dysfunctional cross talk between innate and adaptive immunity…..could be influenced by the timing of gluten introduction into the diet…. and composition of the GI microbiota,” notes Sellitto et al 2012.
Alessio Fasano’s group at University of Maryland’s Center for Celiac Research recently published a dietary intervention trial which teased out the impact that timing of initial exposure to dietary gluten during infancy had on later life autoimmunity towards gluten and development of celiac disease (CD) (1). Reported the March 2012 issue of PLoS ONE, Fassano’s group discovered two novel observations: when infants with a genetic susceptibility for CD delay their initial exposure to dietary gluten by at least 12 months of age their immunological tolerance to gluten is enhanced- as noted the delayed onset of CD autoimmunity- and they prevented gluten-induced increases in intestinal permeability observed among infants whom were exposed to gluten earlier, at 6 months of age. Furthermore this study found key differences in the composition of the gut microbiota between infants with a genetic susceptibility for CD VS those with a non-selected genetic background, suggesting that the micriobial composition may exert functional changes within in the GI mucosal immune system.
For more information on the combined influence that early life nutrition and HLA-DQ genotype have on infant gut microflora development, CLICK HERE for our discussion in February.
The composition of the gut microbiota in infants genetically predisposed to CD was observed to lack bacteria belonging to the Bacteroidetes phyla while at the same time display increased levels of microbes belonging to the Firmuciutes phyla.
This genetic influence on microflora composition is an important clinical finding because arguably the most member of the Bacteroidetes phyla is Bacteroides fragilis, which functions to increase immunological tolerance through inducing the differentiation of FoxP3+ Treg cells (See image to the right). Bacteroides fragilis contains an immunomodulatory polysaccharide A (PSA) on it’s outer membrane which is known to enhance the the expression of Treg subsets, restoring immune tolerance (2).
We hypothesize that the intestinal microbial ecosystem as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals,” notes Sellitto et al 2012.
Study Details and Clinical Implications:
Forty seven infants ages four to six months, all with a first-degree relative having been biopsy proven with celiac disease (CD) were enrolled. Thirty four of the 47 infants were positive for HLA DQ2 and/or HLA DQ8 CD susceptibility genes. Infants in the study were randomly selected to two arms: a delayed-exposure arm (Group A) in which ingestion of gluten containing foods was avoided from birth to month 12 VS an early exposure arm (Group B) in which gluten-containing foods were introduced in the infants between months 6 and 12.
While anti-gliadin antibodies (AGA) are no longer used to diagnose CD, AGA IgG positivity indicates increased gut permeability (See image below).
Figure 1. suggests that delaying initial exposure to gluten in genetically susceptible infants (group A) prevents gluten-induced increases in gut permeability later in life. While the opposite is true for infants of similar genotype whom are exposed to gluten between months 6 and 12; after 24 months of life more than 50% of these so called “early exposure” infants displayed increased AGA IgG antibodies, suggesting a prolonged increase in intestinal permeability.
1) Sellitto M, Bai G, Serena G, Fricke WF, Sturgeon C, et al. (2012) Proof of Concept of Microbiome-Metabolome Analysis and Delayed Gluten Exposure on Celiac Disease Autoimmunity in Genetically At-Risk Infants. PLoS ONE 7(3): e33387. doi:10.1371/journal.pone.0033387
2) Mazmanian, S. K., & Kasper, D. L. (2006). The love-hate relationship between bacterial polysaccharides and the host immune system. Nature Reviews Immunology, 6(11), 849–858. Nature Publishing Group. doi:doi:10.1038/nri1956