Oxalate secretion is stimulated by a cAMP-dependent pathway in the mouse cecum.

Elevated levels of the intracellular second messenger cAMP can stimulate intestinal oxalate secretion however the membrane transporters responsible are unclear. Oxalate transport by the chloride/bicarbonate (Cl/HCO) exchanger Slc26a6 or PAT-1 (Putative Anion Transporter 1), is regulated via cAMP when expressed in Xenopus oocytes and cultured cells but whether this translates to the native epithelia is unknown. This study investigated the regulation of oxalate transport by the mouse intestine focusing on transport at the apical membrane hypothesizing PAT-1 is the target of a cAMP-dependent signaling pathway.

Oxalate Flux Across the Intestine: Contributions from Membrane Transporters.

Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment.

Forty Years of Oxalobacter formigenes, a Gutsy Oxalate-Degrading Specialist.

Oxalobacter formigenes, a unique anaerobic bacterium that relies solely on oxalate for growth, is a key oxalate-degrading bacterium in the mammalian intestinal tract. Degradation of oxalate in the gut by plays a critical role in preventing renal toxicity in animals that feed on oxalate-rich plants. The role of in reducing the risk of calcium oxalate kidney stone disease and oxalate nephropathy in humans is less clear, in part due to difficulties in culturing this organism and the lack of studies which have utilized diets in which the oxalate content is controlled.

Extracellular Vesicle Analysis by Paper Spray Ionization Mass Spectrometry.

Paper spray ionization mass spectrometry (PSI-MS) is a direct MS analysis technique with several reported bacterial metabolomics applications. As with most MS-based bacterial studies, all currently reported PSI-MS bacterial analyses have focused on the chemical signatures of the cellular unit. One dimension of the bacterial metabolome that is often lost in such analyses is the exometabolome (extracellular metabolome), including secreted metabolites, lipids, and peptides.

The role of NHE3 (Slc9a3) in oxalate and sodium transport by mouse intestine and regulation by cAMP.

Intestinal oxalate transport involves Cl /HCO exchangers but how this transport is regulated is not currently known. NHE3 (Slc9a3), an apical Na /H exchanger, is an established target for regulation of electroneutral NaCl absorption working in concert with Cl /HCO exchangers. To test whether NHE3 could be involved in regulation of intestinal oxalate transport and renal oxalate handling we compared urinary oxalate excretion rates and intestinal transepithelial fluxes of C-oxalate and Na between NHE3 KO and wild-type (WT) mice.

Oxalobacter formigenes produces metabolites and lipids undetectable in oxalotrophic Bifidobacterium animalis.

Introduction: In the search for new potential therapies for pathologies of oxalate, such as kidney stone disease and primary hyperoxaluria, the intestinal microbiome has generated significant interest. Resident oxalate-degrading bacteria inhabit the gastrointestinal tract and reduce absorption of dietary oxalate, thereby potentially lowering the potency of oxalate as a risk factor for kidney stone formation. Although several species of bacteria have been shown to degrade oxalate, select strains of Oxalobacter formigenes (O.

The anion exchanger PAT-1 (Slc26a6) does not participate in oxalate or chloride transport by mouse large intestine.

The membrane-bound transport proteins responsible for oxalate secretion across the large intestine remain unidentified. The apical chloride/bicarbonate (Cl/HCO) exchanger encoded by Slc26a6, known as PAT-1 (putative anion transporter 1), is a potential candidate. In the small intestine, PAT-1 makes a major contribution to oxalate secretion but whether this role extends into the large intestine has not been directly tested.

Metabolomic Alteration in the Mouse Distal Colonic Mucosa after Oral Gavage with .

has been investigated for years due to its proposed ability to produce a secretagogue compound that initiates net intestinal oxalate secretion, thereby theoretically reducing circulating oxalate and risk of kidney stone formation. Strains which have been shown to exhibit this function in vivo across native tissue include the human strain, HC1, and the wild rat strain, OxWR. While previous work on these secretagogue-relevant strains has focused on profiling their metabolome and lipidome in vitro, efforts to characterize their influence on host intestinal mucosal biochemistry in vivo are yet to be reported.

Metabolomic profiling of oxalate-degrading probiotic Lactobacillus acidophilus and Lactobacillus gasseri.

Oxalate, a ubiquitous compound in many plant-based foods, is absorbed through the intestine and precipitates with calcium in the kidneys to form stones. Over 80% of diagnosed kidney stones are found to be calcium oxalate. People who form these stones often experience a high rate of recurrence and treatment options remain limited despite decades of dedicated research.

Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6.

Oxalobacter sp. promotion of enteric oxalate excretion, correlating with reductions in urinary oxalate excretion, was previously reported in rats and mice, but the mechanistic basis for this affect has not been described. The main objective of the present study was to determine whether the apical oxalate transport proteins, PAT1 (slc26a6) and DRA (slc26a3), are involved in mediating the Oxalobacter-induced net secretory flux across colonized mouse cecum and distal colon.

Metabolomic and lipidomic characterization of Oxalobacter formigenes strains HC1 and OxWR by UHPLC-HRMS.

Diseases of oxalate, such as nephrolithiasis and primary hyperoxaluria, affect a significant portion of the US population and have limited treatment options. Oxalobacter formigenes, an obligate oxalotrophic bacterium in the mammalian intestine, has generated great interest as a potential probiotic or therapeutic treatment for oxalate-related conditions due to its ability to degrade both exogenous (dietary) and endogenous (metabolic) oxalate, lowering the risk of hyperoxaluria/hyperoxalemia. Although all oxalotrophs degrade dietary oxalate, Oxalobacter formigenes is the only species shown to initiate intestinal oxalate secretion to draw upon endogenous, circulating oxalate for consumption.

Iodide as a surrogate tracer for epithelial chloride transport by the mouse large intestine in vitro.

New Findings: What is the central question of this study? The tracer Cl , currently used to measure transepithelial Cl fluxes, has become prohibitively expensive, threatening its future use. Iodide, previously validated alongside Cl as a tracer of Cl efflux by cells, has not been tested as a surrogate for Cl across epithelia. What is the main finding and its importance? We demonstrate that I can serve as an inexpensive replacement for measuring Cl transport across mouse large intestine, tracking Cl transport in response to cAMP stimulation (inducing Cl secretion) in the presence and absence of the main gastrointestinal Cl -HCO exchanger, DRA.

Absence of the sulfate transporter SAT-1 has no impact on oxalate handling by mouse intestine and does not cause hyperoxaluria or hyperoxalemia.

The anion exchanger SAT-1 [sulfate anion transporter 1 (Slc26a1)] is considered an important regulator of oxalate and sulfate homeostasis, but the mechanistic basis of these critical roles remain undetermined. Previously, characterization of the SAT-1-knockout (KO) mouse suggested that the loss of SAT-1-mediated oxalate secretion by the intestine was responsible for the hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis reportedly displayed by this model. To test this hypothesis, we compared the transepithelial fluxes of C-oxalate, , and Cl across isolated, short-circuited segments of the distal ileum, cecum, and distal colon from wild-type (WT) and SAT-1-KO mice.

Oxalate transport by the mouse intestine in vitro is not affected by chronic challenges to systemic acid-base homeostasis.

In rats, we recently showed how a chronic metabolic acidosis simultaneously reduced urinary oxalate excretion and promoted oxalate secretion by the distal colon leading to the proposition that acid-base disturbances may trigger changes to renal and intestinal oxalate handling. The present study sought to reproduce and extend these observations using the mouse model, where the availability of targeted gene knockouts (KOs) would offer future opportunities to reveal some of the underlying transporters and mechanisms involved. Mice were provided with a sustained load of acid (NHCl), base (NaHCO) or the carbonic anhydrase inhibitor acetazolamide (ATZ) for 7 days after which time the impacts on urinary oxalate excretion and its transport by the intestine were evaluated.

Genome Sequence of Strain OXCC13.

The lack of colonization in the human gut is generally acknowledged as a risk factor for kidney stone formation since this microorganism can play an important role in oxalate homeostasis. Here, we present the genome sequence of OXCC13, a human strain isolated from an individual residing in Germany.

Genome Sequence of Strain HC-1.

The lack of colonization of the human gut has been correlated with the formation of calcium oxalate kidney stones and also with the number of recurrent kidney stone episodes. Here, we present the genome sequence of HC-1, a human strain isolated from an individual residing in Iowa, USA.

Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria.

Background: Hyperoxaluria and oxalate kidney stones frequently develop after Roux-en-Y gastric bypass (RYGB). Oxalobacter formigenes can degrade ingested oxalate.

Objectives: Examine the effect of O.

Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis.

The ileum is considered the primary site of inorganic sulfate ([Formula: see text]) absorption. In the present study, we explored the contributions of the apical chloride/bicarbonate (Cl/[Formula: see text]) exchangers downregulated in adenoma (DRA; Slc26a3), and putative anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial [Formula: see text] and Cl fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma sulfate.

Gut microbiota and oxalate homeostasis.

This perspective focuses on how the gut microbiota can impact urinary oxalate excretion in the context of hyperoxaluria, a major risk factor in kidney stone disease. In the genetic disease of Primary Hyperoxaluria Type 1 (PH1), an increased endogenous production of oxalate, due to a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT), results in hyperoxaluria and oxalate kidney stones. The constant elevation in urinary oxalate in PH1 patients ultimately leads to tissue deposition of oxalate, renal failure and death and the only known cure for PH1 is a liver or liver-kidney transplant.

The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man.

The intestine exerts a considerable influence over urinary oxalate in two ways, through the absorption of dietary oxalate and by serving as an adaptive extra-renal pathway for elimination of this waste metabolite. Knowledge of the mechanisms responsible for oxalate absorption and secretion by the intestine therefore have significant implications for understanding the etiology of hyperoxaluria, as well as offering potential targets for future treatment strategies for calcium oxalate kidney stone disease. In this review, we present the recent developments and advances in this area over the past 10 years, and put to the test some of the new ideas that have emerged during this time, using human and mouse models.

The mechanistic basis of hyperoxaluria following gastric bypass in obese rats.

Roux-en-Y gastric bypass (RYGB) surgery is a popular and extremely effective procedure for sustained weight loss in the morbidly obese. However, hyperoxaluria and oxalate kidney stones frequently develop after RYGB and steatorrhea has been speculated to play a role. We examined the effects of RYGB and the role of dietary fat in an obese rat model by measuring fecal fat content and transmural oxalate fluxes across the distal colon compared to sham-operated controls (SHAM).

Chronic metabolic acidosis reduces urinary oxalate excretion and promotes intestinal oxalate secretion in the rat.

Urinary oxalate excretion is reduced in rats during a chronic metabolic acidosis, but how this is achieved is not clear. In this report, we re-examine our prior work on the effects of a metabolic acidosis on urinary oxalate handling [Green et al., Am J Physiol Ren Physiol 289(3):F536-F543, 2005], offering a more detailed analysis and interpretation of the data, together with new, previously unpublished observations revealing a marked impact on intestinal oxalate transport.

Effects of acid-base variables and the role of carbonic anhydrase on oxalate secretion by the mouse intestine in vitro.

Hyperoxaluria is a major risk factor for calcium oxalate kidney stones and the intestine is recognized as an important extra-renal pathway for eliminating oxalate. The membrane-bound chloride/bicarbonate (Cl(-)/) exchangers are involved in the transcellular movement of oxalate, but little is understood about how they might be regulated. , CO2, and pH are established modulators of intestinal NaCl cotransport, involving Na(+)/H(+) and Cl(-)/ exchange, but their influence on oxalate transport is unknown.

Bifidobacterium animalis subsp. lactis decreases urinary oxalate excretion in a mouse model of primary hyperoxaluria.

Hyperoxaluria significantly increases the risk of calcium oxalate kidney stone formation. Since several bacteria have been shown to metabolize oxalate in vitro, including probiotic bifidobacteria, we focused on the efficiency and possible mechanisms by which bifidobacteria can influence oxalate handling in vivo, especially in the intestines, and compared these results with the reported effects of Oxalobacter formigenes. Bifidobacterium animalis subsp.

Kidney stone incidence and metabolic urinary changes after modern bariatric surgery: review of clinical studies, experimental models, and prevention strategies.

Bariatric surgery has been associated with increased metabolic kidney stone risk and post-operative stone formation. A MEDLINE search, performed for articles published between January 2005 and November 2013, identified 24 pertinent studies containing 683 bariatric patients with 24-hour urine profiles, 6,777 bariatric patients with kidney stone incidence, and 7,089 non-stone forming controls. Of all procedures reviewed, only Roux-en-Y gastric bypass (RYGB) was linked to post-operative kidney stone development, increasing stone incidence two-fold in non-stone formers (8.