The first publication of CDGEMM Study results has been published, open access, in Microbiome. MassGeneral Hospital for Children's Dr. Maureen Leonard shares what the CDGEMM team has learned thus far about celiac disease development by studying infants at risk of celiac disease.
In a study published by our team, and led by our recent PhD graduate Gloria Serena, an interaction was uncovered between components of the immune system and the intestinal microbiome (trillions of microbes that reside in our intestinal tract and help our body to carry out important functions like digestion). The study collected blood and small intestinal tissue samples from individuals with and without celiac disease (CD) to investigate how components of the immune system and the microbiome -- and their interactions -- may contribute to the development of CD. Authors focused on two varieties of a particular protein, called Forkhead-box Protein 3 (FoxP3), which helps to regulate the immune response. Particularly, the FoxP3 proteins are important to help your body not mount an immune response against itself; therefore, proper functioning of this protein helps to prevent the onset autoimmune disease.
The results from the study showed that individuals with and without CD had equal ratios between the two [studied] varieties of the FoxP3 protein circulating in the blood. However, in the intestine, individuals with active, newly-diagnosed celiac disease (still on a gluten-containing diet) had an altered expression of the proteins when compared to individuals without CD and to those with CD on a gluten-free diet. Given this, components of the intestinal microbiome were investigated to understand how they may play a role in the altered protein expression that was found only in the intestine of individuals with active CD.
It was further uncovered that stimulation with both an inflammatory component of the immune system and the metabolite butyrate created a unique environment that differed between patients with and without CD. In non-celiac individuals, the stimulation resulted in a balance between the two types of FoxP3 protein; however, the same balance was not achieved in response to stimulation in individuals with CD. With butyrate stimulation representing an irregular intestinal microbiome, these findings provide evidence of how changes to the microbiome in CD patients can affect the immune system. Additionally, specific attention was given to the molecule lactate, since a study published by our group in 2012 found high levels of lactate in genetically-predisposed children just prior to the development of celiac disease. Indeed, Dr. Serena found that lactate stimulation altered FoxP3 expression in individuals with CD but not in those without the condition.
Overall, the results of this study provide a mechanistic understanding of how interactions between components of the immune system and the microbiome can contribute to CD. This information introduces valuable future therapeutic targets for the treatment or ultimate prevention of CD.
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Maureen Leonard, MD, MMSc, lead study author and clinical director of the Center for Celiac Research and Treatment at MassGeneral Hospital for Children (MGHfC), has been studying infants at risk of celiac disease for the last seven years.
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