Enterocyte synthesizes and secrets uric acid as antioxidant to protect against oxidative stress via the involvement of Nrf pathway

The gut is an important site to excreting uric acid (UA) in addition to the kidney. The gastrointestinal tract is constantly exposed to various potentially harmful substances, triggering intestinal oxidative damage. In the present study, the hypothesis that UA is can be synthesized to function as an antioxidant in the gut is evaluated. The synthesis and secretion of UA by enterocytes were analyzed in the presence of inosine, a precursor of UA, febuxostat (Fx), an inhibitor of xanthine oxidase (XOR), and H2O2. The regulation of Nrf2 pathway on UA secretion and transport were evaluated in the present of agonist (TBHQ) and inhibitor (ML385) of Nrf2. The in vivo result showed that UA and its oxidation product allantoin were presented in gut contents along the gastrointestinal tract and the highest level of UA and allantoin were detected in duodenum and jejunum respectively. The genes in the de novo purine nucleotide synthesis and salvage-catabolism pathways, and UA transporters were expressed in the intestinal tract. In the in vitro cultured enterocytes and everted gut sacs, inosine stimulated UA synthesis and secretion. H2O2 stimulated UA synthesis and secretion and meanwhile induced oxidative damage. UA attenuated H2O2-induced oxidative damage by Nrf2 pathway. UA secretion and transport were reduced by blocking Nrf2 with ML385, while increased by activating Nrf2 with TBHQ. This study provides new insights into the antioxidant effects if UA on intestinal lumen. The result suggests that activation of Nrf2 pathway is involved in the transportation and secretion of UA.