Scientists show how a common zero-calorie sweetener found in many diet drinks may harm the brain's vascular system by increasing oxidative stress and impairing vital blood vessel functions.
Study: The non-nutritive sweetener erythritol adversely affects brain microvascular endothelial cell function. Image credit: Tawan Ramtang/Shutterstock.com
Erythritol, an artificial sweetener, has adversely affected human brain microvascular endothelial cells in laboratory experiments and may contribute to mechanisms underlying an increased risk of ischemic stroke, as reported by a study published in Journal of Applied Physiology.
Background
Erythritol is a low-calorie organic compound most widely used as an artificial sweetener in food products and beverages due to its minimal impact on blood glucose and insulin levels. The U.S. Food and Drug Administration (FDA) has approved the use of erythritol for individuals with diabetes, obesity, or metabolic syndrome to help reduce calorie and sugar intake and control blood glucose levels.
Erythritol is naturally present in several fruits and vegetables and is also produced inside the human body from glucose and fructose. Therefore, erythritol levels in the blood depend on endogenous production and exogenous intake.
Recent evidence links elevated blood erythritol levels with increased risk of cardiovascular and cerebrovascular events, such as myocardial infarction and stroke. This association has been observed in men and women and across population subgroups in the United States and Europe.
Given that endothelial cell dysfunction significantly contributes to cardiovascular and cerebrovascular diseases, researchers at the University of Colorado, USA, investigated the effect of erythritol on cerebral endothelial cell oxidative stress, nitric oxide and endothelin-1 production, and tissue-type plasminogen activator release.
Study design
The study used cultured human cerebral microvascular endothelial cells to investigate the effect of erythritol. The cultured cells were treated with six mM erythritol, equivalent to the typical amount present in artificially sweetened beverages, for 24 hours.
Intracellular oxidative stress was determined by measuring the production of reactive oxygen species (ROS) and the expression of antioxidant enzymes. The production of nitric oxide, which helps regulate blood pressure and blood flow by widening blood vessels, was measured using a commercial assay kit.
The levels of endothelin-1, which helps regulate blood pressure by narrowing blood vessels, and tissue-type plasminogen activator, which helps break down blood clots, were determined using Enzyme-linked Immunosorbent assay (ELISA).
Key findings
The study found that the 24-hour treatment of human cerebral microvascular endothelial cells with erythritol significantly induces ROS production, antioxidant enzyme expressions, and endothelin-1 production and significantly reduces nitric oxide production and tissue-type plasminogen activator release.
Erythritol reduced activation of endothelial nitric oxide synthase (eNOS) by lowering phosphorylation at Ser1177 (an activating site) and increasing phosphorylation at Thr495 (an inhibitory site), mechanisms central to the reduced nitric production observed.
These findings reveal that the non-nutritive artificial sweetener erythritol increases oxidative stress, restricts widening of blood vessels, promotes narrowing of blood vessels, and impairs thrombolytic (blood clot breakdown) activity in human cerebral microvascular endothelial cells, which can potentially affect the brain vasculature but require confirmation in animal and clinical studies before drawing conclusions about stroke risk in humans.
Study significance
The study findings highlight that erythritol, at a concentration typically present in commercially available sweetened beverages, can induce changes in the brain microvascular endothelial cell phenotype, which in turn can lead to cerebrovascular dysfunction and may contribute to increased risk of ischemic stroke.
Due to the presence of high numbers of mitochondria, brain endothelial cells are more prone to ROS-mediated damage and dysfunction. Excessive ROS production in these cells, as observed in this study, can lead to disruption of the blood-brain barrier integrity, resulting in increased vascular permeability, which promotes tissue damage and death.
The increased expression of antioxidant enzymes observed in the study indicates cellular defense mechanisms. However, the study noted that despite this compensatory enzyme response, ROS levels remained elevated, suggesting that these defenses did not fully counteract the oxidative stress. This finding suggests that although erythritol increases ROS production, it does not suppress the antioxidant defense system. However, the researchers could not rule out the possibility that repeated or long-term exposure to erythritol may suppress the antioxidant defense mechanisms.
The production of nitric oxide and endothelin-1 by brain endothelial cells is crucial for regulating blood flow in the brain. The observed reduction in nitric oxide production and induction of endothelin-1 production in brain endothelial cells indicate that erythritol exposure causes biochemical shifts that favor vasoconstriction, leading to impaired cerebral blood flow and potentially increased risk of ischemic stroke.
Tissue-type plasminogen activator released from brain endothelial cells plays a vital role in maintaining cerebral vasculature and preventing blood clot formation. Therefore, erythritol-mediated reduction in tissue-type plasminogen activator release can lead to increased risk of blood clotting and subsequent thrombotic brain injury.
Overall, the study provides experimental evidence on the mechanism of action of erythritol, which supports recent epidemiological evidence linking erythritol exposure with increased risk of cerebrovascular events.
The study used laboratory-cultured human brain cells for experimental purposes. Although the findings derived from laboratory experiments provide valuable insight into the mechanism of erythritol action, further studies are needed to understand these findings in animals and humans for pre-clinical and clinical risk assessments.
The study considered direct exposure of human brain endothelial cells to erythritol. Contrary to some reports, erythritol does cross the blood-brain barrier and can interact with brain vasculature, as noted by the authors. This further highlights the need for animal studies to ascertain the exposure level and duration required for erythritol-induced cerebral vasculature impairments.
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