Celiac disease (CD) is an immune-mediated enteropathy triggered in genetically susceptible individuals by gluten-containing cereals. A central role in the pathogenesis of CD is played by the HLA-restricted gliadin-specific intestinal T cell response generated in a pro-inflammatory environment. The mechanisms that generate this pro-inflammatory environment in CD is now starting to be addressed. In vitro study on CD cells and organoids, shows that constant low-grade inflammation is present also in the absence of gluten. In vivo studies on a population at risk, show before the onset of the disease and before the introduction of gluten in the diet, cellular and metabolic alterations in the absence of a T cell-mediated response. Gluten exacerbates these constitutive alterations in vitro and in vivo. Inflammation, may have a main role in CD, adding this disease tout court to the big family of chronic inflammatory diseases. Nutrients can have pro-inflammatory or anti-inflammatory effects, also mediated by intestinal microbiota. The intestine function as a crossroad for the control of inflammation both locally and at distance. The aim of this review is to discuss the recent literature on the main role of inflammation in the natural history of CD, supported by cellular fragility with increased sensitivity to gluten and other pro-inflammatory agents.

Potential Celiac Patients (PCD) bear the Celiac Disease (CD) genetic predisposition, a significant production of antihuman transglutaminase antibodies, but no morphological changes in the small bowel mucosa. A minority of patients (17%) showed clinical symptoms and need a gluten free diet at time of diagnosis, while the majority progress over several years (up to a decade) without any clinical problem neither a progression of the small intestine mucosal damage even when they continued to assume gluten in their diet. Recently we developed a traditional multivariate approach to predict the natural history, on the base of the information at enrolment (time 0) by a discriminant analysis model. Still, the traditional multivariate model requires stringent assumptions that may not be answered in the clinical setting. Starting from a follow-up dataset available for PCD, we propose the application of Machine Learning (ML) methodologies to extend the analysis on available clinical data and to detect most influent features predicting the outcome. These features, collected at time of diagnosis, should be capable to classify patients who will develop duodenal atrophy from those who will remain potential. Four ML methods were adopted to select features predictive of the outcome; the feature selection procedure was indeed capable to reduce the number of overall features from 85 to 19. ML methodologies (Random Forests, Extremely Randomized Trees, and Boosted Trees, Logistic Regression) were adopted, obtaining high values of accuracy: all report an accuracy above 75%. The specificity score was always more than 75% also, with two of the considered methods over 98%, while the best performance of sensitivity was 60%. The best model, optimized Boosted Trees, was able to classify PCD starting from the selected 19 features with an accuracy of 0.80, sensitivity of 0.58 and specificity of 0.84. Finally, with this work, we are able to categorize PCD patients that can more likely develop overt CD using ML. ML techniques appear to be an innovative approach to predict the outcome of PCD, since they provide a step forward in the direction of precision medicine aimed to customize healthcare, medical therapies, decisions, and practices tailoring the clinical management of PCD children.

Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of this manuscript was to study the role of enterocytes in CD intestinal inflammation and their response to different proinflammatory factors, such as gliadin and viruses. Intestinal biopsies from CD patients on a gluten-containing (GCD-CD) or a gluten-free diet (GFD-CD) as well as biopsies from potential CD patients (Pot-CD) before the onset of intestinal lesions and controls (CTR) were used to investigate IL-1β and IL-6 mRNA levels in situ. Organoids from CD patients were used to test the levels of NF-κB, ERK, IL-6, and IL-1β by Western blot (WB), ELISA, and quantitative PCR. The Toll-like receptor ligand loxoribine (Lox) and gliadin peptide P31-43 were used as proinflammatory stimuli. In CD biopsies inflammation markers IL-1β and IL-6 were increased in the enterocytes, and also in Pot-CD before the onset of the intestinal lesion and in GFD-CD. The inflammatory markers pNF-κB, pERK, IL-1β, and IL-6 were increased and persistent in CD organoids; these organoids were more sensitive to P31-43 and Lox stimuli compared with CTR organoids. Taken together, these observations point to constitutive inflammation in CD enterocytes, which are more sensitive to inflammatory stimuli such as food components and viruses.

Assessment of adherence to gluten-free diet (GFD) represents the cornerstone in the management of coeliac disease. The primary aim of this study was to assess diet adherence through a questionnaire adapted to children. The secondary aim was to identify influencing factors and outcomes related to diet adherence. In this study, data about diagnosis, education, quality of life (QoL) and anti-transglutaminase (anti-TG2) titers of 160 coeliac children were collected. For the assessment of diet adherence, all participants completed the questionnaire modified from Leffler et al. (2009), while a random sample of 37 also underwent an extensive dietary interview. According to the questionnaire, diet adherence was excellent in 95 (59.4%), fair in 46 (28.8%) and low in 19 (11.9%) patients. Children diagnosed with biopsy showed better adherence than those with a biopsy-sparing approach (p = 0.036). Adherence to GFD tended to worsen during the follow up, with the average length of follow up being associated with lower scores of diet adherence (p = 0.009). Moreover, adherence to GFD decreased throughout school career, dropping from elementary until high school (p = 0.037). A positive correlation was observed between adherence to GFD and growth percentiles, which increased when higher scores of adherence were achieved. Diet adherence positively correlated with QoL (p = 0.001). In conclusion, the questionnaire displayed good sensitivity in detecting problems in diet adherence, being useful as a screening tool. Better comprehension of influencing factors and outcomes may allow the development of new strategies to improve diet adherence.

Celiac disease (CeD) is a multifactorial disease influenced by both genetic and environmental risk factors. CeD genetic components are mainly due to HLA class II genes, which account for approximately 40% of the disease heritability. The environmental factor is linked to gliadin ingestion. Despite genetic and epigenetic studies, the pathological molecular mechanism remains unclarified. The strong genetic component does not explain more than half of the hereditability; we identified several epigenetic features that contribute to the understanding of the missing hereditability. The lipid profile of infants has been proposed as a potential biomarker of CeD metabolism that can be measured before they exhibit developmental disorders and clinical symptoms. We suggest that the state of the host is a main factor for the abnormal immune response to gluten. Long before any exposure to the offending agent or any production of specific antibodies, several molecular mechanisms are differentially expressed in infants who will develop CeD compared to their peers matched for the same genetic profile. The present study explored the serum phospholipid profile of a group of infants at risk for celiac disease, followed up to 8 years to monitor the onset of CeD. We compared 30 patients who developed the disease with 20 age- and sex-matched peers with similar genetic profiles who did not develop the disease within 8 years. Serum phospholipids were analysed at 4 months, before exposure to gluten, and at 12 months of age, when none showed any marker of disease. In the 30 CeD patients, we also analysed the serum at the time of diagnosis (>24 months). The serum phospholipid profile was fairly constant across 4 and 12 months of age and, in CeD, up to 24–36 months. The phospholipid signature was dramatically different in infants who developed CeD when compared to that of control NY-CeD (Not Yet developing Celiac Disease) peers. We identified a specific serum phospholipid signature that predicts the onset of celiac disease in HLA at-risk infants years before the appearance of antibodies specific for CeD in the serum and before any clinical symptoms, even before gluten introduction into the diet at 4 months. Specifically, lysophosphatidylcholine, phosphatidylcholine, alkylacyl-phosphatidylcholine, phosphoethanolamines, phosphatidylserines, phosphatidylglycerol and phosphatidylinositol were found to be differentially represented in CeD versus NY-CeD. A set constituted by a limited number of alkylacyl-phosphatidylcholine and lyso-phosphatidylcholine, together with the duration of breast-feeding, allows the discrimination of infants who develop celiac disease before 8 years of age from those at a similar genetic risk who do not develop the disease. In addition to recent discovery, our paper unveiled a specifc phopholipid profile, able to discriminate infants who eventually develop celiac disease years before antibodies or clinical symptoms ensue.