Maternal gluten, cereal, and dietary fiber intake during pregnancy and lactation and the risk of islet autoimmunity and type 1 diabetes in the child

Background & aims: Maternal gluten intake in relation to child's risk of type 1 diabetes has been studied in few prospective studies considering the diet during pregnancy but none during lactation. Our aim was to study whether gluten, cereals, or dietary fiber in maternal diet during pregnancy and lactation is associated with the risk of islet autoimmunity or type 1 diabetes in the offspring. Methods: We included 4943 children with genetic susceptibility to type 1 diabetes from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study, born between 1996 and 2004. Maternal intake of gluten, different types of cereals, and dietary fiber were derived from a semi-quantitative validated food frequency questionnaire covering the eighth month of pregnancy and the third month of lactation. Children were monitored for islet autoantibodies up to age of 15 years and type 1 diabetes until year 2017. Risk of islet autoimmunity and clinical type 1 diabetes were estimated using Cox regression model, adjusted for energy intake, child's sex, HLA genotype, and familial diabetes. Results: Altogether 312 children (6.4%) developed islet autoimmunity at median age of 3.5 (IQR 1.7, 6.6) years and 178 children (3.6%) developed type 1 diabetes at median age of 7.1 (IQR 4.3, 10.6) years. Gluten intake during pregnancy was not associated with islet autoimmunity (HR 0.96; 95% CI 0.68, 1.35), per 1 g/MJ increase in intake nor type 1 diabetes (HR 0.96; 95% CI 0.62, 1.50) in the offspring. Higher barley consumption during lactation was associated with increased risk of type 1 diabetes (HR 3.25; 95% CI 1.21, 8.70) per 1 g/MJ increase in intake. Maternal intake of other cereals or dietary fiber was not associated with the offspring outcomes. Conclusions: We observed no association between maternal intake of gluten, most consumed cereals, or dietary fiber during pregnancy or lactation and the risk of islet autoimmunity or type 1 diabetes in children from a high-risk population

Celiac Disease in Children, Particularly with Accompanying Type 1 Diabetes, Is Characterized by Substantial Changes in the Blood Cytokine Balance, Which May Reflect Inflammatory Processes in the Small Intestinal Mucosa

Cytokines play a pivotal role in the maintenance of intestinal homeostasis inducing pro- or anti-inflammatory response and mucosal barrier function in celiac disease (CD) and type 1 diabetes (T1D). We aimed to compare the levels of pro- and anti-inflammatory cytokines in CD patients without and with coexisting T1D, as well as to evaluate its association with the presence of enteroviruses (EV), regulatory T cells (Tregs), and dendritic cells (DCs) in small bowel mucosa. Altogether, 72 patients (median age 10.1 years) who had undergone small bowel biopsy were studied. The study group consisted of 24 patients with CD (median age 6.5 years), 9 patients with CD and concomitant T1D (median age 7.0 years), two patients with T1D (median age 8.5 years), and 37 patients (median age 14.0 years) with functional gastrointestinal disorders (FGD) and a normal small bowel mucosa as controls. The levels of 33 cytokines in serum were measured by multiple analysis using the Milliplex® MAP Magnetic Bead assay. The densities of FOXP3+ Tregs, CD11c+ DC, indoleamine 2,3-dioxygenase+ (IDO+) DC, langerin+ (CD207+) DCs, and EV were evaluated by immunohistochemistry as described in our previous studies. Circulating anti-EV IgA and IgG were evaluated using ELISA. The most important finding of the study is the significant increase of the serum levels of IL-5, IL-8, IL-13, IL-15, IL-17F, IL-22, IL-27, IP-10, MIP-1β, sIL-2Rα, sTNFRII, and TNFα in CD patients compared to controls and its correlation with the degree of small bowel mucosa damage graded according to the Marsh classification. The leptin level was higher in females in all study groups. The levels of IL-2, IL-6, IL-12 (P70), IL-15, IP-10, and IFNγ correlated significantly with the density of FOXP3+ Tregs in lamina propria of the small bowel mucosa, which supports the evidence about the signaling role of these cytokines in the peripheral maintenance of FOXP3+ Tregs. At the same time, a significant negative correlation occurred between the level of IL-4 and density of FOXP3+ Tregs in controls. Another important finding of our study was the correlation of IL-17F, IP-10, sTNFRII, MCP-1, and GM-CSF with the density of EV-positive cells in the lamina propria of the small bowel mucosa. Correlation of MIP-1 (CCL-4) with CD103+ DC and langerin+ DC densities may point to their significance in the recruitment of immune cells into the lamina propria and in driving the inflammatory response in CD patients. Our results suggest the predominance of Th1 and Th17 immune responses over EV VP1 protein in CD and T1D patients. The significant elevation of Th2 cytokines, like IL-5 and IL-13, but not IL-4, in CD patients and its correlation with the degree of small bowel mucosa damage could reflect the role of these cytokines in gut defense and inflammation

Profiling of peripheral blood B-cell transcriptome in children who developed coeliac disease in a prospective study*

Background: In coeliac disease (CoD), the role of B-cells has mainly been considered to be production of antibodies. The functional role of B-cells has not been analysed extensively in CoD. Methods: We conducted a study to characterize gene expression in B-cells from children developing CoD early in life using samples collected before and at the diagnosis of the disease. Blood samples were collected from children at risk at 12, 18, 24 and 36 months of age. RNA from peripheral blood CD19+ cells was sequenced and differential gene expression was analysed using R package Limma.Findings: Overall, we found one gene, HNRNPL, modestly downregulated in all patients (logFC -0.7; q = 0.09), and several others downregulated in those diagnosed with CoD already by the age of 2 years.Interpretation: The data highlight the role of B-cells in CoD development. The role of HNRPL in suppressing enteroviral replication suggests that the predisposing factor for both CoD and enteroviral infections is the low level of HNRNPL expression.Funding: EU FP7 grant no. 202063, EU Regional Developmental Fund and research grant PRG712, The Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) 2012-2017, grant no. 250114) and, AoF Personalized Medicine Program (grant no. 292482), AoF grants 292335, 294337, 319280, 31444, 319280, 329277, 331790) and grants from the Sigrid Juse ' lius Foundation (SJF).Peer reviewe