Abstract
In the past it was believed that genetic predisposition and exposure to gluten were necessary and sufficient to develop celiac disease (CD). Recent studies however suggest that loss of gluten tolerance can occur at any time in life as a consequence of other environmental stimuli. Many environmental factors known to influence the composition of the intestinal microbiota are also suggested to play a role in the development of CD. These include birthing delivery mode, infant feeding, and antibiotic use. To date no large-scale longitudinal studies have defined if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically-susceptible individuals. Here we describe a prospective, multicenter, longitudinal study of infants at risk for CD which will employ a blend of basic and applied studies to yield fundamental insights into the role of the gut microbiome as an additional factor that may play a key role in early steps involved in the onset of autoimmune disease.
Highlights
Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten containing grains in genetically susceptible individuals [1]
CD represents a unique model of autoimmune disease as, in contrast to other autoimmune diseases, the triggering environmental factor, a close genetic association with human leukocyte antigen (HLA) genes (DQ2 or DQ8), and a highly specific humoral autoimmune response are known [1]
Two recent landmark studies which prospectively screened infants, with a first degree family member with CD, from birth found that CD develops quite early in life in this risk group, further supporting the notion that early environmental factors may be very important in the development of CD
Summary
Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten containing grains (i.e., wheat, barley, and rye) in genetically susceptible individuals [1]. A previous study found that compared to control infants with a non-selected genetic background, at-risk subjects had a decreased representation of Bacteriodetes and a higher abundance of Firmicutes [3] Their microbiota showed a delay in maturation at two years of age [3] while the maturation was complete in not at-risk infants at one year [4]. Two recent landmark studies which prospectively screened infants, with a first degree family member with CD, from birth found that CD develops quite early in life in this risk group, further supporting the notion that early environmental factors may be very important in the development of CD These studies found that 16% of infants who have a first degree relative with CD and who carry HLA DQ2 and/or DQ8 will develop CD by age five, most of whom will be diagnosed by age three [5,6]. We propose to investigate the role of the developing intestinal microbiome and the resulting metabolome as additional factors that may play a key role in the onset of and predisposition to CD autoimmunity
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