Microbiome. 2020 Sep 11;8(1):130. doi: 10.1186/s40168-020-00906-w.

Maureen M Leonard ^1 2 3 4, Hiren Karathia ⁵, Meritxell Pujolassos ⁶, Jacopo Troisi ^6 7 8, Francesco Valitutti ^8 9, Poorani Subramanian ⁵, Stephanie Camhi ^2 4, Victoria Kenyon ^2 4, Angelo Colucci ^6 7, Gloria Serena ^1 2 3 4, Salvatore Cucchiara ¹⁰, Monica Montuori ¹⁰, Basilio Malamisura ¹¹, Ruggiero Francavilla ¹², Luca Elli ¹³, Brian Fanelli ⁵, Rita Colwell ^5 14, Nur Hasan ⁵, Ali R Zomorrodi ^{15 16 17 18}, Alessio Fasano ^{19 20 21 22 23}, CD-GEMM Team

Collaborators,

• CD-GEMM Team: 

Pasqua Piemontese, Angela Calvi, Mariella Baldassarre, Lorenzo Norsa, Chiara Maria Trovato, Celeste Lidia Raguseo, Tiziana Passaro, Paola Roggero, Marco Crocco, Annalisa Morelli, Michela Perrone, Marcello Chieppa, Giovanni Scala, Maria Elena Lionetti, Carlo Catassi, Adelaide Serretiello, Corrado Vecchi, Gemma Castillejo de Villsante

Author information

• ¹Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA.
• ²Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Boston, USA.
• ³Harvard Medical School, Boston, MA, USA.
• ⁴Celiac Research Program, Harvard Medical School, Boston, MA, USA.
• ⁵CosmosID Inc., Rockville, MD, USA.
• ⁶Theoreo srl, University of Salerno, Montecorvino Pugliano, Italy.
• ⁷Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Salerno, Italy.
• ⁸European Biomedical Research Institute of Salerno (EBRIS), Via S. De Renzi, 50, 84125, Salerno, Italy.
• ⁹Pediatric Unit, Maternal and Child Health Department, AOU San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy.
• ¹⁰Pediatric Gastroenterology, Sapienza University of Rome, Rome, Italy.
• ¹¹Pediatric Unit, Maternal and Child Health Department, AOU San Giovanni di Dio e Ruggi d'Aragona, Pole of Cava de' Tirreni, Salerno, Italy.
• ¹²Pediatric Gastroenterology, University of Bari, Bari, Italy.
• ¹³Center for Prevention and Diagnosis of Celiac Disease Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
• ¹⁴Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA.
• ¹⁵Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA. azomorrodi@mgh.harvard.edu.
• ¹⁶Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Boston, USA. azomorrodi@mgh.harvard.edu.
• ¹⁷Harvard Medical School, Boston, MA, USA. azomorrodi@mgh.harvard.edu.
• ¹⁸Celiac Research Program, Harvard Medical School, Boston, MA, USA. azomorrodi@mgh.harvard.edu.
• ¹⁹Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA. afasano@mgh.harvard.edu.
• ²⁰Mucosal Immunology and Biology Research Center, MassGeneral Hospital for Children, Boston, USA. afasano@mgh.harvard.edu.
• ²¹Harvard Medical School, Boston, MA, USA. afasano@mgh.harvard.edu.
• ²²Celiac Research Program, Harvard Medical School, Boston, MA, USA. afasano@mgh.harvard.edu.
• ²³European Biomedical Research Institute of Salerno (EBRIS), Via S. De Renzi, 50, 84125, Salerno, Italy. afasano@mgh.harvard.edu.

Abstract

Background: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD.

Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects.

Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.

Trial registration: ClinicalTrials.gov NCT02061306.