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

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus , Parabacteroides sp., Lachnospiraceae , tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus , Faecalibacterium prausnitzii , and Clostridium clostridioforme ). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp. , high mannose-type N -glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.
Competing Interests: Competing interest statement: M.M.L. serves as a consultant to 9 Meters Biopharma and Anokion and performs sponsored research with Glutenostics LLC. H.K. is a former employee of, B.F. is a current employee of, P.S. is a consultant for, and N.A.H. and R.C. are stockholders at CosmosID Inc. A.F. is a stockholder at Alba Therapeutics, serves as a consultant for Inova Diagnostics and Innovate Biopharmaceuticals, is an advisory board member for Axial Biotherapeutics, and has a speaker agreement with Mead Johnson Nutrition. All other authors have declared that no competing interests exist.
(Copyright © 2021 the Author(s). Published by PNAS.)