**Background**
The intestinal epithelium serves as a critical barrier between the internal environment of the body and the external lumen, playing a vital role in nutrient absorption and immune defense. Maintaining the integrity of this barrier is essential for overall health, as disruption can lead to various metabolic and inflammatory disorders. Recent research has focused on how non-nutritive, high-intensity artificial sweeteners, which are widely used as low-caloric flavor enhancers, interact with the gut environment and the sweet taste receptor T1R3. Understanding the impact of these additives on epithelial cell viability and the gut microbiome is crucial for assessing their long-term safety. In this context, we will introduce a derivative of aspartame—Neotame.
**Definition**
Neotame is a non-nutritive, high-intensity artificial sweetener and flavor enhancer that is 7,000 to 13,000 times sweeter than sugar. According to the Neotame description, it acts as a potent modulator of intestinal epithelial cells and the gut microbiome.
**In Vitro and In Vivo Studies**
The Neotame biological activity has been extensively studied regarding its effects on the intestinal barrier. In vitro studies using Caco-2 cells demonstrated that Neotame (0-10000 μM; 24 h) significantly reduces cell viability at high concentrations. Specifically, Neotame in vitro (100 μM and higher; 6-24 h) induces intestinal epithelial cell death, while lower concentrations (1-100 μM) cause leaks across the epithelial monolayer. Apoptosis analysis revealed increased cell death from 100 μM and significant apoptosis from 10 μM and higher. Furthermore, Western blot analysis showed that Neotame (0-100 μM; 24 h) reduces the expression of Claudin 3 at the Caco-2 cell surface. These effects, including barrier disruption and apoptosis, are mediated by the sweet taste receptor T1R3.
Regarding Neotame In Vivo effects, research using male CD-1 mice (approximately 7 weeks old) showed that daily oral administration of Neotame (0.75 mg/kg; 4 weeks) perturbs the diversity and community composition of the gut microbiome. The results indicated lower alpha-diversity compared to the control group, with an enrichment of the phylum Bacteroidetes and a decrease in Firmicutes. Additionally, it led to a reduction in members of the family Lachnospiraceae and Ruminococcaceae, such as Blautia and Ruminococcus. Metabolite profiling in fecal samples revealed an enrichment in LPS biosynthesis and amino acid metabolism, while fatty acid, carbohydrate, and lipid metabolism were decreased. Specifically, metabolites such as malic acid and linoleic acid were decreased, while cholesterol and campesterol concentrations increased. In conclusion, Neotame is a high-intensity sweetener that negatively regulates the intestinal epithelium and alters the gut microbiota.
Keywords
Neotame, 165450-17-9, Drug Derivative, Apoptosis, Taste Receptor, Drug derivative, sweetener, cell death, gut microbiome, metabolite profiles, Inhibitor, inhibitor, inhibit
References
[1] Liang Chi, et al. Effects of the Artificial Sweetener Neotame on the Gut Microbiome and Fecal Metabolites in Mice. Molecules. 2018 Feb 9;23(2):367.
[2] Anuradha Kumari, et al. Stability of Aspartame and Neotame in Pasteurized and In-Bottle Sterilized Flavoured Milk. Food Chem. 2016 Apr 1;196:533-8.
[3] Shil A, et al. 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 Apr 24;11:1366409.