Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3

Abstract

The breakdown of the intestinal epithelial barrier and subsequent increase in intestinal permeability can lead to systemic inflammatory diseases and multiple-organ failure. Nutrition impacts the intestinal barrier, with dietary components such as gluten increasing permeability. Artificial sweeteners are increasingly consumed by the general public in a range of foods and drinks. The sweet taste receptor (T1R3) is activated by artificial sweeteners and has been identified in the intestine to play a role in incretin release and glucose transport; however, T1R3 has not been previously linked to intestinal permeability. Here, the intestinal epithelial cell line, Caco-2, was used to study the effect of commonly-consumed artificial sweeteners, sucralose, aspartame and saccharin, on permeability. At high concentrations, aspartame and saccharin were found to induce apoptosis and cell death in intestinal epithelial cells, while at low concentrations, sucralose and aspartame increased epithelial barrier permeability and down-regulated claudin 3 at the cell surface. T1R3 knockdown was found to attenuate these effects of artificial sweeteners. Aspartame induced reactive oxygen species (ROS) production to cause permeability and claudin 3 internalization, while sweetener-induced permeability and oxidative stress was rescued by the overexpression of claudin 3. Taken together, our findings demonstrate that the artificial sweeteners sucralose, aspartame, and saccharin exert a range of negative effects on the intestinal epithelium through the sweet taste receptor T1R3.

Sucralose Stimulates Mitochondrial Bioenergetics in Caco-2 Cells

“…Consistently, we showed an increase in reductive power in cells treated with sucralose, suggesting an augmented activity in mitochondrial reductases enzymes as succinate dehydrogenase and cytochrome c oxidase. Van Eyk et al obtained similar results in Caco-2 and HT 29 cells in the presence of 0.1 and 1 mM of sucralose ( 18 ) and Shill et al in Caco-2 cells with 1 mM ( 12 ).…”

“…In MIN6 cells, sucralose increased cytosolic Ca 2+ by inducing its mobilization from intracellular stores and also from the extracellular milieu, mediated by the activation of sweet taste receptor T1R2/T1R3 ( 7 ). Reportedly, Caco-2 cells express the receptor ( 12 , 20 ). Therefore, T1R2/T1R3 activation may be the mediator of the sucralose-induced cytosolic Ca 2+ increase.…”

“…However, sucralose consumption did not induce oxidative stress in the brain of diabetic rats ( 26 ). Recently, it has been reported that sucralose does not increase ROS production in Caco-2 cells, measured with the fluorogenic dye DCFDA at 0.1 mM sucralose ( 12 ). Thus, further investigation is required to unravel the relevance of the sucralose-induced increase in mitochondrial transmembrane potential.…”

“…In opposition, studies shown no effects of sucralose on glucose homeostasis in healthy humans ( 8 – 10 ). At the intestinal level, sucralose affects the composition of the gut microbiota ( 11 ), disrupts the intestinal epithelial barrier ( 12 ), and exacerbated intestinal inflammatory reactivity in an animal model of Crohn's disease ( 13 ). Interestingly, it has been reported that sucralose consumption may impact energy homeostasis independently gut microbiota ( 9 , 14 ).…”

The hidden hazardous effects of stevia and sucralose consumption in male and female albino mice in comparison to sucrose

“… Lenoir et al (2007) allowed rats to choose between saccharin sweetened water and cocaine (a highly addictive substance); they found that 94% of rats preferred the sweet taste of saccharin. Shil et al (2020) added that non-caloric sweeteners like sucralose negatively affected the intestinal epithelium through these sweet taste receptors. Wang et al (2016) showed that sucralose administration increased food consumption by direct stimulation of sweet taste receptors and by indirect stimulation of taste-independent neuronal mechanisms.…”