Investigating a potential protective role for a microbial metabolite in celiac disease pathogenesis 2267135

Abstract

Abstract Introduction Patients with celiac disease (CD) are predisposed by the HLADQ2/DQ8 haplotypes, with 99% of patients possessing one or both of these alleles. 30-40% of the greater population expresses at least one of these alleles, however, only 1-2% of the population is diagnosed with CD. Genetics alone cannot explain the worldwide increase in CD incidence, strongly indicating that environmental factors are at play. One factor of interest is the gut microbiome. Methods We recently conducted a prospective cohort study using plasma and fecal samples from children aged 2.5 and 5 years collected before the onset of disease (CD progressors) from the prospective cohort All Babies in Southeast Sweden (ABIS) study and analyzed the plasma metabolome. We identified a microbial metabolite, taurodeoxycholic acid (TDCA) that was upregulated two-fold. We treated C57BL/B6 mice and DQ8-Dd-villin-IL15-tg mice with TDCA and performed histological analysis on small intestinal tissue and flow cytometry to examine the populations of immune cells present in the small intestines of these mice. Results When C57BL/B6 mice were treated with TDCA, it induced villous atrophy in the duodenum, upregulated CD4+ T-cells, and decreased T regulatory cells. The DQ8-Dd-villin-IL15-tg mice overexpress IL-15 in the lamina propria and possess the predisposing HLA-DQ8 allele. Treating these mice with TDCA (0.4%, n = 16/sex) caused changes in the morphology of the ileum, including a decrease in villous length as defined by a decrease in the villi/crypt ratio in mice on a gluten-free diet. However, mice that were fed a diet containing gluten paired with TDCA did not experience similar changes and also had reduced intraepithelial lymphocytes (IELs) and goblet cells compared to the gluten controls. Additionally, preliminary data suggests that these mice also have decreased numbers of T regulatory cells. Conclusion Our results indicate that TDCA might protect against villous atrophy when combined with gluten in the context of CD. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)