Celiac disease and autophagy: new functional perspectives in diagnosis and treatment

Celiac disease (CD) is the most common inflammatory disease of the intestine. It is a chronic systemic autoimmune disorder affecting the small bowel of genetic susceptible individuals. CD is triggered by the ingestion of gluten, a storage protein present in wheat, barley and rye. CD frequency in the general population of Europe and United States is approximately 1% whereas in Finland and Sweden it reaches peaks of respectively 2% to 3%. In Italy, the estimated prevalence is 0.7%, however the number of patients currently undiagnosed seems to be largely superior to known cases. The only effective therapy is a gluten-free diet (GFD). Nevertheless, 7 to 30% of all patients is not responsive to GFD because inadvertent ingestion of gluten. The two major challenges about CD concern diagnosis and treatment. Auto-antibodies in the serum represent a valuable tool for CD diagnosis, but a percentage of patients remains elusive because of the presence of mild-symptoms. Moreover, despite international established guidelines, there is still controversy about the use of endoscopy as the essential step in CD diagnosis. Nowadays, the attention of the researchers has shifted in the identification of new non-invasive diagnostic biomarkers. Because of their characteristics, microRNAs (miRNAs) have been emerged as promising candidate not only in CD field but also for other disorders, such as Crohn disease and ulcerative colitis. The issues concerning the GFD have prompted researchers to investigate for altervative treatments. Currently, two pharmacological agents are investigated in late clinical trials as non-dietary treatments for CD. Autophagy is a cellular process that is implicated in immunity and autoimmunity as well as in the degradation of protein aggregates. Impairment of autophagic flux contributes to the pathogenesis of several disorders characterized by the accumulation of toxic protein aggregates, such as Alzheimer and Parkinson disease. Accordingly, a collaborative study was born with the Pediatric Auxology Unit and the Pediatric Surgery Unit of the Fondazione IRCCS Policlinico San Matteo. Thus, the first resulted aims of this Thesis is to investigate the role of key autophagic genes and of their regulatory miRNAs sequences as new candidate biomarkers in CD. For this purpose, blood and intestinal biopsies were collected by an exploratory cohort of pediatric CD parients and controls matched for sex and age. The obtained results suggest that the investigated autophagy-related genes and miRNAs could have a potential diagnostic power to distinguish between CD patiens and controls. Moreover, specific expression profiles could be use for CD patients’ stratification. The role of autophagy in the metabolism of gliadin was then studied in an in vitro model obtained with Caco-2 cells and modulation of this cellular process was performed in order to counteract the toxicity of these peptides. The results indicate that autophagy is implicated in gliadin degradation and that impairment of this process affects the release of gliadin outside the cells by exocytosis. On the other hand, autophagy induction leads to gliadin degradation, decreases its secretion and confers a proliferative advantage to cells. On the whole, these preliminary results indicate that the study of autophagy could be interesting for the search of new diagnostic biomarkers. The finding that autophagy is implicated in gliadin metabolism will possibly allow the identification of new therapeutical approaches based on the modulation of this cellular process.