Researchers at the Center for Celiac
Research and Treatment at Mass General for Children (MGfC) are investigating whether imbalances in the gut microbiome play a critical role in the loss of tolerance in celiac disease, an autoimmune disorder in which gluten triggers a reaction that damages the small intestine in genetically vulnerable people. The microbiome exerts an epigenetic influence on how risk genes are expressed and on immune system dynamics, and its composition and metabolites differ among individuals, based on their genes, diet, and history of infection and antibiotic treatment, explains Alessio Fasano, MD, director of the Center and chief of the Department of Pediatric Gastroenterology and Nutrition at MGfC. Dr. Fasano is leading the large, international Celiac Disease Genomic Environmental Microbiome and Metabolomic study (CDGEMM ) to further investigate this hypothesis.
Autoimmune diseases are thought to result from three components: a genetic predisposition, an environmental trigger and an auto-antibody that attacks the body’s own tissues. Celiac disease is considered a model for the study of autoimmunity because all three components are known: HLA-DQ2 and -DQ8 genes; gluten as a trigger; and immunoglobulin A antibody. While a necessary environmental trigger, gluten is not sufficient to initiate autoimmunity, explains Dr. Fasano. Identifying the additional environmental factors contributing to the loss of gluten tolerance could lead to predictive markers for autoimmunity and new approaches for preventing the onset of celiac disease.
Dr. Fasano has previously demonstrated that celiac disease can have adult onset, suggesting that genetically susceptible people may tolerate gluten until additional events cause them to develop autoimmunity.1 He investigated some of the possible contributing factors in a 10-year intervention study with 700 children. The study found that introducing gluten to babies at 12 months instead of six months delayed, but did not prevent, the onset of celiac disease. Breastfeeding also did not prove protective, but vaginal birth did when compared to caesarean birth,2 possibly, Dr. Fasano hypothesized, because of the influence of the microbiome.
For the current CDGEMM study, researchers will analyze the genetic makeup of the infants and environmental variables that contribute to the development of celiac disease: timing of gluten introduction, method of delivery (caesarean or vaginal birth) and other factors. They will also analyze the gut microbiome, its metabolites and their dynamic interplay with diet and other changes in the child’s health and environment.
The researchers hope to define biomarkers that predict the development of celiac disease before it happens, and to identify metabolite pathways with implications for treatment and prevention of celiac disease and, by extension, other forms of autoimmunity.