Objective Celiac disease (CD) is an immune-mediated disease characterized by small intestinal inflammation. CD is associated with HLA-DQ2 and HLA-DQ8 haplotypes, however, genetics alone cannot explain the increasing incidence rates. The main goal of this study was to determine the role of the gut microbiota in CD pathogenesis in the first five years of life.Design We conducted a longitudinal study focusing on three developmental phases of the gut microbiota (ages 1, 2.5 and 5 years). The fecal samples were obtained from 16 children who developed CD and 16 matched controls. We used 16S sequencing combined with functional analysis, flow cytometry, immunoglobulin A (IgA) sequencing (IgA-seq), and plasma metabolomics to determine a microbial link to CD pathogenesis.Results We identified a distinct gut microbiota composition in CD progressors (CDP, children who developed CD during or after their gut microbiota were sampled) in each developmental phase. Pathogenesis and inflammation-related microbial pathways were enriched in CDP. Moreover, they had significantly more IgA coated bacteria and the IgA targets were significantly different compared to controls. Proinflammatory and pathogenesis-related metabolic pathways were enriched in CDP. Further, we identified inflammatory metabolites, particularly microbiota-derived taurodeoxycholic acid (TDCA) as increased in CDP.Conclusion Our study defines an inflammatory gut microbiota for the CDP including its composition, function, IgA response and related plasma metabolites. The inflammatory nature of CD gut microbiota during development is potentially related to the onset of the disease. Targeting inflammatory bacteria in this critical window could affect the pathogenesis and prognosis of CD.What is already known on this subject? What are the new findings? How might it impact clinical practice in the foreseeable future?

Children Developing Celiac Disease Have a Distinct and Proinflammatory Gut Microbiota in the First 5 Years of Life