TY - JOUR
T1 - Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study
AU - Leonard, Maureen M.
AU - Valitutti, Francesco
AU - Karathia, Hiren
AU - Pujolassos, Meritxell
AU - Kenyon, Victoria
AU - Fanelli, Brian
AU - Troisi, Jacopo
AU - Subramanian, Poorani
AU - Camhi, Stephanie
AU - Colucci, Angelo
AU - Serena, Gloria
AU - Cucchiara, Salvatore
AU - Trovato, Chiara Maria
AU - Malamisura, Basilio
AU - Francavilla, Ruggiero
AU - Elli, Luca
AU - Hasan, Nur A.
AU - Zomorrodi, Ali R.
AU - Colwell, Rita
AU - Fasano, Alessio
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the families that participate in this study and whose contribution was instrumental to the findings described in this manuscript and the CDGEMM team, including Monica Montuori, Pasqua Piemontese, Angela Calvi, Mariella Baldassarre, Lorenzo Norsa, Celeste Lidia Raguseo, Tiziana Passaro, Paola Roggero, Marco Crocco, Annalisa Morelli, Michela Perrone, Naire Sansotta, Marcello Chieppa, Giovanni Scala, Maria Elena Lionetti, Carlo Catassi, Adelaide Serretiello, Corrado Vecchi, and Gemma Castillejo de Villsante. This work was partially supported by funding from NIH, National Institute of Diabetes and Digestive and Kidney Diseases Grants DK109620 (to M.M.L.), K23DK122127 (to M.M.L.), and DK104344 (to A.F.); funding from Nutrition Obesity Research Center at Harvard Grant P30-DK040561 (to M.M.L.); the Thrasher Research Fund (M.M.L.); the faculty start-up funding by the Mucosal Immunology and Biology Research Center at Massachusetts General Hospital (A.R.Z.); and the support of Joyce and Hugh McCormick and Hilary and Langley Steinert. Partial funding for R.C. is from NSF Grant CCF1918749.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/7/20
Y1 - 2021/7/20
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Celiac disease
KW - Gut microbiome
KW - Multiomics analysis
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U2 - 10.1073/pnas.2020322118
DO - 10.1073/pnas.2020322118
M3 - Article
AN - SCOPUS:85109962490
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 29
M1 - e2020322118
ER -