Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.

Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.

Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants.

Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.

Detection of Celiac disease in primary care: a multicenter case-finding study in North America.

BACKGROUND: Celiac disease (CD) is one of the most common lifelong disorders in western countries. However, most cases remain currently undiagnosed in North America, mostly due to poor awareness of CD by primary care physicians. OBJECTIVES: The aims of this study were (a) to determine whether an active case-finding strategy in primary care could increase the frequency of CD diagnosis and (b) to determine the most common clinical presentations of the condition. METHODS: This was a multicenter, prospective study involving adult subjects during the years 2002-2004, attending one of the participating practices. All individuals with symptoms or conditions known to be associated with CD were tested for immunoglobulin A anti-transglutaminase (tTG) antibodies, and those with elevated anti-tTG were subsequently tested for IgA antiendomysial antibodies (EMA). All subjects who were positive for EMA were advised to undergo an intestinal biopsy and HLA typing. RESULTS: The study group included 737 women and 239 men, with a median age of 54.3 yr. A positive anti-tTG test was found in 30 out of 976 investigated subjects (3.07%, 95% CI 1.98-4.16). CD was diagnosed in 22 patients (18 women, 4 men). The most frequent reasons for CD screening in these 22 cases were bloating (12/22), thyroid disease (11/22), irritable bowel syndrome (7/22), unexplained chronic diarrhea (6/22), chronic fatigue (5/22), and constipation (4/22). The prevalence of CD in the serologically screened sample was 2.25% (95% CI 1.32-3.18). The diagnostic rate was low at baseline (0.27 cases per thousand visits, 95% CI 0.13-0.41) and significantly increased to 11.6 per thousand visits (95% CI 6.8-16.4, P < 0.001) following active screening implementation. CONCLUSIONS: This study demonstrates that an active case-finding strategy in the primary care setting is an effective means to improve the diagnostic rate of CD in North America.