Hyperoxaluria is considered to be a major risk factor in calcium oxalate stone disease which occurs in about 12% of the American population and, apart from reducing dietary sources of oxalate, there is currently no pharmacological treatment available. More serious complications associated with hyperoxaluria and hyperoxalemia, such as renal failure, stones, and tissue deposits of oxalate (oxalosis) also occur in Primary Hyperoxaluria (PH), a progressive inherited metabolic disorder caused by a liver deficiency of the enzyme alanine-glyoxylate aminotransferase (AGT) which is cured only by a combined liver-kidney transplant. Clearly, alternative treatment options for the oxalate-associated diseases require attention and we are proposing to examine promoting intestinal elimination and degradation of oxalate as a way of reducing both hyperoxaluria and hyperoxalemia. Several key pieces of information from our recent studies of colonic oxalate transport in rats/mice have provided the direction for the studies proposed here. First, we have shown that, in addition to degrading dietary sources of oxalate, the substrate/oxalate-specific microorganism, Oxalobacter sp., which resides exclusively in the large intestine, can significantly lower urinary oxalate excretion by inducing colonic oxalate secretion/excretion. We also have compelling results indicating this anaerobic bacterium interacts with the transporting mucosa by producing a secretagogue that activates these beneficial changes in intestinal oxalate handling. Second, based upon our studies using wild type (WT) and knockout (KO) mice, we have identified two key anion exchangers, namely PAT1 (slc26a6) and DRA (slc26a3), that contribute significantly to the movements of oxalate in the intestine and we hypothesize that the changes in oxalate transport induced by Oxalobacter are dependent upon the expression and function of these transporters. Thus, we will examine intestinal and renal handling of oxalate in PAT1 and DRA single KO mice as well as in a PAT1/AGT double KO mouse model and WT mice colonized with Oxalobacter and compared to their appropriate non-colonized counterparts. An understanding of the mechanistic basis for bacterial cell modulation of intestinal oxalate handling is fundamental to future efforts in identifying which strains of bacteria and/or bacterial products will be effective in the treatment of Primary Hyperoxaluria and calcium oxalate stone disease.
The studies proposed address the mechanisms by which Oxalobacter colonization of the large intestine induces enteric oxalate elimination and lowers urinary oxalate excretion. In addition, these studies will evaluate whether Oxalobacter modulates the function of two known important oxalate transporters using knockout mouse models with targeted deletion of slc26a3 (DRA) and slc26a6 (PAT1). Especially important and relevant to the present application, however, is the recent availability of a PAT1/AGT double KO mouse model which affords us a unique opportunity to evaluate PAT1 function/activity in the setting of Primary Hyperoxaluria, type1 (PH1), with and without Oxalobacter colonization. Understanding oxalate handling in PH1 and the potential roles and interactions of PAT1 and Oxalobacter in modulating the excessive body burden of oxalate in this genetic disease are now possible.
| Whittamore, Jonathan M; Hatch, Marguerite (2017) The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man. Urolithiasis 45:89-108 |
| Hatch, Marguerite; Freel, Robert W (2013) A human strain of Oxalobacter (HC-1) promotes enteric oxalate secretion in the small intestine of mice and reduces urinary oxalate excretion. Urolithiasis 41:379-84 |
| Hatch, Marguerite; Gjymishka, Altin; Salido, Eduardo C et al. (2011) Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter. Am J Physiol Gastrointest Liver Physiol 300:G461-9 |
