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. One of her goals is to better understand the factors that may contribute to celiac disease development.

Living with celiac disease herself, Leonard understands the impact that a celiac disease diagnosis can have on physical and mental health, as well as lifestyle.

Since the spring of 2014, Leonard and her research collaborators have generated extensive data through the Celiac Disease Genomic, Environmental, Microbiome and Metabolomic Study (CDGEMM), a longitudinal, prospective study with nearly 500 infants and children currently enrolled in Italy, Spain and the United States.

Over 15,000 stool samples, 5,000 blood samples and 100,000 data points have been collected by the CDGEMM team as of November 2020. This research has culminated in the publication of the first study results in Microbiome.

First Study Findings

Researchers know that genetic predisposition and exposure to gluten are necessary for celiac development, but there is mounting evidence suggesting that environmental triggers may play a key role in celiac disease pathogenesis.

Results from a recent study of 31 infants at risk of celiac disease pinpoint early links between certain genetic and environmental factors and alterations in the developing gut microbiome, the community of microorganisms in the gastrointestinal tract. This study investigates the impact of three early-life environmental triggers on the microbiome during the first six months of life: birth delivery mode, antibiotic exposure and infant feeding type.

Each genetic risk profile and environmental trigger, when considered alone, was associated with changes in the bacterial species, functional pathways and metabolites in the gut microbiome.

When grouped together, the infants exposed to at least one of the three environmental triggers had alterations in the microbiome that were associated with immune dysfunction and inflammatory conditions. Alternately, the infants not exposed to any of the environmental triggers had alterations in the microbiome associated with beneficial immune-modulatory and anti-inflammatory effects.

Identifying these biological changes that occur prior to the onset of celiac disease is a vital first step toward a better understanding of celiac disease development.

The MGHfC CDGEMM Study

The recent study was the first in a series of planned studies drawing from the large-scale CDGEMM cohort of infants at risk of celiac disease. Because celiac disease has a genetic component, infants with first-degree relatives with the condition are considered at risk. The cohort aims to enroll 500 at-risk infants and follow them from birth through 10 years to study celiac disease development. As of October 2020, 231 infants from the United States and 252 from Italy have been enrolled.

The study’s clinical coordinator, Victoria Kenyon, emphasizes that “this study would not be possible without the dedication and participation of our 483 children and their families. They remain committed and eager to help, even when so much is required of them.” Giving back to the families, members of the CDGEMM study team are always accessible and busy planning fun activities and incentives for the children. The children, affectionately called “GEMMS,” even have their very own lab coats! Due to the efforts of all parties, study retention rates remain high.

An Overview of Celiac Disease

Celiac disease is an autoimmune disease that affects approximately one percent of the population worldwide. When individuals with celiac disease ingest gluten, a protein found in wheat, barley and rye, an inappropriate immune response causes damage to the small intestine. People of all ages can develop celiac disease, which can manifest through a variety of systemic symptoms. The only treatment at this time is a strict gluten-free diet, which typically resolves symptoms and allows the intestine to heal.

Study Methods and Analysis

The 31 infants enrolled in the first CDGEMM study were included based on qualifying criteria. First, they needed to match the study’s factors of interest: underlying genetics and exposure/non-exposure to certain environmental triggers. The environmental triggers studied are birth delivery mode (vaginal or cesarean section delivery), antibiotic exposure at or during birth, and infant feeding type (formula-fed, breastmilk or combination).

Second, the infants needed to have stool samples available from three time points: birth, three months and six months of age. None of the 31 infants chosen were exposed to gluten during data collection.

The study further categorized the infants into “environmentally exposed” and “non-exposed” groups, in which infants exposed to at least one trigger counted as exposed. The infants were also categorized based on their level of genetic risk for celiac disease.

Out of the 31 infants, 26 were genetically predisposed and 5 were not. The genetically predisposed infants were those carrying at least one of the two versions (alleles) of the Human Leukocyte Antigen (HLA) gene that predispose people to celiac disease: HLA-DQ2 and HLA-DQ8. All people with celiac disease carry at least one of these alleles, passed down from one or both of their parents. Infants with one copy of HLA-DQ2 or HLA-DQ8, or infants with one copy of each (heterozygous), were deemed “standard risk” in this study. Those with two copies of HLA-DQ2 (homozygous) were deemed “high risk.” Therefore, the genetic groupings were non-predisposed, standard and high risk.

The researchers looked for patterns and relationships between many factors at once in this study. They collected cross-sectional data, taken from one “slice” of time, as well as longitudinal data, collected at specific time points as the infants grow. This gives them data from snapshots of time as well as dynamic data. 

Using 87 stool samples, researchers explored how the genetic and environmental risk factors altered the composition, function and metabolite production of the gut microbiome in these infants.

Exploring New Territory

The groundbreaking study design allows for the investigation of both the taxonomic composition of the microbiome (which species are present in the gut) and the functional characterization of these microbiota (what these species are
doing). The study subjects are also unique due to their lack of exposure to gluten. In addition, the nature of the CDGEMM cohort allows the researchers to study biological changes that occur prior to the emergence of disease symptoms.

Based on these early results, researchers cannot yet link the microbiome alterations seen in this study directly to celiac disease onset, but “the results lay a solid and promising foundation for future studies,” said Leonard.

She is hopeful that with additional longitudinal studies that follow these infants from birth through disease onset, it will become clear if, and how, the alterations noted in this study directly contribute to celiac disease onset.

For more information and updates on the CDGEMM study, please visit: https://www.massgeneral.org/children/celiac-disease/genomic-environmental-microbiome-and-metabolomic-study/.

Gut Microbiota in Infants: First Results from the CDGEMM Study https://www.youtube.com/watch?v=Cy2g67BcbwA