Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization withOxalobacter

Abstract

Hatch M, Gjymishka A, Salido EC, Allison MJ, Freel RW. 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-G469, 2011. First published December 16, 2010; doi:10.1152/ajpgi.00434.2010.-Oxalobacter colonization of rat intestine was previously shown to promote enteric oxalate secretion and elimination, leading to significant reductions in urinary oxalate excretion (Hatch et al. Kidney Int 69: 691-698, 2006). The main goal of the present study, using a mouse model of primary hyperoxaluria type 1 (PH1), was to test the hypothesis that colonization of the mouse gut by Oxalobacter formigenes could enhance enteric oxalate secretion and effectively reduce the hyperoxaluria associated with this genetic disease. Wild-type (WT) mice and mice deficient in liver alanine-glyoxylate aminotransferase (Agxt) exhibiting hyperoxalemia and hyperoxaluria were used in these studies. We compared the unidirectional and net fluxes of oxalate across isolated, short-circuited large intestine of artificially colonized and noncolonized mice. In addition, plasma and urinary oxalate was determined. Our results demonstrate that the cecum and distal colon contribute significantly to enteric oxalate excretion in Oxalobacter-colonized Agxt and WT mice. In colonized Agxt mice, urinary oxalate excretion was reduced 50% (to within the normal range observed for WT mice). Moreover, plasma oxalate concentrations in Agxt mice were also normalized (reduced 50%). Colonization of WT mice was also associated with marked (up to 95%) reductions in urinary oxalate excretion. We conclude that segment-specific effects of Oxalobacter on intestinal oxalate transport in the PH1 mouse model are associated with a normalization of plasma oxalate and urinary oxalate excretion in otherwise hyperoxalemic and hyperoxaluric animals. cecum; proximal colon; distal colon; slc26a6 CONSIDERABLE EVIDENCE HAS emerged from human and animal studies suggesting that colonization of the intestinal tract by the anaerobic bacterium Oxalobacter formigenes plays an important role in degrading dietary sources of oxalate in the intestine, leading to reduced intestinal oxalate absorption and, consequently, a lower urinary oxalate excretion (9, 10, 15, 18 -20, 22, 25-27, 29). Importantly, these bacteria, discovered by Allison et al.(1) in 1985, use oxalate as a sole carbon and energy source. In most of the studies involving human subjects, the approach has been to determine whether the lack of Oxalobacter colonization is associated with increased urinary oxalate excretion and stone formation (9, 10, 18 -20, 22, 26, 29). Clinical findings suggest a direct correlation between the complete absence or decreased activity of luminal Oxalobacter and the development of recurrent oxalate stone disease (18), as well as the hyperoxaluria associated with conditions such as inflammatory bowel disease, jejunoileal bypass, and cystic fibrosis (9,10,2...

Transcellular oxalate and Cl−absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate

“…Cecal epithelia from WT mice exhibited a prominent net absorption of oxalate (8 pmol·cm Ϫ2 ·h Ϫ1 ) under shortcircuit conditions, as we reported earlier (20). The unidirectional oxalate fluxes in this segment were similar in magnitude to those measured in the ileum, even though the conductance of cecal tissues was 30% lower.…”

“…In the present study, the distal colon of WT mice exhibited a net absorption of oxalate, whereas we previously observed a small net oxalate secretion in another strain/colony with the C57BL/6 background (20). The basis of this difference is not clear but resides in the higher secretory component observed in the latter study, as the magnitudes of J ms Ox were similar in both strains.…”

“…Fecal samples were collected directly from the mouse intestinal lumen at the time the tissues were being prepared for the flux studies. The presence of anaerobic oxalatedegrading bacteria in the luminal contents was determined by inoculation of anaerobically sealed vials containing 20 mM oxalate with ϳ20 mg of fecal material (20). Any change in oxalate concentration by microbial action in these vials incubated at 37°C was determined 1 wk later by our routine enzymatic oxalate assay.…”

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

“…Three microbial enzymes are known to participate in the catabolism of oxalate: an oxalate:formate antiporter, which allows oxalate to enter the bacterial cell; formyl-CoA transferase, which converts oxalate to oxalyl-CoA; and oxalyl-CoA decarboxylase, which yields formyl-CoA. Oxalobacter formigenes is one of the key bacteria responsible for this reaction: (a) it can use oxalate as a sole carbon source (27); (b) lack of O. formigenes is associated with increased risk of hyperoxaluria and kidney stones (28); and (c) administration of O. formigenes reduces urinary oxalate concentrations (29,30).…”

Probiotics for prevention of urinary stones

“…The hoped-for net effect is to increase gut and decrease urinary oxalate elimination. Studies in a mouse model of type 1 PH support the possible effect of this strategy (35). Indeed, in a small unblinded pilot study of four PH patients, urine oxalate excretion fell up to 50% during 4 weeks on an oral preparation of O. formigenes (36).…”