PMID- 36639805 OWN - NLM STAT- MEDLINE DCOM- 20230118 LR - 20230325 IS - 2049-2618 (Electronic) IS - 2049-2618 (Linking) VI - 11 IP - 1 DP - 2023 Jan 13 TI - Dynamics of the gut microbiome, IgA response, and plasma metabolome in the development of pediatric celiac disease. PG - 9 LID - 10.1186/s40168-022-01429-2 [doi] LID - 9 AB - BACKGROUND: Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. Almost all CD patients possess human leukocyte antigen (HLA) DQ2/DQ8 haplotypes; however, only a small subset of individuals carrying these alleles develop CD, indicating the role of environmental factors in CD pathogenesis. The main objective of this study was to determine the contributory role of gut microbiota and microbial metabolites in CD onset. To this end, we obtained fecal samples from a prospective cohort study (ABIS) at ages 2.5 and 5 years. Samples were collected from children who developed CD after the final sample collection (CD progressors) and healthy children matched by age, HLA genotype, breastfeeding duration, and gluten-exposure time (n=15-16). We first used 16S sequencing and immunoglobulin-A sequencing (IgA-seq) using fecal samples obtained from the same children (i) 16 controls and 15 CD progressors at age 2.5 and (ii) 13 controls and 9 CD progressors at age 5. We completed the cytokine profiling, and plasma metabolomics using plasma samples obtained at age 5 (n=7-9). We also determined the effects of one microbiota-derived metabolite, taurodeoxycholic acid (TDCA), on the small intestines and immune cell composition in vivo. RESULTS: CD progressors have a distinct gut microbiota composition, an increased IgA response, and unique IgA targets compared to healthy subjects. Notably, 26 plasma metabolites, five cytokines, and one chemokine were significantly altered in CD progressors at age 5. Among 26 metabolites, we identified a 2-fold increase in TDCA. TDCA treatment alone caused villous atrophy, increased CD4+ T cells, Natural Killer cells, and two important immunoregulatory proteins, Qa-1 and NKG2D expression on T cells while decreasing T-regulatory cells in intraepithelial lymphocytes (IELs) in C57BL/6J mice. CONCLUSIONS: Pediatric CD progressors have a distinct gut microbiota composition, plasma metabolome, and cytokine profile before diagnosis. Furthermore, CD progressors have more IgA-coated bacteria and unique targets of IgA in their gut microbiota. TDCA feeding alone stimulates an inflammatory immune response in the small intestines of C57BJ/6 mice and causes villous atrophy, the hallmark of CD. Thus, a microbiota-derived metabolite, TDCA, enriched in CD progressors' plasma, has the potential to drive inflammation in the small intestines and enhance CD pathogenesis. Video Abstract. CI - (c) 2023. The Author(s). FAU - Girdhar, Khyati AU - Girdhar K AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Dogru, Yusuf Dogus AU - Dogru YD AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Huang, Qian AU - Huang Q AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Yang, Yi AU - Yang Y AD - Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA. FAU - Tolstikov, Vladimir AU - Tolstikov V AD - BERG, LLC, Framingham, MA, USA. FAU - Raisingani, Amol AU - Raisingani A AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Chrudinova, Martina AU - Chrudinova M AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Oh, Jaewon AU - Oh J AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Kelley, Kristina AU - Kelley K AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. FAU - Ludvigsson, Jonas F AU - Ludvigsson JF AD - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. AD - Department of Paediatrics, Orebro University Hospital, Orebro, Sweden. FAU - Kiebish, Michael A AU - Kiebish MA AD - BERG, LLC, Framingham, MA, USA. FAU - Palm, Noah W AU - Palm NW AD - Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06510, USA. FAU - Ludvigsson, Johnny AU - Ludvigsson J AD - Crown Princess Victoria Children's Hospital, Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linkoping University, 58185, Linkoping, SE, Sweden. FAU - Altindis, Emrah AU - Altindis E AD - Boston College Biology Department, Chestnut Hill, MA, 02467, USA. altindis@bc.edu. LA - eng GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Video-Audio Media DEP - 20230113 PL - England TA - Microbiome JT - Microbiome JID - 101615147 RN - 0 (Cytokines) RN - 8002-80-0 (Glutens) RN - 0 (Immunoglobulin A) SB - IM MH - Animals MH - Child, Preschool MH - Humans MH - Mice MH - Atrophy MH - *Celiac Disease/genetics MH - Cytokines MH - *Gastrointestinal Microbiome MH - Glutens MH - *Immunoglobulin A MH - Metabolome MH - Mice, Inbred C57BL MH - Prospective Studies PMC - PMC9840338 OTO - NOTNLM OT - Celiac disease OT - Cytokines OT - Gut microbiota OT - IgA sequencing OT - Metabolites OT - NKG2D OT - Qa-1 OT - Taurodeoxycholic acid COIS- J.F.L coordinates a study on behalf of the Swedish IBD quality register (SWIBREG), and this study has received funding from Janssen Corporation. M.A.K and V.T are current employees of BERG, LLC, and have stock options. The other authors declare that they have no competing interests. EDAT- 2023/01/14 06:00 MHDA- 2023/01/18 06:00 PMCR- 2023/01/13 CRDT- 2023/01/13 23:41 PHST- 2022/08/09 00:00 [received] PHST- 2022/11/16 00:00 [accepted] PHST- 2023/01/13 23:41 [entrez] PHST- 2023/01/14 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2023/01/13 00:00 [pmc-release] AID - 10.1186/s40168-022-01429-2 [pii] AID - 1429 [pii] AID - 10.1186/s40168-022-01429-2 [doi] PST - epublish SO - Microbiome. 2023 Jan 13;11(1):9. doi: 10.1186/s40168-022-01429-2.