New research published in the Journal of Applied Physiology suggests that erythritol, a popular sugar substitute, may negatively affect the cells lining blood vessels in the brain. In laboratory experiments, researchers found that erythritol increased oxidative stress, disrupted nitric oxide production, promoted the release of a blood vessel-constricting compound, and impaired the release of a key clot-busting protein. These changes are all associated with a higher risk of stroke.
Erythritol is widely used as a low-calorie sweetener. It is found in many “sugar-free” or “keto” products, including soft drinks, baked goods, and candies. Because it has minimal impact on blood sugar and insulin, erythritol has been promoted as a healthier alternative to sugar for people with obesity, diabetes, or metabolic syndrome. It is naturally present in small amounts in fruits and vegetables and can also be produced in the body. The U.S. Food and Drug Administration approved erythritol for use as a food additive in 2001.
But concerns about erythritol’s effects on cardiovascular health have been rising. A 2023 study by Witkowski and colleagues reported that higher levels of erythritol in the blood were linked to a greater risk of heart attack and stroke over a three-year period. This association held true across sexes and across populations in the United States and Europe. The same research group also found that drinking a beverage containing erythritol led to increased platelet reactivity—a potential contributor to blood clots. Other studies have similarly noted a possible link between erythritol and heart-related health risks. However, until now, there has been limited direct evidence on how erythritol affects blood vessel function at the cellular level.
To address this gap, researchers in the new study examined how erythritol influences brain microvascular endothelial cells, which line the small blood vessels in the brain and help regulate blood flow. These cells also play a role in controlling inflammation, preventing clot formation, and maintaining the blood-brain barrier. When they become dysfunctional, the risk of stroke and other brain disorders can increase.
The researchers used an in vitro model, meaning they grew human cerebral microvascular endothelial cells in the lab and exposed them to erythritol. The dose they used—6 millimolar—was equivalent to the amount of erythritol found in a typical artificially sweetened beverage, or about 30 grams. The cells were exposed to erythritol for three hours, after which various markers of cell function were measured. These included oxidative stress levels, nitric oxide and endothelin-1 production, and the ability of cells to release tissue-type plasminogen activator (t-PA), a protein that helps dissolve blood clots.
The results revealed several concerning changes. First, the erythritol-treated cells produced significantly more reactive oxygen species—compounds that can damage cells and are a key sign of oxidative stress. Specifically, cells exposed to erythritol showed about a 75% increase in reactive oxygen species compared to untreated cells. This rise in oxidative stress was accompanied by an increase in antioxidant proteins like superoxide dismutase-1 and catalase, suggesting that the cells were attempting to counteract the harmful effects of the stress but were not able to fully do so.
Next, the researchers examined nitric oxide production. Nitric oxide is a molecule produced by blood vessel cells that helps keep blood vessels open and maintains healthy blood flow. While the overall level of the enzyme responsible for nitric oxide production—endothelial nitric oxide synthase—did not change, the activation of this enzyme was significantly reduced in erythritol-treated cells.
In particular, one form of activation, called phosphorylation at Ser1177, dropped by about 65%, while an inhibitory modification, phosphorylation at Thr495, increased by roughly 85%. As a result, nitric oxide production dropped by about 20%. Reduced nitric oxide availability is a hallmark of endothelial dysfunction and is linked to increased risk of stroke and other cardiovascular events.
At the same time, the study found an increase in the production of endothelin-1, a peptide that causes blood vessels to constrict. Levels of its precursor, Big ET-1, were significantly higher in erythritol-treated cells, and the amount of endothelin-1 released into the surrounding environment was about 30% higher. Elevated endothelin-1 can lead to excessive narrowing of blood vessels and impair cerebral blood flow, especially during times of increased demand.
The final part of the study looked at the cells’ ability to release t-PA, a protein that helps dissolve blood clots and is essential for preventing stroke. While baseline t-PA levels were similar between treated and untreated cells, the erythritol-treated cells failed to increase their t-PA output in response to thrombin, a compound that normally triggers clot-busting activity. In contrast, untreated cells showed a robust increase in t-PA release. This suggests that erythritol impairs the cells’ ability to respond to clot-promoting conditions, potentially weakening the body’s natural ability to prevent strokes.
Taken together, the findings point to a concerning pattern. Erythritol exposure increased oxidative stress, reduced nitric oxide availability, increased production of a vessel-constricting compound, and blunted the release of a key clot-dissolving enzyme. All of these changes are well-established features of cerebrovascular dysfunction and are known contributors to the development and severity of ischemic stroke.
“While erythritol is widely used in sugar-free products marketed as healthier alternatives, more research is needed to fully understand its impact on vascular health,” said Auburn Berry, a graduate student at the University of Colorado Boulder and first author of the study, in a news release. “In general, people should be conscious of the amount of erythritol they are consuming on a daily basis.”
But the researchers caution that the study was conducted in vitro and cannot directly predict how erythritol will affect brain blood vessels in a living person. The experimental model used isolated human endothelial cells and tested only a single, acute exposure. Real-world effects might depend on the dose, frequency, and duration of erythritol consumption, as well as individual health factors. Still, the study’s findings align with recent clinical and epidemiological research linking erythritol consumption to increased cardiovascular risk.
More research is needed to determine whether repeated or long-term exposure to erythritol produces similar effects in living organisms, including humans. Future studies should also explore whether other non-nutritive sweeteners have similar impacts on endothelial health, and whether certain populations may be more vulnerable.
The study, “The Non-Nutritive Sweetner Erythritol Adversely Affects Brain Microvascular Endothelial Cell Function,” was authored by Auburn R. Berry, Samuel T. Ruzzene, Emily I. Ostrander, Kendra N. Wegerson, Nathalie O. Fersiva, Madeleine F. Stone, Whitney B. Valenti, João E. Izaias, Joshua P. Holzer, Jared J. Greiner, Vinicius P. Garcia, and Christopher A. DeSouza.
