Abstract

Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease

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.

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