Gut Microbiota in Infants: First Results from the CDGEMM Study

Note: This video transcript has been edited for length and clarity.

 

KG: Hello. My name is Katharine Grant and I'm a communications coordinator at Mass General for Children. I'm lucky enough to be here with Dr. Maureen Leonard, clinical director of the Center for Celiac Research and Treatment at MGfC. Dr. Leonard is actively involved in the collaborative CDGEMM Study, which collects and analyzes data on infants who have first-degree relatives diagnosed with celiac disease. She's also the lead author of the first publication of the CDGEMM Study results, which has been published in the journal Microbiome. So Dr. Leonard, first of all, congratulations to you and your team. In this study, you explore the influence of genetic and environmental risk factors on the developing gut microbiome in these children who are at risk of celiac disease. Before we dive into the results of your study, can you give us a bit more background on the goal and the scope of the CDGEMM Study?

ML: Sure. So CDGEMM stands for Celiac Disease Genomic Environmental Microbiome and Metabolomic study. This study really aims to enroll at least 500 infants at risk of celiac disease from the United States, Italy and Spain. We want to follow them from birth through ten years of age to study what triggers celiac disease.

These infants are at higher risk of having celiac disease because, in order to enroll, they need to have a first-degree family member (so a parent or a sibling) with celiac disease. Instead of having a one percent chance of developing celiac disease, they have an increased risk that is 10 or 20 times greater than the general population. By following these infants at risk of celiac disease, the larger goal of this work is really to understand what happens before celiac disease develops, and to then use that information to learn how to prevent celiac disease.

KG: Right. So out of this larger CDGEMM cohort, you and your team isolated infants to be included in this recent study. How did you go about making that decision?

ML: We selected 31 infants who either did or did not have exposures to certain environmental factors of interest for the study. This work has really taken a long time to come to fruition, so these were 31 infants from very early in the study that had the three sample time points that we were looking to study. And those were seven days after birth, three months after birth and six months after birth. And again, who also were either exposed or not exposed to these environmental factors.

KG: I know that there are a lot of different environmental risk factors that have been considered in association with the development of celiac disease. Which specific environmental risk factors for celiac were assessed in this particular study?

ML: In this study, we looked at birth delivery mode (C-section or vaginal delivery), infant feeding type (breast milk or bottle/formula), antibiotic exposure at birth and underlying genetic type.

KG: Right. And from reading your publication I saw that none of these infants have ever been exposed to solid foods, which includes gluten. So why is this important to this study?

ML: Well, we know the trigger of celiac disease is gluten, but in this case we wanted to examine whether there may be changes in the developing gut microbiome due to other environmental factors that happen even before the trigger of celiac disease is introduced. So we wanted to begin to examine whether exposures as early as birth might predispose individuals who have the compatible genetics and a higher risk, because of a family history, to go on to develop celiac disease. Ultimately, to answer this question we need to follow the infants to see who develops celiac disease. But by doing this early on we could at least start to address that question.

KG: Okay, right. So how does this study explore these risk factors that you mentioned by looking at the gut microbiome in these growing infants?

ML: We studied three different time points between birth and six months of age and we compared the gut microbiome of infants exposed to certain environmental factors previously shown to alter the microbiome (C-section delivery, formula feeding and exposure to antibiotics) to infants not exposed to those risk factors.

KG: Thank you. So kind of shifting back now to the overarching study goal, why is it that you and other celiac researchers are interested in learning about the role of environmental risk factors in celiac disease development?

ML: So we know that in order to develop celiac disease, you need to have compatible genetics. And then you need to have exposure to the trigger, which is gluten. But thirty percent of the population has the compatible genetics, and yet only two to three percent of these individuals will develop celiac disease during their lifetime. This means there are other factors that have to be playing a role in “turning celiac disease on”. We think those are environmental factors because the incidence of celiac disease has really increased tremendously over the past 50 years. And that's in line with other autoimmune conditions. We think that's happening so quickly that it really must be explained by environmental factors.

KG: Definitely, right. So I know it's early, but have you been able to draw any conclusions based on your findings regarding these associations between the environmental risk factors and the microbiome changes? Or is it too early to really draw any conclusions yet?

ML: Yeah, so our analysis revealed several microbial species, functional pathways and metabolites that were associated with each genetic or environmental risk factor alone, or even differentially abundant between when we combine them all together in what we called environmentally exposed infants compared to the non-exposed infants. We found several things. For one, we found that infants born via cesarean section delivery had microbes, pathways and metabolites that were implicated in immune system dysfunction and inflammatory conditions. We also found that there were microbes and metabolites that were differentially abundant in infants not exposed to these environmental factors, that have been linked in other studies to beneficial immunomodulatory and anti-inflammatory effects.

KG: Okay so I mean just listening to your answer, it sounds like this study compares a lot of different variables kind of simultaneously. Can you explain what multi-omics analysis is and why you chose this multi-omics approach for the study?

ML: Sure. So most microbiome studies to date have looked at the diversity of the microbiome or how many different microbes are present and the composition of the microbiome. Essentially, what microbes are there. And these studies describe differences in who's there in the microbiome. But we don't know which one of these microbes are actually functionally active at the time and that's what we're trying to determine. Not just who's there, but who's contributing to changes in in the underlying immune system. Who's contributing to changes in the pathogenesis of celiac disease. So what we looked at is not just what microbes are there, but also the function of what the microbiome is doing and what chemicals or metabolites it's producing. Our goal is really to link the metabolites and the biological functions to specific microbes to understand how environmental factors alter the microbiome and contribute to disease.

KG: That's quite an undertaking! So you mentioned in this paper that your study attempts to fill a research gap. In what ways do you consider your study to be exploring new territory?

ML: As I mentioned, in addition to looking at who's there in the microbiome, we're also looking at the function of the microbiome and the metabolites that are being produced. So that's one way we're sort of taking another different approach to looking at the microbiome. But in addition, most studies to date have really looked at patients with a particular disease state compared to healthy patients. And they've looked at differences in the microbiome in patients with this disease versus patients that don't have the disease. Our prospective cohort allows us to follow infants from birth so we can learn about what changes occur in the microbiome before, during and after disease. And because we have been following individuals throughout this time course, we can really understand at the individual level what changes [occur] before celiac disease develops and after to try and understand how these environmental factors are altering the microbiome and contributing to disease.

KG: What are some limitations that you see to this study, if any?

ML: I think the major limitation for the work is that we follow the infants just until six months of age, so we can't comment on whether these alterations that we see contribute to disease onset. We can just say that we see changes that are related to these particular environmental factors or this underlying genetic type. Ultimately, we need our work to go further. We need to follow the infants through the onset of disease to see whether these alterations actually play a role in the pathogenesis of disease. Our cohort is designed so that we can work towards that.

KG: Your answer kind of leads us into this next and final question which is, how do the findings of the study inform your next steps and research goals?

ML: Our goal is really to identify changes in the microbiome and metabolome that occur before celiac disease onset in order to predict celiac disease, and then use this information to learn how to prevent celiac disease. This study lays the groundwork because we ultimately want to connect the alterations that we find in the microbiome with environmental exposures. To do this, we need to start examining the microbiome soon after birth in these individuals that have an increased genetic risk to develop celiac disease.

KG: This is very exciting research, but we have many more things to learn. Dr. Leonard, thank you so much for your time. The CDGEMM study publication is available here: https://doi.org/10.1186/s40168-020-00906-w