By Van Waffle

The Celiac Disease Genomic Environmental Microbiome and Metabolomic (CDGEMM) study is revealing how genetic and lifestyle factors make children susceptible to autoimmune diseases such as celiac disease, inflammatory bowel disease, and multiple sclerosis. In 26 infants with a genetic risk for celiac disease, those born by C-section, fed formula, or exposed to antibiotics during their first six months developed a distinct gut microbiome.

The microbiome is the community of microorganisms inhabiting the human digestive tract. A child is born with an immature microbiome. While it is unknown how the infant normally obtains the right bacteria for a healthy gut, some are believed to come from the birth canal. Human breast milk appears to encourage health-promoting bacteria. Antibiotics are known to affect the microbiome adversely. Developing the right bacteria may be equally important as eating the right nutrients. Bacteria play a vital role in digesting food. Experts believe a healthy microbiome also helps the baby’s immune and digestive systems mature. For example, bacteria produce butyrate, a short-chain fatty acid good for gut health. CDGEMM is studying both the kinds of microbes and their role in metabolism.

The research will help doctors understand how the microbiome can veer off course by identifying differences in types of microbes, or what metabolic chemicals they produce. In this study, infants exposed to environmental disturbances developed a microbiome more likely to promote inflammation compared to that of children with a genetic risk who were born naturally, exclusively breastfed, and not exposed to antibiotics.

In theory, maintaining a healthy microbiome in children at risk could prevent celiac disease.

In theory, maintaining a healthy microbiome in children at risk could prevent celiac disease. How to restore the microbiome when environmental factors cause it to become pro-inflammatory remains unknown. 

Previous research has studied the microbiome after patients are diagnosed with celiac disease, and found differences in the bacterial species. However such data provides only a snapshot of the disease condition. Without direct evidence of how it developed, there is no proof of whether microbes caused the disease or changed after gluten damaged the gut.

“The overall goal of the CDGEMM Project is to create a crystal ball that we can see into and predict who is going to develop celiac disease later on in time, so that we can intervene, intercept the disease,” and prevent it, says Alessio Fasano, MD, an author of the study. He is professor of pediatrics and division chief of pediatric gastroenterology and nutrition at MassGeneral Hospital for Children, Harvard Medical School, in Boston.

CDGEMM is the first large study to track infants at risk from the time they are in utero or are born, gathering extensive detail on risk factors in infancy, through the introduction of solid food, and until possible onset of celiac disease and beyond. Data on blood, stool, and milk from both mother and child is collected at regular intervals.The study includes 455 children in the United States and Italy so far, with recruitment continuing.

Stool samples from study participants have been analyzed for both bacterial species and how food was metabolized by the microbiome. While the data from this study published in Microbiome does not show a significant difference in species, it does reveal degrading microbial metabolism in infants exposed to environmental upsets. For example, exposed infants showed higher evidence of fatty acid metabolism and increasing abundance of ribose, a simple sugar. The continuation of CDGEMM is expected to show whether this metabolic shift is enough to cause disease.

Fasano says CDGEMM will address the question, “For those that developed celiac disease, what was the microbiome composition before, during, and after the onset of the disease, and how this compares to matched controls who start exactly from the same point, but eventually did not develop the disease.”

Fasano was unsurprised to see the impact on the microbiome of environmental factors including C-section births, non-exclusive breastfeeding and antibiotics. While mothers should not avoid C-sections or formula feeding where necessary for the mother’s and baby’s health, CDGEMM may soon reveal how to support a healthy infant microbiome in case these measures are necessary. Fasano says the findings encourage him as a doctor to avoid prescribing antibiotics when unnecessary.

Having two copies of the HLA-DQ2 gene altered the metabolism of gut microbes significantly in these infants, making them more vulnerable to gut disease.

“The thing that surprised me most was the genetic component,” he says. Having two copies of the HLA-DQ2 gene altered the metabolism of gut microbes significantly in these infants, making them more vulnerable to gut disease. 

This early paper only leads up to the introduction of solid food and offers no direct evidence about the cause of celiac disease. However, Fasano says CDGEMM has already identified a few children who developed celiac disease and will continue to follow and report on this at-risk cohort for 10 years. It will investigate additional environmental factors, such as early viral infections and geographical data indicating exposure to pollution.

“Right now, we have roughly collected 120,000 data points on these kids and more than 22,000 specimens,” says Fasano.

Elena Verdu, MD, PhD, associate professor of medicine and member of Farncombe Family Digestive Health Research Institute at McMaster University in Hamilton, Canada, says, “Our lab has worked more than a decade on the hypothesis that gut microbes are key determinants of the responses to gluten in an individual at risk,” and to understand, “mechanisms by which specific gut microbes or pathogens can increase or mitigate progression of inflammation in celiac disease.” She says the early CDGEMM data is reassuring in providing more context for her lab’s findings.

She adds, “The main takeaway is that there is more than gluten and genes to the development of celiac disease, and that the study of the gut microbial environment, and specifically the mechanisms by which they incite or prevent disease need to be studied and funded.”