Article Impact Level: HIGH Data Quality: STRONG Summary of Journal of Applied Physiology, 138(6), 1571–1577. https://doi.org/10.1152/japplphysiol.00276.2025 Dr. Auburn R. Berry et al.
Points
- New research on brain endothelial cells provides a cellular mechanism explaining how the sweetener erythritol may increase the risk of ischemic stroke and other cardiovascular events.
- In laboratory experiments, exposing human cerebral endothelial cells to erythritol substantially increased intracellular reactive oxygen species, prompting a significant upregulation of key antioxidant defense proteins.
- The study found that erythritol impaired nitric oxide bioavailability by unfavorably altering eNOS enzyme phosphorylation, which significantly decreased nitric oxide production.
- Researchers observed that erythritol exposure promoted a pro-vasoconstrictive cellular state by significantly elevating the potent vasoconstrictor peptide endothelin-1 production compared to controls.
- Furthermore, the sweetener blunted the cells’ critical fibrinolytic capacity, as the regular release of tissue-type plasminogen activator in response to thrombin was significantly inhibited.
Summary
This in vitro study investigated a potential mechanism linking erythritol consumption with adverse cerebrovascular events by evaluating its effects on human cerebral microvascular endothelial cells (hCMECs). Researchers exposed cultured hCMECs to 6 mM erythritol for 3 hours, a concentration equivalent to consuming a beverage containing 30 g of the sweetener. The study aimed to quantify changes in oxidative stress, nitric oxide (NO) and endothelin (ET)-1 signaling, and fibrinolytic capacity, which are key cellular functions for maintaining cerebrovascular health.
The results indicate that erythritol exposure significantly increased oxidative stress. Intracellular reactive oxygen species (ROS) production was substantially higher in treated cells versus controls (204 ± 32% vs. 105 ± 4%). This was accompanied by upregulation of antioxidant proteins superoxide dismutase-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). Furthermore, erythritol impaired NO bioavailability, decreasing NO production (5.8 ± 0.8 vs. 7.3 ± 0.7 µmol/L) by reducing activating eNOS phosphorylation at Ser1177 (52.1 ± 2.1 vs. 77.3 ± 9.1 AU; P < 0.001) and increasing inhibitory phosphorylation at Thr495 (63.4 ± 8.0 vs. 45.6 ± 6.9 AU; P = 0.006).
Concurrently, erythritol promoted a pro-vasoconstrictive and pro-thrombotic state. ET-1 production was significantly elevated (34.6 ± 2.3 vs. 26.9 ± 1.5 pg/mL), driven by higher Big ET-1 expression (56.4 ± 9.8 vs. 40.9 ± 6.5 AU; P = 0.02). The fibrinolytic response was also blunted; thrombin-stimulated tissue-type plasminogen activator (t-PA) release was negligible in erythritol-treated cells (87.4 ± 6.3 to 87.6 ± 8.3 pg/mL), whereas it increased substantially in controls (90.1 ± 5.5 to 110.2 ± 6.4 pg/mL). These findings suggest that erythritol induces endothelial dysfunction, providing a plausible cellular mechanism for the observed epidemiological association with increased ischemic stroke risk.
Link to the article: https://journals.physiology.org/doi/full/10.1152/japplphysiol.00276.2025
References Berry, A. R., Ruzzene, S. T., Ostrander, E. I., Wegerson, K. N., Orozco-Fersiva, N. C., Stone, M. F., Valenti, W. B., Izaias, J. E., Holzer, J. P., Greiner, J. J., Garcia, V. P., & DeSouza, C. A. (2025). The non-nutritive sweetener erythritol adversely affects brain microvascular endothelial cell function. Journal of Applied Physiology, 138(6), 1571–1577. https://doi.org/10.1152/japplphysiol.00276.2025
