Proof of Concept of Microbiome-Metabolome Analysis and Delayed Gluten Exposure on Celiac Disease Autoimmunity in Genetically At-Risk Infants

Abstract

Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.

Breast milk, microbiota, and intestinal immune homeostasis

“…The ensuing dysbiosis has been associated with an increase in diseases such as asthma (8) and celiac disease (9). In addition, perinatal use of antibiotics, particularly in premature infants, can interfere with the balance of bacterial phyla and diversity of individual species and makes the newborn much more susceptible to infectious inflammatory diseases (10,11).…”

Intestinal microbiota during early life – impact on health and disease

“…The most constant finding is the higher abundance of Bacteroides spp. in faeces and duodenal biopsies of CD patients (152,153,163) , although a complete lack of the members of phylum Bacteroidetes was observed in CD predisposed infants in a prospective study (149) . Furthermore, another study reported a reduction in IgA-coated bacteria, especially IgA-coated Bacteroides in faeces of untreated and treated CD patients when compared to healthy controls (151) .…”

“…A specific role for the intestinal microbiota in CD development has been suggested (149,151,152) . Indeed, deviations in faecal and duodenal microbiota associated with CD have been reported (149,(151)(152)(153) , although recent studies utilising high-throughput methods have reported comparable microbiota compositions in patients and healthy controls (154)(155)(156)(157) .…”

Celiac Disease as a Model for the Evolution of Multifactorial Disease in Humans

“…Recently, study of the human gut microbiome has been applied to CD pathogenesis (Sellito et al 2012;Cheng et al 2013;Sjöberg et al 2013). Almost a decade ago, Forsberg and colleagues (2004) In contrast, a slightly later study by Cheng and colleagues (2013) found no significant differences in the overall composition and diversity of gut microbiota (including Bacteroidetes) between a sample of 10 children with newly diagnosed CD (aged 3-14) and 9 healthy controls (aged 4-16).…”