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

Nutrients. 2020 Jun 22;12(6):1862. doi: 10.3390/nu12061862.


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.

Keywords: Caco-2; claudin; intestinal epithelium; permeability; sweeteners.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Aspartame / administration & dosage
  • Caco-2 Cells
  • Claudin-3 / genetics
  • Claudins / genetics
  • Gene Expression / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Permeability / drug effects
  • Receptors, G-Protein-Coupled / drug effects*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology
  • Sucrose / administration & dosage
  • Sucrose / analogs & derivatives
  • Sweetening Agents / administration & dosage
  • Sweetening Agents / pharmacology*
  • Tight Junctions / drug effects*
  • Tight Junctions / physiology


  • CLDN3 protein, human
  • Claudin-3
  • Claudins
  • Cldn3 protein, mouse
  • Receptors, G-Protein-Coupled
  • Sweetening Agents
  • claudin 15
  • taste receptors, type 1
  • Sucrose
  • trichlorosucrose
  • Aspartame