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.

Highlights

  • Under normal conditions, the intestinal epithelial barrier maintains selective gut permeability to allow for nutrient absorption but provide a robust barrier and prevent the entry of pathogens and pathogenic molecules into circulation

  • T1R3 protein and mRNA in the intestinal epithelium where they have been identified to act as sensors to stimulate glucose absorption and modulate incretin release [36,37,38]

  • Given the wide range of concentrations of different artificial sweeteners consumed in the diet [23], we sought to understand the dose-dependent effect of the commonly consumed artificial sweeteners sucralose, aspartame, and saccharin on Caco-2 cell viability, apoptosis, and cell death

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Summary

Introduction

The intestinal epithelial barrier maintains selective gut permeability to allow for nutrient absorption but provide a robust barrier and prevent the entry of pathogens and pathogenic molecules into circulation. The disruption of the intestinal epithelial barrier results in a ‘leaky gut,’ a key pathophysiological event seen in several chronic inflammatory disorders such as diabetes, pancreatitis, multiple organ failure, and autoimmune diseases [1,2,3]. The intestinal barrier is maintained by two key mechanisms: epithelial cell homeostasis to regulate cell numbers forming the barrier and homotypic junctional complexes to regulate paracellular permeability across the barrier [7]. Intestinal epithelial homeostasis is established by equilibrium between cell proliferation and cell death, with dysregulated or excessive epithelial cell death associated with diseases of impaired barrier integrity and leakage across the paracellular space [4]. The paracellular space is largely modulated by tight junction (TJ) proteins that control the movement of water, nutrients, and electrolytes across the epithelium into the interstitial fluid [8].

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