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

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, 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, three months and six 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.

Role of the Gut Microbiota and Its Metabolites in Tumorigenesis or Development of Colorectal Cancer

“…It protects the gut epithelium through preventing invasive E. coli, thereby relieving acute diarrhea in infants, and small-intestinal methotrexate-induced mucositis in rat models. [69] Gavage of S. thermophilus inhibited tumor formation in both Apc min/+ and azoxymethane-injected mice. Moreover, production of 𝛽-galactosidase by S. thermophilus enhances the abundance of probiotics, such as Bifidobacterium and Lactobacillus.…”

Important denominator between autoimmune comorbidities: a review of class II HLA, autoimmune disease, and the gut

“…Future research could benefit from analyzing risk haplotypes against each other to verify their similarities and differences in influence over the microbiome. Compared to low-risk or neutral haplotypes, high-risk HLA DR3-DQ2 and DR4-DQ8 are associated with higher abundance of Prevotella copri at the species level, Agathobacter, Bacteroides, Blautia, Dorea, Enterococcus, Intestinimonas, Klebsiella, Veillonella at the genus level, and Enterobacteriaceae, which includes Klebsiella, Lachnospiraceae, which includes Agathobacter, Blautia, and Dorea, and Ruminococcaceae, which includes Intestinimonas, at the family level (36,(129)(130)(131)(132). Bifidobacterium and Lactobacillus stand out as either negatively associated or in lower abundance in DR3-DQ2 and DR4-DQ8 compared to protective or neutral alleles (36,39,133,134).…”

Cohort profile: Celiac disease genomic, environmental, microbiome and metabolome study; a prospective longitudinal birth cohort study of children at-risk for celiac disease

“…We previously published work examining the influence of the HLA genetics and environmental factors including birth delivery mode, infant feeding type, and antibiotic exposure on the gut microbiota composition, function, and metabolome prior to the introduction of gluten [10]. We performed multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at three consecutive timepoints (birth, 3 months, and 6 months of age) from 31 children selected from the CDGEMM cohort [10].…”

“…Factors such early life infections [6], infant feeding practices [7], antibiotic exposure [8], and viral pathogens [9] have all been implicated in contributing to CD onset. These factors have also been shown to influence the microbiome [10,11]. However, to explore these factors, detailed data and sample collection must begin before disease onset [12].…”