibiotics on OF colonization. Intestinal colonization by OF is associated with reduced urinary oxalate excretion. Exposure to antibiotics may be an important factor determining rates of colonization. MATERIALS AND METHODS: The effect of antibiotics on OF colonization was compared in two groups: A group receiving antibiotics for gastric infection with Helicobacter pylori (HP) and a group without HP whose members were not receiving antibiotics. OF colonization in stool was detected by oxalate degradation at baseline and after 1 and 6 months. RESULTS: The prevalence at baseline of intestinal colonization with OF was 43.1% among all patients screened. Among the 12 patients who were positive for OF who did not receive antibiotics, 11 (92%) had OF on stool tests at 1 month and 6 months. Of the 19 participants who were positive for OF and who received antibiotics for HP, only 7 (36.8%) continued to be colonized by OF on follow-up stool testing at 1 and 6 months (P=0.003 by Fisher exact test). Amoxicillin and clarithromycin caused 62.5% of subjects to become negative for OF at 1 month; 56.2% remained negative for OF at 6 months. CONCLUSIONS: Antibiotics for HP infection effectively reduced colonization with OF, an effect present at 1 and 6 months after treatment. The lasting elimination of OF could be associated with hyperoxaluria and be a factor in recurrent kidney stone disease.

Factors related to colonization with Oxalobacter formigenes in U.S. adults.

GOALS: To elucidate the determinants of Oxalobacter formigenes colonization in humans. BACKGROUND: O. formigenes is a gram-negative anaerobic bacterium that colonizes the colon of a substantial proportion of the normal population and metabolizes dietary and endogenous oxalate. The bacterium has been associated with a large reduction in the odds of recurrent calcium oxalate kidney stones. Subjects were 240 healthy individuals from Massachusetts and North Carolina. O. formigenes was detected by culture of fecal swabs. Information on factors of interest was obtained by telephone interviews and self-administered questionnaires. STUDY RESULTS: The overall prevalence of O. formigenes was 38%. Use of specific antibiotics previously thought to affect the bacterium was significantly related to colonization, with prevalences of 17%, 27%, and 36%, for those who had used these drugs <1, 1-5, and >5 years ago, compared with 55% in nonusers. There were no significant associations with demographic factors, nutrient intake, or medical history, although the prevalence appeared to increase somewhat with increasing oxalate consumption. CONCLUSIONS: Some antibiotics markedly affect colonization with O. formigenes. Although no other factor was identified as having a material influence on the prevalence of the bacterium, there is much to learn about how an individual acquires the organism and which factors affect persistence of colonization.

An animal model of calcium oxalate urolithiasis based on a cyclooxygenase 2 selective inhibitor.

Our aim was to develop a stone-forming animal model involving renal tubular injury using a cyclooxygenase 2 selective inhibitor. Male Sprague-Dawley rats fed chow containing 3% sodium oxalate with or without 100 mg/kg celecoxib were compared to animals fed normal chow. Rats were killed after 2 or 4 weeks and the kidneys were harvested for morphological examination. Collections of 24-h urine were made before kidney harvest. After 2 weeks only a few crystals were observed in rats that received oxalate and celecoxib, but after 4 weeks more crystals were observed at the renal papilla than in rats that received only oxalate. Few crystals were found in rats fed normal chow with or without celecoxib. The urinary activities of gamma-glutamyl transpeptidase (GGT) were increased by celecoxib administration whereas creatinine clearance rates were unchanged. In rats fed oxalate, urinary oxalate excretion increased, but calcium excretion decreased. This model using a cyclooxygenase 2 selective inhibitor is a useful stone forming animal model involving mild renal tubular injury together with mild hyperoxaluria.

Effect of antibiotics on Oxalobacter formigenes colonization of human gastrointestinal tract.

BACKGROUND AND PURPOSE: Oxalobacter formigenes is a bacterium residing in the human gastrointestinal tract that degrades oxalate and reduces its availability for absorption. This bacterium is assumed to be antibiotic sensitive, and repeated antibiotic therapies could eradicate it. The aim of the present study was to determine the differences in the colonization by O. formigenes of individuals who had been on antibiotics for at least 5 days at the time of sample collection and individuals who had not taken antibiotics for at least 3 months. PATIENTS AND METHODS: Stool samples were collected from 80 individuals without stone disease (35 with and 45 without antibiotic consumption) and 100 patients with stone disease (20 with and 80 without antibiotic consumption). Oxalobacter formigenes was detected by a polymerase chain reaction-based method, and the presence/absence of O. formigenes was correlated with urinary oxalate concentrations. RESULTS: Lower percentages of individuals without stone disease and with stone disease who were consuming antibiotics had O. formigenes colonization than individuals without antibiotic consumption. Urinary oxalate concentrations were higher in the individuals without O. formigenes than in colonized individuals. CONCLUSION: Our observations confirm a direct association between antibiotic consumption and absence of O. formigenes. Absence of intestinal O. formigenes could represent a pathogenic factor in calcium oxalate urolithiasis when antibiotics are prescribed generously.

Infections and urinary stone disease.

The relationship between urinary infections and stone formation has been recognized since antiquity and it has been over a century since bacterial degradation of urea was postulated to cause struvite stones. Specific therapy for urease-producing bacteria, such as urease-inhibitors and antibiotics, has allowed for treatment for this subset of urinary stones. Future directions for research include development of novel urease-inhibitors and chemicals to enhance the protective glycosaminoglycan layer. An improved understanding of the pathogenesis of calcium-based stones has led to the discovery of potential roles for nanobacteria and Oxalobacter formingenes. Methods of altering intestinal regulation of oxalate by reintroduction of lactic acid bacteria may significantly impact the treatment of calcium oxalate stones. The use of catheters, both urethral and ureteral, is common in the urinary tract and is associated with significant morbidity, primarily from associated infections. Catheters to prevent bacterial colonization and formation of biofilms have been created using various coatings, including ciprofloxacin, hydrogel, and silver. Use of these types of catheters may minimize infections and encrustation inherent with their placement in the urinary tract.

Oxalobacter formigenes and its potential role in human health.

Oxalate degradation by the anaerobic bacterium Oxalobacter formigenes is important for human health, helping to prevent hyperoxaluria and disorders such as the development of kidney stones. Oxalate-degrading activity cannot be detected in the gut flora of some individuals, possibly because Oxalobacter is susceptible to commonly used antimicrobials. Here, clarithromycin, doxycycline, and some other antibiotics inhibited oxalate degradation by two human strains of O. formigenes. These strains varied in their response to gut environmental factors, including exposure to gastric acidity and bile salts. O. formigenes strains established oxalate breakdown in fermentors which were preinoculated with fecal bacteria from individuals lacking oxalate-degrading activity. Reducing the concentration of oxalate in the medium reduced the numbers of O. formigenes bacteria. Oxalate degradation was established and maintained at dilution rates comparable to colonic transit times in healthy individuals. A single oral ingestion of O. formigenes by adult volunteers was, for the first time, shown to result in (i) reduced urinary oxalate excretion following administration of an oxalate load, (ii) the recovery of oxalate-degrading activity in feces, and (iii) prolonged retention of colonization.