REGULATION OF ENTERIC HYPEROXALURI BY OXALOBACTER

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Oxalobacter formigenes, a recently identified bacterium that colonizes the gastrointestinal (GI) tracts of all vertebrates, has gained considerable attention due to its important symbiotic relationship with its hosts in regulating oxalic acid absorption in the intestines as well as oxalic acid levels in plasma two factors associated with the risk to develop calcium-oxalate kidney stones. Oxalic acid is a by-product of metabolism and a common constituent of most diets; however, if permitted to accumulate, it can cause numerous pathological conditions, including hyperoxaluria, cardiac conductance disorders, calcium oxalate stones, renal failure, death and possibly inflammatory bowel disease and vulvovestibulitis. Despite the potential significance of O. formigenes in controlling enteric hyperoxaluria, and thus oxalate-related disorders, research has been limited due to inherent difficulties in culturing and identifying this bacterium. Nevertheless, preliminary studies already suggest a correlation between the number of colony forming units of Oxalobacter sp. per gram feces and the frequency of recurrent urolithiasis, inflammatory bowel disease and hyperoxaluria/nephrocalcinosis in cystic fibrosis. With the development of a rapid and sensitive DNA-based detection system highly specific for O. formigenes, we are now able to investigate the correlation between an increased risk for urolithiasis and the absence of O. formigenes from the GI tract. Using the laboratory rat as a model, we propose to: 1) study the colonization of non-colonized rats with various sub-strains of O. formigenes to determine if variations exist in the efficacy of different strains of O. formigenes to colonize and if primary colonization precludes secondary colonizations, 2) determine whether O. formigenes can prevent hyperoxaluria and subsequent formation of calcium-oxalate crystals in rats colonized with various sub-strains of the bacterium and challenged with high oxalate-containing diets, and 3) examine the relationship between diet and/or antibiotic treatment with subsequent decolonization of the GI tract by O. formigenes known to occur in human populations and whether decolonization of the GI tract is irreversible. Results from these studies should provide insight into the role O. formigenes plays in regulating oxalate homeostasis in vertebrates, including humans, and should offer new modalities in prevention therapy for oxalate-associated disorders, such as recurrent kidney stone formation.