Erythritol sweetener increase risk of heart attack and stroke

New Cleveland Clinic research showed that erythritol, a popular artificial sweetener, is associated with an increased risk of heart attack and stroke. Findings were published in Nature Medicine.

https://www.nature.com/articles/s41591-023-02223-9

Erythritol-Naturally Occurring and Endogenously Produced

Erythritol is approximately 70% as sweet as sucrose and has a mild cooling effect in the mouth with no aftertaste [16]. Erythritol is a naturally occurring sugar alcohol (or polyol) that is found a variety of fruits such as melon, watermelon, pears, grapes; and in fermented foods such as cheese, soy sauce [17,18,19].

Erythritol is also detected in plasma and urine in human subjects and animals [20,21]. It was detected in the plasma and urine of a child with an inborn error of the pentose phosphate pathway (PPP) [21]. Later Hootman et al. demonstrated that erythritol is endogenously produced in healthy human erythrocytes from glucose via PPP [22].

The PPP is a branch of glucose metabolism, present in all organisms, that synthesizes building block for nucleic acid and DNA; generates nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), which is an essential co-factor in many anabolic reactions such as synthesis of fatty acids and non-essential amino acids; and regenerates the antioxidant, glutathione [23].

Schlicker et al. confirmed production of erythritol via PPP in human lung cancer cells and characterized two NADPH-dependent enzymes that catalyze the reduction of erythrose to erythritol, alcohol dehydrogenase 1 (ADH1) and sorbitol dehydrogenase (SORD) [24]. As these enzymes are highly expressed in liver and kidney, the authors [24] further proposed these metabolically active tissues as main contributors to endogenous synthesis of erythritol in mammals. However, factors influencing endogenous erythritol production require investigation.

Commercial Production of Erythritol

Erythritol occurs in fruits at levels too low to allow it to be extracted economically. It can be produced chemically, however, this method is also not cost-efficient [25]. In the 1950s, traces of erythritol were found in residue of blackstrap molasses fermented by yeast [26]. This led to the discovery that erythritol can be produced via fermentation by yeast and yeast-like fungi via PPP [25].

Erythritol can also be produced by some lactic acid bacteria from glucose via the phosphoketolase pathway [27]. Fermentation by yeast and yeast-like fungi is currently used as a cost-effective method for commercial large-scale erythritol production utilizing substrates such as glucose, fructose, xylose, sucrose, cellulose, and glycerol [25,27].

Following fermentation, the fermented broth is heated, filtered to remove microorganism and other impurities before it is dried into crystals. The erythritol yields have been increased by optimizing the fermentation parameters and/or by gene-targeting biotechnologies to produce strains with higher activity of enzymes involved in synthesis pathways and/or lower activity of enzymes that enable the organism to utilize erythritol. Methods directed towards improving the cost-efficiency and bio-sustainability of production continue to be investigated, including utilizing readily available byproducts such as molasses or employing bacteria capable of generating the erythritol from wheat straw [26].

Because erythritol occurs in nature, the FDA considers microbial-produced erythritol to be a natural sweetener [3]. Possibly many consumers do not agree and this explains the low health perception ratings that erythritol received in the surveys already discussed [1,9]. However, preliminary results of a 2020 survey showed that 77% of 278 respondents had a positive or very positive attitude towards microbial applications in food production [28].

Interestingly, consumers who considered themselves “environmentally concerned” were more positive towards microbial applications in food compared to those who considered themselves “health concerned”. This perspective of the latter consumers may change, however, as the potential for reprogramed microbes to meet the planet’s increasing demands for the production of environmentally friendly biomolecules related to nutrition, pharmaceuticals, and even biodegradable plastic, continues to grow [6,29].

Effects of Erythritol on Glycemia and Insulin Secretion

Studies in human subjects; lean and obese, with diabetes and without; have clearly demonstrated that acute doses of erythritol (20–75 gm) do not affect blood levels of glucose or insulin [45,57,58]. Livesey utilized the available data to calculate the glycemic and insulinemic indices of the sugar alcohols [59]. Compared to the glucose reference score of 100 for both indices, the glycemic index for erythritol was 0, and the insulinemic index was 2.

While these characteristics make erythritol potentially beneficial for subjects with diabetes, controlled clinical trials examining the effect of erythritol intake in subjects with diabetes are limited, with only one published study to support this notion. In a 2-week intervention trial, patients with diabetes consumed erythritol (20 gm/day) and exhibited a significant decrease in hemoglobin A1c (HbA1c) from 8.5 to 7.5% [58]. In acute clinical studies (24 h or less), erythritol delayed gastric emptying and glucose absorption from the small intestine, which was accompanied by dose-dependent increases in gut hormones: glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), and Peptide YY (PYY) [57,60].

In multiple diabetic animal models, erythritol treatment reduces blood glucose [61,62]. Compared to an oral glucose bolus, the acute feeding of erythritol with a glucose bolus delayed gastric emptying, attenuated the rise in blood glucose, improved oral glucose tolerance test (OGTT) response, increased expression of muscle glucose transporter type 4 (GLUT4, required for transporting glucose into cells), and increased expression of insulin receptor substrate 1 (IRS-1, required for insulin function) [63].

Studies by Wen et al. provided a mechanism by which erythritol may reduce or delay glucose absorption from the small intestine [61]. First, they reported that the administration of bolus starch with erythritol to diabetic mice resulted in reduced postprandial glucose levels via inhibited α-glucosidase activity, an intestinal epithelial enzyme that catalyzes the hydrolysis of glucose polymers into glucose. Then, using a computational molecular modeling technique, they demonstrated that erythritol can directly interact with α-glucosidase by competitively occupying the active catalytic pocket.

A recent clinical dietary intervention study does not support the above findings. Bordier et al. compared the effects of chronic intake (5–7 weeks) of erythritol (12 g 3 times daily), xylitol (8 g 3 times daily) or no sweetener on intestinal glucose absorption in obese subjects [64]. OGTTs were conducted pre- and post-intervention utilizing 3-Ortho-methyl-glucose (a marker of glucose absorption).

The results showed that chronic consumption of erythritol, or xylitol, had no between- or within-group effects on intestinal glucose absorption. However, it is important to note that in the animal studies [61,63], the glucose or starch boluses were preceded by or paired with erythritol consumption, while in the clinical study the OGTTs were performed after an overnight fast and without concurrent erythritol consumption [64]. If the proposed model, that erythritol can directly interact with α-glucosidase by competitively occupying the active catalytic pocket [61], is valid, then it is reasonable that erythritol can only impede intestinal glucose absorption when glucose and erythritol are consumed in proximity.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9824470/#:~:text=Erythritol%20is%20approximately%2070%25%20as,17%2C18%2C19%5D.

the study case :

Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n = 1,157; discovery cohort, NCT00590200), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE; includes death or nonfatal myocardial infarction or stroke).

Subsequent targeted metabolomics analyses in independent US (n = 2,149, NCT00590200) and European (n = 833, DRKS00020915) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18–2.77) and 2.21 (1.20–4.07), respectively).

At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study (NCT04731363), erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.

Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.