Multi-omics analysis reveals the influence of genetic and environmental risk factors on developing gut microbiota in infants at risk of celiac disease
Authors: Leonard Maureen M. , Karathia Hiren , Pujolassos Meritxell , Troisi Jacopo , Valitutti Francesco , Subramanian Poorani , Camhi Stephanie , Kenyon Victoria , Colucci Angelo , Serena Gloria , Cucchiara Salvatore , Montuori Monica , Malamisura Basilio , Francavilla Ruggiero , Elli Luca , Fanelli Brian , Colwell Rita , Hasan Nur , Zomorrodi Ali R. , Fasano Alessio ,   the CD-GEMM Team, Piemontese Pasqua , Calvi Angela , Baldassarre Mariella , Norsa Lorenzo , Trovato Chiara Maria , Raguseo Celeste Lidia , Passaro Tiziana , Roggero Paola , Crocco Marco , Morelli Annalisa , Perrone Michela , Chieppa Marcello , Scala Giovanni , Lionetti Maria Elena , Catassi Carlo , Serretiello Adelaide , Vecchi Corrado , de Villsante Gemma Castillejo 
Published: September 2020

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.