Emerging lines of research evidence point to a vital role of gut–kidney axis in the development of hyperuricemia (HUA), which has been identified as an increasing burden worldwide due to the high prevalence. The involved crosstalk which links the metabolic and immune-related pathways is mainly responsible for maintaining the axial homeostasis of uric acid (UA) metabolism. Nowadays, the urate-lowering drugs only aim to treat acute gouty arthritis as a result of their controversial clinical application in HUA. In this study, we established the HUA model of C57BL/6J mice to evaluate the effectiveness of folic acid on UA metabolism and further explored the underlying mechanisms. Folic acid attenuated the kidney tissue injury and excretion dysfunction, as well as the typical fibrosis in HUA mice. Molecular docking results also revealed the structure–activity relationship of the folic acid metabolic unit and the UA transporters GLUT9 and URAT1, implying the potential interaction. Also, folic acid alleviated HUA-induced Th17/Treg imbalance and intestinal tissue damage and inhibited the active state of the TLR4/NF-κB signaling pathway, which is closely associated with the circulating LPS level caused by the impaired intestinal permeability. Furthermore, the changes of intestinal microecology induced by HUA were restored by folic acid, including the alteration in the structure and species composition of the gut microbiome community, and metabolite short-chain fatty acids. Collectively, this study revealed that folic acid intervention exerted improving effects on HUA by ameliorating gut–kidney axis dysfunction.

The placenta is particularly susceptible to inflammation and oxidative stress, leading to placental vascular dysfunction and placental insufficiency, which is associated with fetal intrauterine growth restriction (IUGR). It is unknown whether folic acid (FA) supplementation can alleviate high-fat diet-induced IUGR in rats by improving placental function. In this study, pregnant rats were randomized into one of four diet-based groups: (1) control diet (CON), (2) control diet supplemented with FA, (3) high-fat diet (HFD), and (4) high-fat diet supplemented with FA (HFD + FA). Dams were sacrificed at gestation day 18.5 (GD18.5). The results indicated that dietary FA supplementation normalized a maternal HFD-induced decrease in fetal weight. The decrease in placental efficiency, labyrinth zone (LZ) area, blood sinusoid area, vascular density, and the levels of angiogenesis factors induced by a maternal HFD were alleviated by the addition of FA, suggesting that FA supplementation can alleviate placental vascular dysplasia. Furthermore, FA supplementation increased the protein expressions of SIRT1, inhibited NF-κB transcriptional activation, attenuated the levels of NF-κB/downstream pro-inflammatory cytokines, induced Nrf2 activation, and increased downstream target protein expression. In conclusion, we found that dietary FA supplementation during pregnancy could improve maternal HFD-induced IUGR by alleviating placental inflammation and oxidative stress, which may be associated with the regulation of SIRT1 and its mediated NF-κB and Nrf2 signaling pathways.