Dynamics of Gut Microbiome, IgA Response and Plasma Metabolome in Development of Pediatric Celiac Disease

Abstract

29Objective: Celiac disease (CD) is an immune-mediated disease characterized by small intestinal 30 inflammation. CD is associated with HLA-DQ2 and HLA-DQ8 haplotypes, however, genetics 31 alone cannot explain the increasing incidence rates. The main goal of this study was to determine 32 the role of the gut microbiota in CD pathogenesis in the first five years of life. 33Design: We conducted a longitudinal study focusing on three developmental phases of the gut 34 microbiota (ages 1, 2.5 and 5 years). The fecal samples were obtained from 16 children who 35 developed CD and 16 matched controls. We used 16S sequencing combined with functional 36 analysis, flow cytometry, immunoglobulin A (IgA) sequencing (IgA-seq), and plasma 37 metabolomics to determine a microbial link to CD pathogenesis. 38 Results:We identified a distinct gut microbiota composition in CD progressors (CDP, children 39 who developed CD during or after their gut microbiota were sampled) in each developmental 40 phase. Pathogenesis and inflammation-related microbial pathways were enriched in CDP. 41 Moreover, they had significantly more IgA coated bacteria and the IgA targets were significantly 42 different compared to controls. Proinflammatory and pathogenesis-related metabolic pathways 43 were enriched in CDP. Further, we identified inflammatory metabolites, particularly microbiota-44 derived taurodeoxycholic acid (TDCA) as increased in CDP. 45 Conclusion:Our study defines an inflammatory gut microbiota for the CDP including its 46 composition, function, IgA response and related plasma metabolites. The inflammatory nature of 47 CD gut microbiota during development is potentially related to the onset of the disease. 48Targeting inflammatory bacteria in this critical window could affect the pathogenesis and 49 prognosis of CD. 50 51 Significance of this study 52What is already known on this subject? 53• Celiac Disease (CD) is a gluten induced immune-mediated disease in genetically 54 predisposed individuals. 55• CD incidence is increasing worldwide which genetics alone cannot explain. Previous 56 studies have shown that the gut microbiota of CD patients differ from that of healthy 57 populations. However, the role of the microbiome in CD pathogenesis and its role in 58 chronic inflammation is yet be established. 59What are the new findings? 60• In a prospective longitudinal study in children using samples representing all three phases 61 of gut microbiota development (ages 1, 2.5 and 5), we identified significant differences in 62 the composition and function of gut microbiota at each phase. Pathogenesis and 63 inflammation-related functions are enriched in the gut microbiome of CD progressors. 64• We applied IgA-sequencing to identify inflammatory bacteria in both healthy subjects 65 and CD progressors. Flow Cytometry analysis identified more IgA coated bacteria at ages 66 1 and 5 in CD progressors, indicating an early inflammatory response. CD bacterial IgA 67 targets also differed significantly from healthy controls. 68• We analyzed plasma meta...

Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study

“…For example, our analysis identified a significantly higher abundance of Dialister invisus strain DSM_15470 in CD at all time points (except −3 mo) compared with CD onset. An increased abundance of Dialister has been previously reported in children with pre-T1D compared with controls (32) and in subjects who later developed CD (20). We also observed increased abundance of Parabacteroides species and strains prior to CD onset in cases (Figs.…”

“…While these studies provide an important foundation concerning alterations in gut microbiota of subjects at risk for CD early in life, they analyzed only up to three time points in the first year after birth (17,18,20) or were restricted to only one subject with CD (15). In addition, the studies used 16S rRNA sequencing to analyze intestinal microbiota, which cannot provide information about functional characteristics of the microbiota nor provide taxonomic data at the strain level, both of which are necessary to design effective treatment for CD.…”

The Multiomics Analyses of Fecal Matrix and Its Significance to Coeliac Disease Gut Profiling

“…[ 220 ]. IgA-coated gut bacteria, possibly associated with increased inflammatory response, were more prevalent in the gut of CeD children and its abundance levels shown to increase with age, further separating the microbial composition from healthy children, with major changes occurring at the age of 5 years old [ 221 ]. The phylogenetic investigation of gut microbial communities and the combination of Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis demonstrated the enrichment of bacterial pathogenic pathways in CeD patients involved with bacterial invasion of epithelial cells, otherwise absent in healthy subjects [ 221 ].…”

“…CeD-diagnosed children showed the presence of microbiota-derived taurodeoxycholic acid (TDCA), a proinflammatory conjugated bile acid. TDCA is mainly synthesized by Clostridium XIVa and Clostridium XI; the latter increased in the gut microbiota of CeD patients [ 221 ].…”

Intestinal microbiota and dysbiosis in celiac disease

“…Другие метаболиты, связанные с дисбиозом кишечника, уровень которых был значительно увеличен у детей с целиакией, включали провоспалительную конъюгированную желчную кислотутауродезоксихолевую кислоту, глюконо-D-лактон и изобутирил-L-карнитин [30]. Кроме того, недавно получены данные о нарушении бактериального метаболизма триптофана у больных целиакией, влекущего уменьшение продукции индольных производных триптофана -лигандов AhR (Aryl hydrocarbon receptor -рецептор ароматических углеводородов), защищающих от аутоиммунного воспаления, ассоциированного с потерей толерантности к глютену [31].…”