Enhanced gastrointestinal passive paracellular permeability contributes to the obesity-associated hyperoxaluria

Abstract

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 [13C]oxalate following oral gavage with [13C]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.

Effect of Vitamin B2‐Deficient Diet on Hydroxyproline‐ or Obesity‐Induced Hyperoxaluria in Mice

“…Current evidence indicates that obesity accompanied by hyperoxaluria, which is mainly caused by increased oxalate intake due to overeating, can result in increased paracellular absorption from the intestine, and decreased oxalate excretion from the intestine due to inflammation. [ 29,30 ] We also found that GO activity was reduced in aged obese mice. These results suggest that endogenous production of oxalate in our obese model may not make a substantial contribution to hyperoxaluria.…”

“…[ 25,26 ] A study using a mouse model of obesity showed that hyperoxaluria is caused not only by excessive oxalate intake that accompanies overeating but also by enhanced passive gastrointestinal absorption via inflammation‐induced disruption of tight junctions and reduced expression of an oxalate exporter in the ileum. [ 29,30 ]…”

Effects of the Gut Microbiota and Barrier Function on Melatonin Efficacy in Alleviating Liver Injury

“…Disruption of the intestinal barrier function results in changes in intestinal permeability; Cd exposure has been suggested to down-regulate genes related to enhanced intestinal permeability in the mouse gut, such as tight junction (TJ) genes claudin-1 and occludin [ 43 ]. The disruption of the intestinal barrier function and the increase in intestinal permeability promotes the translocation of toxic luminal substances and pathogenic microorganisms from the intestine into circulation, and this is related to liver injury development [ 44 ].…”

Role of Impaired Oxalate Homeostasis in Cardiovascular Disease in Patients With End-Stage Renal Disease: An Opinion Article

“…On the other hand, oxidative stress and chronic inflammation, which are present in all CKD stages, with the highest levels in ESRD (Cobo et al, 2018;Vasylchenko et al, 2020), might themselves contribute to the reduced SLC26A6-mediated transcellular oxalate transport and the enhanced passive paracellular intestinal oxalate absorption (Amin et al, 2018;Bashir et al, 2019;Kumar et al, 2021). In an obese mouse model, oxidative stress and systemic/intestinal inflammation were found to reduce active intestinal oxalate secretion and increase passive intestinal oxalate absorption, eventually resulting in obesity-associated hyperoxaluria (Amin et al, 2018;Bashir et al, 2019). Therefore, this vicious circle of complex molecular mechanisms precludes the accurate determination of the root cause of oxalate dyshomeostasis and its relationship with CVD in patients with ESRD.…”