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Common Sweetener Neotame Damages Gut Cells

Sweetener being added to a beverage.
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Sweeteners and human health

In our increasingly health-conscious society, artificial sweeteners are widely used by individuals looking to reduce their sugar consumption without sacrificing sweetness in their food and beverages. Most artificial sweeteners – also known as non-sugar sweeteners (NSS) – are at least very low in calorie content, if not completely calorie-free.

It’s perhaps no surprise, therefore, that the predicted global market value of artificial sweeteners is estimated to reach $3 billion by 2025.

Despite many sweeteners having been on the market for decades, their effects on human health remain under active research. At present, there doesn’t appear to be a global consensus on whether these first-generation sweeteners can be deemed “good” or “bad” for our health. Last July, the World Health Organization (WHO) listed aspartame as a possible carcinogen, but the US Food and Drug Administration (FDA) stated that it disagreed with the report that ultimately led to this decision.

As studies continue to probe the effects of traditional artificial sweeteners such as saccharin and aspartame, researchers are turning their attention to more recently developed sweeteners, like neotame. Neotame was developed in the 1990s and authorized as safe for the general population by the FDA in 2002. It is derived from and is chemically similar to aspartame, but it is roughly 30–60 times sweeter.

Dr. Aparna Shil, associate professor in the Department of Botany at Jahangirnagar University in Bangladesh, and Dr. Havovi Chichger, associate professor in Biomedical Science at Anglia Ruskin University (ARU) in the UK, have published their findings from an in vitro study assessing neotame’s effects on the gut epithelium and microbiome.

Neotame acceptable daily intake

The acceptable daily intake (ADI) of neotame is 2 mg per kg of body weight per day. In an individual of average weight, this would be equivalent to 10 mM per day.

“We use a model of the intestinal epithelium (Caco-2) and microbiota (Escherichia coli and Enterococcus faecalis) to investigate how physiologically-relevant exposure of neotame impacts intestinal epithelial cell function, gut bacterial metabolism and pathogenicity and gut epithelium–microbiota interactions,” the authors explained in Frontiers in Nutrition.

Neotame negatively affects intestinal epithelium

Chichger’s previous work demonstrated that sucralose, saccharin and aspartame reduce the viability of epithelial cells. In the new study, the researchers tested cell viability up to the recommended ADI of neotame (10 mM) and found that this sweetener also reduced viability at higher concentrations. At low concentrations (1–100 μM), it caused leaks across the epithelial monolayer.

Exploring whether this effect was because of a direct interaction between neotame and the sweet taste receptor, T1R3, the researchers transfected cells with siRNA targeting T1R3. This attenuated some of the cytotoxic and pro-apoptotic effects of the sweetener on the cell models.

Neotame also caused indirect damage to the intestinal epithelium via its pathogenic effects on the common gut bacteria E.coli and E. faecalis. In co-cultures, neotame had pathogenic effects at 100 Μm concentrations, which is lower than typical concentrations found in food and beverage products, as well as the ADI.

“The negative effect of neotame on the epithelium–microbiota relationship in the gut has the potential to influence a range of gut functions resulting in poor gut health which impacts a range of conditions including metabolic and inflammatory diseases, neuropathic pain and neurological conditions,” the authors described.

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“Understanding the impact of these pathogenic changes occurring in the gut microbiota is vital. Our findings also demonstrate the need to better understand common food additives more widely and the molecular mechanisms underlying potential negative health impacts,” Chichger said.

The researchers note that the analyses were performed after 24 hours of exposure to neotame, whereas it normally takes around five hours to pass through the intestine. This is a limitation to the translation of the research, as cells in the epithelium and the gut bacteria may not, in reality, be exposed to the sweetener for such long periods of time.

Reference: Shil A, Ladeira Faria LM, Walker CA, Chichger H. The artificial sweetener neotame negatively regulates the intestinal epithelium directly through T1R3-signaling and indirectly through pathogenic changes to model gut bacteria. Front nutr. 2024;11. doi: 10.3389/fnut.2024.1366409

This article is a rework of a press release issued by Anglia Ruskin University. Material has been edited for length and content.