Furone, Francesca (2025) Autophagy and low-grade inflammation in Celiac Disease intestinal mucosa and its comorbidities. [Tesi di dottorato]

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Abstract

Cellular vulnerability is increasingly recognised as a key element in the onset and progression of chronic inflammatory and autoimmune diseases [1]. Genetic predisposition, together to environmental factors could lead to a state of cellular fragility, making cells more sensitive to pro-inflammatory stimuli and stress conditions. In this contest, the intestine has recently emerged as a central hub of inflammation [2], because of its role of primary barrier to external antigens. At this point it’s clear that intestine is not only the site of digestion and absorption of nutrients, but represents a crucial interface between environmental triggers, microbiota population, and immunity system. This perspective has highlighted the importance of maintaining intestinal homeostasis as a fundamental mechanism to preserve cellular integrity. Celiac disease (CeD) is the most characterised example of this intestinal fragility. In genetically predisposed individuals, gliadin peptides, contained in gluten, trigger an abnormal immune response that involves both innate and adaptive mechanisms, leading to the change of intestinal mucosa and epithelial damage. Many studies have suggested that functional alterations of the epithelial barrier and signs of immune activation may persist in patients with celiac disease even after a GFD, although the intestinal mucosa may appear histologically normal. Such data indicate that components of constitutive inflammation may not depend solely on gluten exposure [3–5]. So, the presence of human leukocyte antigen (HLA) -DQ2/DQ8, as genetic predisposition of CeD is necessary but not sufficient to allow the onset of the disease. Genome-wide association studies (GWAS) confirmed that, in addition to HLA, a number of non-HLA susceptibility loci contribute to CeD, including genes such as PTPRK, LPP and C1ORF106, which are involved in cytoskeleton remodelling, adhesion and epithelial proliferation [6]. Moreover, the study of protein tyrosine phosphatases (PTPs), and in particular of PTPRK, has highlighted the importance of phosphorylation balance in controlling epithelial proliferation and inflammation in CeD, thus linking genetic susceptibility with altered cellular signalling [6,7]. This report creates a further link among autoimmune inflammatory diseases. Similar alterations of epithelial vulnerability are also described in other conditions, such as type 1 diabetes (T1D) and Down syndrome (DS). In both cases disfunctions in the epithelial barrier, changes in endocytic trafficking and a systemic pro-inflammatory background contribute to amplify autoimmunity [8,9]. This evidence seems to underline how the intestine can shift from a protective barrier to a main actor in the pathogenesis of chronic inflammatory diseases. At the molecular level, mechanisms such as inflammation, autophagy, proliferation and mTOR signalling have a crucial role in maintaining intestinal homeostasis, by regulating epithelial turnover, metabolic balance, and stress responses [10,11]. Alterations of these processes have been described in CeD and may contribute to the constitutive fragility of the intestinal mucosa. Advanced cellular models need to be required to better understand the role of these pathways in CeD pathogenesis. Intestinal organoids, derived from patient biopsies, represent a model system that reproduces intestinal epithelial complexity, while intestinal fibroblasts, thanks to their stability and ability to keep epigenetic and transcriptional features of the patient they are derived from, provide a complementary tool for the study of disease-specific alterations [12,2]. Finally, translational approaches are emerging, and postbiotics such as soluble factors from Lactobacillus rhamnosus GG have been shown to prevent gliadin-induced inflammation and autophagy defects, representing a possible therapeutic tool [13,14]. The main purpose of this thesis therefore focuses on the study of the fragile nature of the intestinal epithelium and its role in the pathogenesis of CeD and related co-morbidities, by investigating intestinal organoids and mesenchymal cells.

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