Department of Medicine, The University of Chicago , Chicago, Illinois.
Department of Surgery, University of Calgary , Calgary, Alberta , Canada.
Am J Physiol Gastrointest Liver Physiol. 2019 Jan 1;316(1):G1-G14. doi: 10.1152/ajpgi.00266.2018. Epub 2018 Oct 11.
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 small 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 [C]oxalate following oral gavage with [C]oxalate, indicating increased intestinal oxalate absorption in vivo. The observation of higher oxalate absorption in vivo compared with ex vivo suggests 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, zonula occludens-1, and claudins-1 and -3 mRNA and total protein expression. Proinflammatory cytokines and oxidative stress, which are elevated in obesity, significantly enhanced paracellular intestinal oxalate absorption in vitro and 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. NEW & NOTEWORTHY This study shows that the obese ob/ob mice have significantly increased gastrointestinal paracellular oxalate absorption and remarkably enhanced paracellular permeability along the entire gut in vivo, which are likely mediated by the obesity-associated increased systemic and intestinal inflammation and oxidative stress. A transepithelial oxalate concentration gradient driving gastrointestinal paracellular oxalate absorption exists, and therefore, our novel findings likely contribute to the hyperoxaluria observed in the ob/ob mice and hence to the pathogenesis of obesity-associated hyperoxaluria.
大多数肾结石（KS）由草酸钙组成，尿液中草酸的小幅度增加会增加结石的风险。肥胖是 KS 的一个危险因素，并且随着体型的增加，尿草酸盐的排泄也会增加。我们之前建立了肥胖 ob/ob（ob）小鼠模型（尿液草酸盐增加 3.3 倍），以定义肥胖相关高草酸尿症（OAH）的发病机制。本研究的目的是检验这样一个假设，即肥胖相关的小肠细胞旁通透性增强通过增加被动细胞旁肠草酸吸收而导致 OAH。ob 小鼠的空肠（1.6 倍）和回肠（1.4 倍）细胞旁草酸吸收明显增加，并且口服[C]草酸后尿液[C]草酸明显增加（5 倍），表明体内肠道草酸吸收增加。体内观察到的草酸吸收高于体外提示沿着整个肠道通透性增加的可能性。事实上，ob 小鼠给予的蔗糖（1.7 倍）、乳果糖（4.4 倍）和三氯蔗糖（3.1 倍）分别有更大比例排泄到尿液中，分别反映胃、小肠和结肠细胞旁通透性增加。ob 小鼠的胃肠道闭合蛋白、紧密连接蛋白-1 和紧密连接蛋白-3 的 mRNA 和总蛋白表达明显减少。肥胖时升高的促炎细胞因子和氧化应激显著增强了体外和体内细胞旁肠草酸吸收。我们得出结论，肥胖小鼠的肠道草酸吸收明显增加，体内胃肠道细胞旁通透性增强，这可能有助于 OAH 的发病机制，因为存在跨上皮草酸浓度梯度来驱动细胞旁肠草酸吸收。新的和值得注意的是，这项研究表明，肥胖的 ob/ob 小鼠的胃肠道细胞旁草酸吸收明显增加，并且体内整个肠道的细胞旁通透性显著增强，这可能是由肥胖相关的全身性和肠道炎症以及氧化应激增加介导的。跨上皮草酸浓度梯度驱动胃肠道细胞旁草酸吸收，因此，我们的新发现可能有助于解释 ob/ob 小鼠中观察到的高草酸尿症，从而有助于肥胖相关高草酸尿症的发病机制。
