In this application we are proposing to examine the promotion of active intestinal elimination and luminal degradation of oxalate by probiotics as a way of managing two different clinical entities having in common an increased urinary excretion of oxalate leading to kidney stone formation. 1) 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 calcium oxalate kidney stone formation in addition to tissue deposition of oxalate (oxalosis), renal failure and death unless early aggressive clinical management is instigated. Unfortunately, the only known cure for PH1 is a liver or liver-kidney transplant. 2) A new population of hyperoxaluric patients who have undergone bariatric surgery for obesity has been steadily emerging and the increased incidence of kidney stone formation in this group is significant. In addition to the population of patients with PH1 and bariatric surgery, the potential impact of this therapeutic approach, if effective, will extend to a much larger population of idiopathic calcium oxalate stone formers who comprise ~12% of Americans and is associated with a substantial health care cost. Several key pieces of information have emerged from our studies of intestinal oxalate transport in rats and mice have provided the direction for the studies proposed here. First, the large intestine is the primary site for compensatory enteric excretion of oxalate in oxalate-challenged rats and in rats with chronic renal failure. Second, we have shown that the substrate/oxalate-specific microorganism, Oxalobacter sp., which resides exclusively in the large intestine, can significantly lower urinary oxalate excretion by altering the direction of colonic oxalate transport from absorption to active secretion/excretion. Third, we have acquired results from a pilot study using a mouse model of PH1 (AGT knockout mouse) showing the entire large intestine of the Oxalobacter-colonized AGT knockout mouse functions in an oxalate secretory mode that is correlated with a normalization of oxalate excretion in otherwise hyperoxaluric animals. Other bacteria including Lactobacillus sp. and Bifidobacterium sp. that are "generalists" in terms of their oxalate-degrading activity have been demonstrated to significantly reduce urinary oxalate excretion in humans and in rats;however, it is not known whether these bacteria can interact with the intestinal mucosa to promote changes in oxalate transport similar to Oxalobacter. Regardless of the precise mechanism, perhaps it is possible to exploit the activities of these intestinal bacteria, either individually or together, in order to reduce the oxalate burden in PH1. Now that we have an animal model of PH1 as well as a rat model for bariatric surgery, we have a unique opportunity to directly address these questions and obtain novel information regarding a treatment for hyperoxaluria. Thus in Aims 1 and 2 we will test the hypothesis that normalization of urinary oxalate excretion can occur in AGT KO mice and in the rat bariatric surgical model due to an induction of enteric oxalate elimination following the administration of either a pure culture or a combination of pure cultures of interest, including Oxalobacter sp., Lactobacillus sp., and Bifidobacterium sp.
In Aim 3, we will test the hypothesis that compensatory adaptations in the expression patterns of intestinal oxalate transport proteins can explain changes in function. The results from these studies should reveal a novel direction leading to the development of a probiotic system based upon bacteria/bacterial products that promote both enteric oxalate excretion and degradation thereby normalizing urinary oxalate excretion.

Public Health Relevance

The studies proposed will examine the activity and effectiveness of several non-pathogenic bacteria, either individually or combined, to promote intestinal oxalate excretion and degradation in the setting of Primary Hyperoxaluria, Type 1 (PH1) and following bariatric surgery which is associate with hyperoxaluria and kidney stone disease. Especially important and relevant to the present application is the availability of a knockout mouse model that mimics PH1, namely the AGT (alanine-glyoxylate aminotransferase) null mouse as well as an obese rat bariatric surgical model which affords us a unique opportunity to evaluate the interaction between these bacteria and the oxalate-transporting mucosa of the large intestine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088892-03
Application #
8328707
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rasooly, Rebekah S
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$296,236
Indirect Cost
$90,811
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611