Malabsorption Syndromes

The immune-epithelial-stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood. To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples. Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations. Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4+ T cells, intraepithelial lymphocytes, CD8+ and γδ T cell subsets, with skewed T cell antigen receptor repertoires. Mucosal changes remained detectable despite treatment, representing a persistent immune-epithelial 'scar'. Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell-B cell interactions. Receptor-ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.

BackgroundThe D1Ce Screen pilot study stems from the Italian Republic Law 130/2023 introducing the screening based on autoantibody measurement on capillary blood for the identification of people in pre-symptomatic, early phase of type 1 diabetes (T1D) and/or having silent celiac disease (CD) in the general paediatric population to reduce the impact of the two more frequent and severe chronic diseases of childhood.AimPrimary aim is to assess, on a smaller scale, the organizational feasibility, acceptability and sustainability by the National Health Service of the screening program to be conducted nationwide in Italy according to the law.Methods and analysisThis is an observational multicenter study, planning to screen 5,363 children from four Italian regions (Lombardy, Marche, Campania, Sardinia), proportionally distributed according to population of the single Regions, representative of the North, Centre, South and Islands of Italy. Participants are screened by autoantibodies within three classes of age 2-2.9, 6-6.9, and 10-10.9 years, corresponding to reported peaks of seroconversion, in order to maximize the identification of future cases of disease. HLA typing for HLA DQ2 and DQ8 is also performed for CD risk in dry blood spots (DBS). Screening procedures are conducted by primary care paediatricians (PCPs), responsible for: direct contact with families; information about the study; administration of written informed consent, privacy statement and questionnaires; execution of blood drawing by finger prick; capillary blood collection for autoantibody and HLA testing and shipment to the central laboratory. Feasibility, acceptability and sustainability will be estimated by number of participating paediatricians; screened children in the four Regions and within the classes of age; feedback questionnaires; number of fingerpicks to obtain sufficient capillary blood for assays; any adverse events; costs evaluation in relation to assigned budget. Secondary objectives include frequency of T1D and CD specific autoantibodies to assess the prevalence of pre-symptomatic (Stage 1 and Stage 2) TD1 and undiagnosed CD in the three classes of age of general paediatric population.Study registrationD1Ce Screen is not registered to any International Study Registry, as it is a pilot observational study requested by the Italian law 130/2023.

Hyperhomocysteinemia (HHcy), a condition characterized by elevated plasma levels of the sulfur-containing amino acid homocysteine, has emerged as a multifactorial and systemic risk factor with profound effects on neural and vascular integrity. This review integrates recent findings from epidemiological studies, clinical data, and mechanistic research to provide a comprehensive overview of HHcy's contribution to neurovascular dysfunction. We examine how nutritional deficits, aging, genetic polymorphisms-such as in the methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes-pharmacological agents, and comorbid conditions shape homocysteine homeostasis and susceptibility to pathology. Emphasis is placed on molecular pathways, including oxidative and nitrative stress, inflammasome activation, autophagy, and epigenetic modulation, which link HHcy to cognitive decline, memory impairment, endothelial dysfunction, and increased disease burden in neurodegenerative disorders. By consolidating multidisciplinary evidence, we position HHcy as a pivotal but under-recognized target for intervention in neurochemical and vascular health.

ObjectiveCoeliac disease (CeD) is a relatively common autoimmune disease in Caucasian populations, but is rarely reported in China. The metabolic characteristics of Chinese patients with coeliac disease remain insufficiently characterised. Therefore, this study attempted to describe the metabolic profile of a small cohort Chinese patients with coeliac disease.MethodsPlasma samples and dietary pattern information were collected from 15 patients with CeD, 15 healthy volunteers, and 30 patients with inflammatory bowel disease (IBD). Plasma metabolomic analysis was performed using a pseudo-targeted metabolomics approach based on ultra-high-performance liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS). Dietary intake was assessed via food frequency questionnaires, and metabolomics data were adjusted according to energy and 17 specific nutrient covariates.ResultsDespite reporting significantly higher daily intakes of protein and carbohydrate when compared to controls or IBD patients, CeD patients exhibited a relative insufficiency of micronutrient niacin. Several distinct metabolic alterations were identified in CeD patients relative to healthy controls, independent of dietary intake. These included decreased metabolites in the pentose phosphate pathway and increased intermediates of the citric acid cycle. The abundances of L-proline, D-proline, microbiota-related aromatic amino acid metabolites, glycine-conjugated bile acids, and the plant sterol panuosterone were increased. In contrast, the abundances of several long-chain acylcarnitines were reduced despite higher fat intake. These metabolic alterations existed in CeD but not in IBD patients.ConclusionsCeD patients in Northwest China exhibit a unique metabolic profile distinct from IBD and healthy controls, involving host central carbon metabolism, glycerophospholipid metabolism, gut microbiota, and other factors. This might underscore the multifactorial nature of coeliac disease, implicating other factors beyond genetics and gluten.