Enhanced Gastrointestinal Passive Paracellular Permeability Contributes to the Obesity-associated Hyperoxaluria.

Most kidney stones (KS) are composed of calcium oxalate and small increases in urine oxalate enhance the stone risk. Obesity is a risk factor for KS and urinary oxalate excretion increases with increased body size. We previously established the obese ob/ob ( ob) mice as a model (3.3-fold higher urine oxalate) to define the pathogenesis of obesity-associated hyperoxaluria (OAH). The purpose of this study was to test the hypothesis that the obesity-associated enhanced intestinal paracellular permeability contributes to OAH by increasing passive paracellular intestinal oxalate absorption. ob mice have significantly higher jejunal (1.6-fold) and ileal (1.4-fold) paracellular oxalate absorption ex vivo, and significantly higher (5-fold) urine 13C-oxalate following oral gavage with 13C-oxalate, indicating increased intestinal oxalate absorption in vivo. Observing higher oxalate absorption in vivo compared to ex vivo suggest the possibility of increased paracellular permeability along the entire gut. Indeed, ob mice have significantly higher fractions of the administered sucrose (1.7-fold), lactulose (4.4-fold), and sucralose (3.1-fold) excreted in the urine, reflecting increased gastric, small intestinal, and colonic paracellular permeability, respectively. The ob mice have significantly reduced gastrointestinal occludin, ZO-1, and claudins-1 & 3 mRNA and total protein expression. Proinflammatory cytokines and oxidative stress, which are elevated in obesity, significantly enhanced paracellular intestinal oxalate absorption in vitro & ex vivo. We conclude that obese mice have significantly higher intestinal oxalate absorption and enhanced gastrointestinal paracellular permeability in vivo, which would likely contribute to the pathogenesis of OAH, since there is a transepithelial oxalate concentration gradient to drive paracellular intestinal oxalate absorption.