Erythritol Increases Oxidative Stress and Reduces Nitric Oxide Production in Human Cerebral Microvascular Endothelial Cells

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Erythritol is a widely used non-nutritive sweetener that has been purported to be a safe alternative to sugar due to its minimal impact on blood glucose and insulin levels. However, recent evidence has linked erythritol to increased risk of cardiovascular and cerebrovascular events, particularly ischemic stroke. The direct and indirect effects of erythritol on brain endothelial cells are poorly understood. The experimental aim of this study was to determine, in vitro, the effect of erythritol on cerebral endothelial cell oxidative stress and nitric oxide (NO) production. Increased oxidative stress and reduced NO bioavailability are etiologically involved in cerebral vascular dysfunction and thrombotic events. Human cerebral microvascular endothelial cells (hCMECs) were cultured (3rd passage) and incubated with culture media containing 6 mM erythritol (equivalent to a typical amount of erythritol [30g] in a single can of commercially available artificially sweetened beverage) for 3 hours. Cells were harvested and intracellular reactive oxygen species (ROS) production was determined using CellROX Deep Red Reagent and expression of key antioxidant defense proteins (superoxide dismutase 1 (SOD-1) and catalase) and well as expression of endothelial NO synthase (eNOS) were determined by capillary electrophoresis immunoassay. ROS production was significantly higher (~100%) in hCMECs treated with erythritol (204+32%) compared with untreated cells (105+4%). Concordantly, expression of SOD-1 (332.1±16.2 vs 214.9±4.7 AU; P=0.002) and catalase (30.9±0.3 vs 24.4±0.9 AU; P=0.002) were higher in cells treated with erythritol, indicative of a cellular response to increased oxidative burden. Phosphorylation is the primary post translational modification regulating eNOS enzyme activity and, in turn, NO production. Phosphorylation of Ser1177 confers the greatest activation of eNOS. Although total eNOS expression was not significantly altered (107.0±16.8 vs 104.1±14.8 AU); expression of p-eNOS (Ser1177) was markedly lower (51.5±1.1 vs 81.1±6.1 AU; P=0.009) in hCMECs treated with erythritol. As a result, NO production was also significantly lower in erythritol treated cells (5.7±0.3 vs 7.4±0.3 mol/L). In summary, erythritol adversely affects oxidative stress and NO production in brain endothelial cells in vitro. Increase in oxidative stress and reduction NO bioavailability may contribute to the increased risk of cerebrovascular disease and ischemic stroke associated with erythritol. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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