A Microbiome Is Born

MANOUSH ZOMORODI: This is Science Friday. I’m Manoush Zomorodi, host of WNYC’s Note to Self podcast. Sitting in for Ira Flatow. A baby in the womb is protected from most microorganisms. But when that baby enters the outside world, it’s quickly greeted by a welcoming committee of bacteria. And those bacteria are there to stay. They take up residence on the baby’s skin, and in the gut, and help form the infants microbiome.

Now researchers are trying to sort out what affect factors, like an infant’s delivery method, and early diet, have on its community of microorganisms. Joining me now are two authors of a paper published, this week, in the journal JAMA Pediatrics on that topic. Juliette Madan is a pediatrician and neonatologists at the Dartmouth Hitchcock Medical Center. And Anne Hoen is an assistant professor of epidemiology and of biomedical data science, at the Geisel School of Medicine of Dartmouth College, as well. And they both join me from Vermont Public Radio Studios. Welcome.

ANNE HOEN: Thank you.

JULIETTE MADAN: Hi, great to be here.

MANOUSH ZOMORODI: So Anne, why do this? Didn’t we already know that the microbiome of babies can be different depending on whether they are delivered via c-section, versus a vaginal delivery?

ANNE HOEN: Umm– yeah, that’s something that has been studied before. In fact, there’s a study out there that showed that– these effects can persist months or even years into childhood. So we weren’t surprised when we found that in our study. But what we did want to do is compare the effect of delivery mode, with that of feeding. And when I say feeding in young babies, we’re talking about either breast milk or formula feeding. And find out which one is more important, and sort of what their relative effects are. So that’s one of the new things that we did in our study.

MANOUSH ZOMORODI: Okay, so trying to figure out what is a normal– what a normal healthy infant microbiome is. And Juliet who are these babies?

JULIETTE MADAN: These are babies who are part of a large birth cohort study in New Hampshire. And we’re a part of a Children’s Center for Environmental Research and Disease Prevention at Dartmouth. So we’ve been able to study a cohort that’s growing and it will ultimately be a cohort of 1,500 mothers and babies in the state of New Hampshire. So we’re collecting data about pregnancies. Both biologic data, and health information about pregnant women.

And then subsequently, very detailed biologic and health data from their babies, up until approximately five years of age.

MANOUSH ZOMORODI: So, sort of a longer look at this. And so, Anne, what is the difference in the microbial communities of babies born via vaginal delivery versus c-section?

ANNE HOEN: So, we looked at– we looked at the overall microbiome profiles in these two groups of infants. And we found a number of– we found that they were, first of all, significantly different overall. But we also drill down and looked at which specific bacteria were driving those differences. And one of the bacterial groups that we found was more abundant in vaginally born babies, as opposed to c-section born babies, was a bacterium called [? Bacteroides, ?] which has been shown before to be differentially abundant and vaginally born infants. And it’s important for immune training, so it helps T-cells to mature. So we think that that’s likely got important consequences for diseases that are associated with the immune system, like allergies, and risk for common infections. And we found a number of other bacteria. Some of them we know more about than others, overall their communities where we’re very different.

MANOUSH ZOMORODI: I mean I have to say, I’m surprised that the c-section babies had bacteria at all. Because aren’t they being born in a sterilized operating room? Or that’s the idea anyway?

JULIETTE MADAN: So we’re just starting to understand that fetuses are probably not sterile. We worked– when I was trained as a neonatologist not much more than a decade ago. And in my training we were told– and we went on to teach our trainees, that babies are sterile. And as we think about it today, as we start to understand more about microbes and how they interact with humans, it is a little hard to believe that anything in non-humans are sterile. So it’s something that is not actually unexpected now that we think more closely about it. But babies are essentially sterile.

They do interact with quite a large bolus of bacteria at the time of delivery. And babies who were delivered by cesarean section, their first introduction to these large bolus is a microbes are through the skin of their Mom and the skin of the people in their– the operating room. And ultimately all that the nurses, and doctors, and their family that handles them.

MANOUSH ZOMORODI: And then vaginal delivery babies are also taking in through the mouth presumably? Or just through their– are there other ways as well?

JULIETTE MADAN: Correct. So through the mouth, and their nose, all their mucous membranes, and their skin, they’re exposed to a large bolus of vaginal microbes. That have evolved over time to be particularly health promoting for babies with a very large bolus of lactobacillus in particular. That is very helpful with babies, so that they can digest their breast milk.

MANOUSH ZOMORODI: So you also looked at the difference in the microbiome of babies who were fed differently. Right? So with a formula versus breast fed. What did you find?

ANNE HOEN: So that was another factor that has been shown previously to be important for the development of the infant gut microbiome. What we did here that was a little different was that we looked at overall microbial community composition in three groups of babies. So we looked exclusively breastfed babies, and exclusively formula fed babies. Which haven’t been studied a bit before, but we’re also really interested in babies that are breastfed but supplemented with formula. And we know that that’s something that commonly breastfeeding mothers do is supplement their babies with formula for various reasons.

And so we were really interested in that group. And we knew that– we expected to be a difference between the exclusively breastfed babies and they exclusively formula fed babies in terms of their gut microbiome composition. But what we weren’t sure about was whether the combination fed babies would be somewhere in between. Or if they would look more like the exclusively breastfed babies or the formula fed babies in terms of their gut microbiome composition. And we were a bit surprised to find out that babies fed both breast milk and formula had a gut microbiome that resembled that of the babies that were fed exclusively formula. And that the exclusive breastfeeding was associated with a rather unique gut microbiome composition.

MANOUSH ZOMORODI: I mean as someone– I have two kids. First one was only breast milk, second one, I got to admit, there was a little supplementing with formula. Should the nurses at the hospital have told me to resist the second time around?

JULIETTE MADAN: It’s a really great question. And one that I think plagues moms and pediatricians worldwide. So when we think about that, it’s important to think about it from a public health standpoint. And so the CDC, and the AAP, and ACOG all of these very large health organizations are fully in support of exclusive breastfeeding.

And so, there has been quite a lot of research that’s shown, from epidemiological perspective, about the vast and profound short and long term health benefits of breast milk, and exclusive breast milk. But what our study I think is getting at, in a somewhat different perspective, is we have not really understood in the past, very well, some of the mechanisms behind the health benefits of breast milk exposure. And ours has been able to show, as Annie explained, that there is a difference and microbial structure between babies to receive formal supplementation and those who do not. So, Baby Friendly Hospital Initiative, led by the World Health Organization. The CDC, these are organizations that not only promote exclusive breastfeeding, but they’re collecting data based on birth centers and how they’re meeting goals of supporting moms. And not providing formula unless it’s medically necessary.

MANOUSH ZOMORODI: Yeah, I mean, that support element could definitely use some stepping up just from what I’ve seen in my own experience. I want to ask you further with the breast milk, do we know if it’s the microbes? Or the actual nutrients in the mike that is helpful?

JULIETTE MADAN: It’s both. And so breast milk is very exciting to study, and again it’s somewhat of a black box. But we’re starting to understand, more and more, about the health benefits of breast milk, and the mechanism behind these health benefits. But breast milk is not just nutrition for babies. It’s also a very important transfer of mom’s immune system and her strength to her baby directly.

So when babies are delivered their immune system is very immature, and that’s true for premature babies, but also for full term healthy babies. And they’re unable to fight off pathogens because their immune system is immature. So mom is transferring immune cells, she’s transferring white cells, T-cells, immunoglobulins. But they’re also important bacteria that she’s transferring that are health promoting for her baby. As well as what we call prebiotics, or special bioactive components in breast milk, that feed healthy bacteria that are immune training for the baby’s immune health.

ANNE HOEN: I just wanted to add that the breast has its own microbiome. And so in this cohort, as we collect stool samples from our infants enrolled in the cohort, and analyze them in light of their microbiota. We’re also collecting breast milk samples from the mothers. So we’re profiling the breast milk microbiome as well. And we’re also doing some nutrient profiling in these breast samples. So we should be able to get– in future research we should be able to get– at some of the relative effects of those different factors in breast milk that shape the gut microbiome of infants.

MANOUSH ZOMORODI: And correct me if I’m wrong, but did you previously do work on microbiome verses cystic fibrosis? Or the sort of indicators there?

JULIETTE MADAN: Yeah, so we– my research program includes two high risk baby populations. So babies who are born very prematurely, we’ve studied the intestinal microbiome in that population and how it relates to health. And we also have a large cohort of infants who are born with Cystic Fibrosis. We’ve enrolled nearly every baby in a state of New Hampshire born with Cystic Fibrosis since 2009.

And we’re carefully following, not only their health outcomes and their exposures, but we’re also looking at their respiratory microbiome and their intestinal microbiome. It’s been a very rewarding research program. Trying to understand the relationship with between dietary exposures and babies and young children with Cystic Fibrosis. And how the microbiome shapes their risk for disease.

MANOUSH ZOMORODI: And then in terms of the thoughts of giving c-section babies a dose of the bacteria found in vaginal delivery babies. Are people looking into that? Are they seeing if that could just sort of even the playing field, so to speak?

ANNE HOEN: Yeah there’s a really exciting– some really exciting research going on, right now at NYU that’s looking at the effectiveness of potentially transferring the maternal vaginal microflora to newborn babies after they’re born by c-section. So I think that research is ongoing. But it’s really promising in terms of very simple and low cost intervention that might help to restore the microbiota and the gut of infants born by c-section to potentially a more health promoting one. If that’s the case. And then a lot of other exciting opportunities, in terms of developing therapeutics through the administration of probiotics to kids and infants in early life. That I think are just starting to be investigated. So really excited about that kind of research as well.

MANOUSH ZOMORODI: Manoush Zomorodi, this is Science Friday from PRI, Public Radio International. Anne and Juliet I just want to double check with you. We want to make clear that we don’t know if the difference between these two different [? microbiome, ?] the bacteria, is good or bad difference. We just know there is know there is a difference, right?

JULIETTE MADAN: That’s correct. So we know that that breast milk exclusivity, from epidemiological studies is associated with terrific health benefits. So we know that babies to receive breast milk have lower risk of cancer and autoimmune disease, asthma– the list is quite long. And we’re just starting to understand with research like ours, some of the mechanisms behind why the biology of breast milk exposure is important. But our study today is simply defining what exposure shape the microbiome in infant’s gut, and a healthy population. And our study is hoping to see, over the next five years with this cohort, of the relationship between these microbial patterns and some health outcomes.

MANOUSH ZOMORODI: And so in terms of long term goals, I guess that that is really the answer that you want to come to. Which are the ones that actually contribute to our health, versus just sort of go along for the ride.

JULIETTE MADAN: That’s exactly right. We’re hoping to understand in this healthy population, what are the patterns in the gut microbiome in early life? In this really critical window, when microbes are required to interact with the immune system to develop a healthy immune system for a lifetime of health. If we can characterize the microbes in the gut, in a healthy baby, we’re hoping that we might be able to then, dream up interventions, so that we can tailor a healthy microbiome in high risk populations. Or populations who have had exposures that need to be remedied.

MANOUSH ZOMORODI: And just to clarify, what is the difference between say, the mother, or a healthy adult’s microbiome, verses an infant’s. Do we know the difference?

JULIETTE MADAN: I think we’re starting to understand the difference. What we know about babies, is that they are not necessarily sterile at first like we mentioned before. But that they are receiving quite large boluses of bacteria when they’re introduced to the environment outside of the womb. And that there is quite a lot of variability and there’s a lot of change in their gut microbiome over the first year, to probably, the first three years of life.

And after about three years of life, it looks particularly stable, and mirrors that of an adult’s. So there’s quite a lot of variability because things are becoming acquired over the course of infancy.

MANOUSH ZOMORODI: Just fascinating. I am so looking forward to hearing what you discover as you go forward. Thank you both so much.

JULIETTE MADAN: Thank you.

MANOUSH ZOMORODI: Thank you.

MANOUSH ZOMORODI: Juliette Madan is a pediatrician and neonatologists at the Dartmouth Hitchcock Medical Center. Anne Hoen is an assistant professor of epidemiology, and a biomedical data science at the Geisel School of Medicine of Dartmouth College.

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