Celiac disease, inflammation and oxidative damage: a nutrigenetic approach

Abstract

Celiac disease (CD), a common heritable chronic inflammatory condition of the small intestine caused by permanent intolerance to gluten/gliadin (prolamin), is characterized by a complex interplay between genetic and environmental factors. Developments in proteomics have provided an important contribution to the understanding of the biochemical and immunological aspects of the disease and the mechanisms involved in toxicity of prolamins. It has been demonstrated that some gliadin peptides resistant to complete proteolytic digestion may directly affect intestinal cell structure and functions by modulating gene expression and oxidative stress. In recent years, the creation of the two research fields Nutrigenomics and Nutrigenetics, has enabled the elucidation of some interactions between diet, nutrients and genes. Various dietary components including long chain ω-3 fatty acids, plant flavonoids, and carotenoids have been demonstrated to modulate oxidative stress, gene expression and production of inflammatory mediators. Therefore their adoption could preserve intestinal barrier integrity, play a protective role against toxicity of gliadin peptides and have a role in nutritional therapy of celiac disease.

Keywords: celiac disease; fitonutrients; gliadin peptides; inflammation; nutrigenetic; nutrigenomic; oxidative stress; proteomic.

Figure 1

Intestinal epithelial damage in celiac disease: role of “toxic” and “immunogenic” peptides. “Toxic” peptides in intestinal cells induce tight junction (TJ) dysfunctions and several cytotoxic effects such as apoptosis and altered cell differentiation. Most of these effects are mediated by increased oxidative stress induced by gluten peptides in enterocytes. These alterations reflect in an impairment of the epithelial barrier and increased permeability. As a consequence, both “toxic” and “immunogenic” peptides of gliadin pass through the enterocytes leading to activation of the immune response (native and adaptive) contributing to cell damage and villous atrophy in celiac disease (CD) subjects. LPMC, lamina propria mononuclear cells; tTG, Tissue transglutaminase.

Figure 2

Effect of gluten on oxidative stress and gene expression. Alteration in oxidative balance induced by gliadin peptides in enterocytes is involved in the activation of transcription factor NF-κB. NF-κB activation induces the transcription of pro-inflammatory cytokines and enzymes such as COX2 and iNOS with consequent higher production of prostaglandins and NO metabolites contributing to the oxidative stress. The increased oxidative stress is also involved in the down-regulation of PPARγ mediated by tissue transglutaminase (tTG). The down-regulation of PPARγ may contribute to NF-κB activation. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; COX, cyclooxygenase; LOX, lipoxygenase; iNOS, inducible nitric-oxide synthase; PPARδ, peroxisome proliferator-activated receptors gamma; ONOO•, peroxynitrite; LOOH, lipid hydroperoxides; •OH, hydroxyl radical; H₂O₂ hydrogen peroxide.

Figure 3

Protective effect of phytonutrients on cytotoxicity of gluten peptides. Antioxidant vitamins (vitamin C and E), polyphenols and carotenoids from dietary vegetable food and oil, were absorbed by intestinal cells and could exert protective effects against toxic effects exerted by gluten peptides on intestinal cells.