evolution of the intestinal microbiome

The following is a transcript from a web-based CME-/CPEU-certified activity.This activity is provided by Haymarket Medical Education.

This activity is supported by an educational grant from Nestlé Nutrition Institute.

Evolution of the Intestinal Microbiome:

Helping Parents Lay the Foundation for Childhood Health

PROGRAM FACULTY

Michael D. Cabana, MD, MPH – Chair Professor of Pediatrics, Epidemiology & Biostatistics Chief, Division of General Pediatrics University of California, San Francisco San Francisco, CA

Ardythe L. Morrow, PhD Director, Human Milk Research Laboratory Professor, Departments of Environmental Health, Pediatrics, and Nutrition University of Cincinnati Cincinnati, OH

Philip M. Sherman, MD, FRCPC Hospital for Sick Children Staff Gastroenterologist Gastroenterology, Hepatology, and Nutrition Professor of Paediatrics, Microbiology, Nutritional Sciences, and Dentistry University of Toronto Toronto, Ontario, Canada

2

Evolution of the Intestinal Microbiome: Helping Parents Lay the Foundation for Child Health

DR. MICHAEL CABANA: Welcome to this discussion on the evolution of the intestinal microbiome.

My name is Michael Cabana. I’m a Professor and Chief of the Division of General Pediatrics at the University of California in San Francisco. I’m joined by 2 colleagues who are going to help us review the role of pre- and probiotics in laying the foundation for childhood health.

Dr. Ardythe Morrow is Director of the Human Milk Research Laboratory and Professor in the Departments of Environmental Health, Pediatrics, and Nutrition at the University of Cincinnati.

And Phil Sherman is a gastroenterologist at Toronto’s Hospital for Sick Children, as well as Professor of Pediatrics, Microbiology, Nutritional Sciences, and Dentistry at the University of Toronto.

One of the first things to probably establish is some of the terminology. We’ll be talking about the microbiome and the microbiota. My understanding is that the microbiota refers to different clusters of bacteria in different parts of the body, whereas the microbiome refers to the genes within the microbiota that are contained in that part of the body.

And it seems like in the last 10 or 15 years, this has really exploded. Why this focus on the gut microbiome?

DR. PHILIP SHERMAN: Well, Michael, there has been, as you say, a huge advance in our understanding of both the gut microbiome and how it’s composed and what it’s doing. A lot of that relates to technology.

DR. ARDYTHE MORROW: It’s true.

DR. PHILIP SHERMAN: There have been advances in the “omics” technology, including genomics, transcriptomics and proteomics, which together tell us who is colonizing the gut, who is there. And that’s been a 10-year study around the world to understand the composition of the intestinal microbiome, including bacteria, viruses, phages, fungi and proteos. [sic: Proteobacteria]

And now we’re moving from not only knowing who is there but what are they doing—so the functional consequences of the microbiome in both health and in the disease state.

We think this is going to open a whole new venue for research activities that will impact on the clinical management of newborns, infants, and children under our care, if not today, in the near future.

3


DR. MICHAEL CABANA: And some of these studies are descriptive? Or have they started moving into actual interventions?

DR. PHILIP SHERMAN: It’s both. This is a rapidly moving field where the description is still going on. The function has certainly started with animal models and moving into the human setting. So there are descriptive trials, mostly to date associative, describing changes in certain settings, disease states. But it’s moving very rapidly into the cause and effect relationships, describing whether altering the microbiome, for example using some of the materials that we’re going to talk about later in this program, relate to impacting human health and disease.

DR. MICHAEL CABANA: Some of the things that I see as a primary care pediatrician include eczema, allergies, and asthma. I know there has been some work associating the microbiome with some of those outcomes as well, too.

DR. PHILIP SHERMAN: Precisely, and you’re absolutely right. A lot of the interesting part of that work is it’s not just the microbiome that you have today, but the microbiome that you were born with and that developed during that first year of life has a huge impact on you and your innate and adaptive immune system and how it functions later in life in both health and in disease states.

DR. ARDYTHE MORROW: I think we’re going to be talking about this later, but it’s not only atopic disease, et cetera, but also infectious disease that, you know, is being described, and neurologic-associated diseases. So there is an explosion of work on this, and it is an emerging domain of work, rather than fully defined. But it’s an exciting domain.

DR. MICHAEL CABANA: Yeah. It’s interesting to think that what happens in the first 1,000 days could influence so many things, not just in the GI tract, but in the respiratory tract or even the gut-brain axis, which we’ll talk about a little later.

DR. ARDYTHE MORROW: It’s true.

DR. MICHAEL CABANA: So some of the factors that might influence the composition and function of the gut microbiome, there is a bunch of them. Maybe we can discuss some of those things. There are things that potentially you could influence as a provider or as a parent, and there are things you can’t. But what are some of the things that might be influential?

4


DR. MICHAEL CABANA: You mentioned where you were born, so not just where you were born in terms of the hospital or outside the hospital, or the specific part of the world?

DR. PHILIP SHERMAN: Yeah. So it turns out—it’s interesting that geographic location of birth may make a big difference in your microbiome. And that is one of the complicating factors in trying to understand the studies that are being reported, because there are such differences, depending on where in the world you were born and who you were born to.

So the genes of the host, the mom, and the baby do impact on the composition and function of the microbiome.

And of course it should be mentioned that the mode of delivery for babies, caesarian section versus vaginal delivery, has a huge impact on whether you have a skin-predominant microbiome or your mama’s microbiome for the little baby when they’re born.

Born premature versus term also has an impact, and in the short-term for sure, the delivery of either breast milk or formula feeding does impact on the composition and probably the function of the gut microbiome.

DR. MICHAEL CABANA: Ardythe, that’s an area you worked on.

DR. ARDYTHE MORROW: Definitely. That’s been much of my career, and I think it would be exciting to talk about. Before we move on to, you know, talking about that in detail, you know, one of the things I had also read that’s not my area, but is that both exercise and also being in nature.

DR. PHILIP SHERMAN: So this has been an exciting area of research in the last few years, describing what are the factors that influence the composition of the microbiome, focused primarily on the composition of the bacterial microbes that colonize the gut and the large intestine in particular.

And those relate to where you were born, who you were born to, whether you were born in the hospital or outside of the hospital, and very importantly whether or not you’ve been exposed to antibiotics. So it turns out that antibiotics have a huge effect, not only for the short time that you’re on the antibiotics, but for long—many months or years—even on to adult life from an impact early in life.

5


There is some work on the idea of being nature-deprived these days. You know, if you can get out into nature, it influences the microbiota, and also that exercise can. So good healthy running around (kids) outside—that could be an important influence. Do you agree?

DR. MICHAEL CABANA: Yeah. I suspect with athletes, there is probably a very different microbiota.

DR. PHILIP SHERMAN: Yeah. So it turns out in elite athletes, there is a microbial composition that’s different from the rest of us regular folks who are plodding along in life. And the part that’s uncertain, at least to me, is whether that’s really a difference in the elite athlete or the foods that elite athletes eat. Because I’m not sure they eat the same foods that I do and you do.

DR. MICHAEL CABANA: Well, maybe. So where you’re born, how you’re born, what you eat, what you do—

DR. PHILIP SHERMAN: Who you’re born to.

DR. MICHAEL CABANA: Who you’re born to, yeah.

DR. ARDYTHE MORROW: Yeah, so there is a lot of influence. And, of course, I want to talk about breastfeeding and the importance of that.

DR. MICHAEL CABANA: Sure.

DR. ARDYTHE MORROW: But going back to the idea of birth, I want to start there. Recently, I had a grandchild who—

DR. MICHAEL CABANA: Congratulations.

DR. ARDYTHE MORROW: Thank you. Was—the intention was vaginal delivery, but went on to C-section. Of course, many mothers are aware, as well as pediatricians certainly, that there is literature saying that C-section babies have some disadvantage potentially to the kind of microbiota that they would have had if there was a vaginal delivery. So there is a question about that.

But when I think about birth regardless, I think about this microbial challenge. You know, think about a baby that in utero—a nice, warm environment; not sterile, as it turns out potentially, but pretty close. And as they get closer to birth, there is some microbial colonization.

But immediately at that birth process, either vaginal or C-section, an onslaught of microbes, which is really quite an amazing—trillions of microbes that are colonizing at that moment. And it’s amazing that we really can survive that. And I think it’s the gift of mom in many ways, the placental antibody that’s transferred, and also then breast milk, colostrum.

DR. MICHAEL CABANA: So when a baby is born vaginally, there is a benefit from being exposed to the mother’s vaginal microbiota?

6


DR. ARDYTHE MORROW: Yes. Yes. And, you know, that’s where the, I think, the evidence is tying—and I think Phil you can comment on this—but tying the idea of the C-section–delivered baby [to] having higher risk of allergic disease later, and that this may well be differences in microbial colonization.

And so then I can talk more about how breast milk may address that kind of thing. But did you want to talk more about the C-section part?

DR. PHILIP SHERMAN: Well, it turns out that babies born by caesarian section do have a skin-predominant microflora. So people have wondered, “Well, why not give a transplant of the mother’s vaginal and fecal flora to that baby?”

DR. MICHAEL CABANA: Yeah, we’ve gotten some requests for that.

DR. PHILIP SHERMAN: In fact, there is a study. It’s a very interesting study, but it’s very preliminary, only for human subjects. But you can transfer the mother’s flora to caesarian section—their baby born by caesarian section. Whether that’s the right thing to do, whether we should be doing that, really requires further study.

DR. MICHAEL CABANA: I think linking it to specific long-term outcomes and, of course, a larger sample size would make a difference as well, too. But it seems like it’s an area—active area of research.

DR. PHILIP SHERMAN: Absolutely.

DR. ARDYTHE MORROW: So my obstetrical colleagues tell me that they have a lot of requests for that.

DR. MICHAEL CABANA: Already.

DR. ARDYTHE MORROW: Yeah. And ACOG, or American College of Obstetrics and Gynecology, isn’t recommending it yet. And can you speak to why that might be?

7


DR. PHILIP SHERMAN: Well, I think many medical professional societies, including the American Society [sic] of Obstetrics and Gynecology, practice evidence-based medicine. So yes it’s important to have laboratory stories and animal models, but we really do need carefully controlled studies in human subjects; one, to show benefit, and two, to be sure there are no adverse consequences—as you say, Michael, not only in the short-term, but in the long-term, where we’re talking about a little baby who has got 80 to 100 years of life ahead of him.

DR. ARDYTHE MORROW: Yeah.

DR. MICHAEL CABANA: It’s an exciting area, and one way you can potentially influence the microbiota in a child, but there are other ways of doing it—

DR. ARDYTHE MORROW: Right.

DR. MICHAEL CABANA: —in terms of how you feed your baby.

DR. ARDYTHE MORROW: Yes, exactly. And so one of the things we really want to encourage is feeding with mother’s milk from the earliest time. That starts with colostrum, and that serves you immediately following birth, and there is a lot of work that’s gone into kind of making hospitals more so-called baby-friendly, but just really meaning encouraging and supporting breastfeeding.

And worldwide, breastfeeding initiation rates have been going up. In the US, there is more and more breastfeeding going on. And this is important because—for lots of reasons. For years and years—I’m an epidemiologist—and for years and years we’ve studied what breastfeeding is associated with, and there is a very deep evidence of protection against a number of infectious diseases, including respiratory infections of various kinds.

Certainly, my own work has been on gastro—gastroenteritis or diarrheal disease and protection against that, in the preterm infant protection against necrotizing enterocolitis, also evidence of reduced atopic dermatitis and evidence of some other things that were initially surprising, but things like childhood leukemia and type 1 and type 2 diabetes (potentially) type 1.

So there’s a lot of, you know, immune factors that have been—you know, in other words, human milk or breastfeeding is protection against not only infectious disease, but immune disorders of various kinds.

And it comes back to a basic principle about the microbiota, which is that we are the ones that came into our great planet much later than the microbes. They were here first.

As we developed, as humans evolved, you know, we were developed in the context of a microbial world. And so it turns out that we actually need those microbes for our own healthy development of the GI tract, of our immune system, and potentially even our brain development.

DR. MICHAEL CABANA: So what do you see in infants who aren’t exposed to this microbiota? So there can be extreme circumstances or antibiotic exposure as well too. What happens in those cases?

DR. ARDYTHE MORROW: So that’s really an important question. And I think we have more evidence from animal models and tissue models. What we see is that when [an] antibiotic is given, it’s actually not only changing the composition of the gut microbiota, it changes their functionality. It kind of, I think—I’d like to describe it as hunkering down. They are not as active. And certainly microbes may thrive more than others.

We certainly know about antibiotic resistance, but it’s also that it’s tending to select certain microbes. And some of our friends, beneficial microbes, may be some of the most affected by having antibiotics. So I like to—tend to think that there is a recovery process that needs to go on. We know that when we take an antibiotic that it can influence the very expression of genes in the GI tract of some of the things that help us with natural defense.

So it’s important after an antibiotic to know that antibiotics are life-saving and important, but we also need to recover from them, and regrow a healthy microbiome.

8


DR. MICHAEL CABANA: So the link between breastfeeding and the development of the microbiota, can you walk us through that a little bit?

DR. ARDYTHE MORROW: So human milk has got many different components that really can help shape a healthy microbiota. First of all, we have to survive, so there are a lot of antipathogenic components of human milk. And over my career, I’ve looked at antibody and other things, but most recently I have really focused on human milk oligosaccharide. And I’d like to talk about that.

But what has been shown is that a baby who had C-section, for example, or potentially [an] antibiotic, that seems to even out more when the baby is also breastfed. There are strong influences from breastfeeding, and they begin with the fact that human milk has microbes in it. And it also—with all these defense proteins, antibody and then human milk oligosaccharide.

Human milk oligosaccharide is one of the more recently studied components. Really, it’s over the last 10 years, even as the microbiome revolution—that’s what I call it—has come online. Study of human milk oligosaccharide has also exploded and is one of the hot topics in infant nutrition.

It’s because it appears that this is one of the most abundant components of human milk. Even though we haven’t talked about it over many, many decades, but after lactose and lipid, so after the—you know, the primary sugar of human milk is lactose, of course, and then the fat component. The third most abundant is human milk oligosaccharide, and very similar concentration to protein.

So it appears that its functionalities are to help manage the microbial world in various ways, to help grow beneficial organisms, such as Bifidobacteria, and blunt the edge of pathogens.

DR. MICHAEL CABANA: So oligo—so human milk oligosaccharides; so oligo—a few saccharides?

DR. ARDYTHE MORROW: Yes, saccharides. Right.

DR. MICHAEL CABANA: These are just a few—

9


You add things like fucose or sialic acid and [get] more of a set—a limited set, a repertoire. I kind of think of it like tinker toys. You’re adding on complexities over time. And this—these structures are very similar to structures that are found in the infant gut. So this is a pairing between what mom provides and what the baby has endogenously. It’s a beautiful example of systems biology. And there are multiple functionalities.

I like to say mom can—mom has many tricks up here sleeve in general when raising a child. That’s also true of human milk. There is not just one thing. There are many. And in the human milk oligosaccharide fraction—it’s not just one molecule. It is more than 200 molecules. And we are, in science, only just beginning to learn how to make them, and then only recently being able to make them commercially available.

DR. ARDYTHE MORROW: Right. So let me tell you that lactose—that we talked about—everybody knows is in milk, and that’s the core molecule. So the disaccharide, the lactose and glucose in combination is the core of what oligosaccharides are. They build on that. So different enzymes go into build[ing] things that go from 3 up to 32 sugars in the link.

10


But mother has this incredibly complex array of sophisticated structures in her milk that help do a series of things.

One, what I call pathogen-binding inhibition. I’ll talk about that. Two, it has a prebiotic effect that really helps change bacterial metabolism in a healthy way and grow healthy microbes. And three, immune-system modulation as well, we understand.

And this is from preclinical studies, a lot of preclinical studies, and a few clinical studies that suggest that this results in lowering infection rates.

DR. MICHAEL CABANA: So oligosaccharides—so [a] few saccharides. But there’s really over 100 different types of oligosaccharides.

DR. ARDYTHE MORROW: That is true. And every mother, or mothers, have different combinations of oligosaccharides in their—in their milk. But they’re all healthy and beneficial.

DR. MICHAEL CABANA: So if you took 100 different mothers—100 different cocktails or combinations of oligosaccharides?

DR. ARDYTHE MORROW: Yeah, that’s right. And I call it a cocktail.

DR. MICHAEL CABANA: Okay. Yeah.

DR. ARDYTHE MORROW: It’s kind of a fun way of thinking about it. But I like to say the simplest ones are 3-sugar combinations, so trisaccharide, building on lactose, and the most complex ones, 32. And we’re just beginning to really understand what each one of them does. This is really the beginning of our scientific journey on human milk oligosaccharide.

DR. MICHAEL CABANA: So clinicians might be familiar with something called fructooligosaccharides [FOS] or galactooligosaccharides [GOS]. That’s different than what you’re describing here.

11


DR. ARDYTHE MORROW: Yes. And actually what’s so interesting is that it was so complex to make human milk oligosaccharide. Once they were discovered—and actually it was in the 30s—1930s that they were first discovered. But it was so complex to make them, but it seemed simple. You know? But it wasn’t.

Industry went to making a substitute in order to be able to put them in infant foods and to give babies a chance to have something that I think of as a health food that helps—a prebiotic effect. I think we’ll talk about what that means.

So FOS and GOS—that’s what they are—are substitute structures that were made to be as similar to human milk oligosaccharide as industry was able to make. And now there is a pipeline basically of a number of different companies and groups that are working on making human milk oligosaccharides.

The first to come out commercially is something called 2’-FL, or 2’-fucosyllactose, 2’-FL. And it’s just a simple trisaccharide. But it’s a very abundant one, and there is the most evidence around that one of any of them.

But we also know that mother’s milk, because of this complexity, because there are many different structures, the idea is to try and incrementally go with the most abundant and most functional ones and ones that can be made, because some of them are so complicated.

12


DR. MICHAEL CABANA: So there is FOS and there is GOS, and then there is human milk oligosaccharides.


DR. MICHAEL CABANA: And within there, there is 2’-FL, which is potentially the first of many.


DR. PHILIP SHERMAN: Well, just to add on to what Ardythe said/mentioned, I think it’s important to remind folks that these important human milk oligosaccharides are present in mom’s milk, but not normally present in cow’s milk–based formula or soy-based formulas. So that’s why they are added to be closer to mama’s—human mama’s milk.

DR. ARDYTHE MORROW: Right. Exactly. An important point.

DR. MICHAEL CABANA: So bovine milk, or cow’s milk does not have—

DR. ARDYTHE MORROW: It only has trace amounts. It’s very interesting. And we know that—well, first of all, all milk over every species of mammals is distinct in its composition, and that includes in the oligosaccharides. But in the milks that we could access commercially, the oligosaccharide levels, even in goat’s milk, is low. But it may be slightly higher than cow’s milk where it is virtually absent. It’s very low.

DR. MICHAEL CABANA: And I might have gotten this wrong, but human milk oligosaccharides are the third most common component in human milk.


DR. MICHAEL CABANA: So it must play a—it seems like it should play a pretty important role.

DR. ARDYTHE MORROW: Well, just conceptually. You could say, “Well, we know that there is an energy cost to production,” and we know that protein is important. So if it is as abundant as protein, it’s a suggestion that by our natural biology that it’s logical that it would be important. And then, of course, there has been a lot of research, in vitro, in vivo studies, preclinical studies of a variety of kinds, epidemiology, which I have done as well as others, and then recently several trials.

DR. MICHAEL CABANA: So I think we were discussing this before, but one way to look at human milk oligosaccharides was like different blood types.

DR. ARDYTHE MORROW: Yeah. So, I mean, think of it—many of us may not be aware that our blood-group types are actually sugars. They’re oligosaccharides too, on the surface of our red blood cells. But they’re not only on our red blood cells.

In fact, Landsteiner, who discovered the ABO blood-group system, also discovered this—that in secretions there were also these structures. So milk is a major secretion. But the cool thing about milk is that it’s the equivalent of an O blood group. It’s like universal donor. That means any mom can give milk to—regardless of her baby type, if you will, and it’s all—the oligosaccharide structures, there is no A-B part to worry about.

DR. MICHAEL CABANA: Okay. So if 100 women had a 100 different types of breast milk, it’s still okay for a baby to use—

DR. ARDYTHE MORROW: Yeah, like donor milk banks or pooling milk from all sorts of moms, right, and giving it. And it’s all safe.

13


DR. PHILIP SHERMAN: Well, the donor milk banks, to carry on that theme, some of the product, the bioactive compounds in the milk that’s provided, because it goes through pasteurization, are degraded. But the milk oligosaccharides are not.

DR. ARDYTHE MORROW: They’re not, no.

DR. PHILIP SHERMAN: So they stay intact from the donor to the recipient.

DR. ARDYTHE MORROW: That’s true.

DR. MICHAEL CABANA: So if a baby was born to a mother that wasn’t going to receive—that didn’t have 2’-FL in her specific breast milk, there would be no harm to receiving 2’-FL?

DR. ARDYTHE MORROW: That’s correct.

DR. MICHAEL CABANA: Okay. So it’s like O-negative blood is what you’re saying.

DR. ARDYTHE MORROW: Right. So yeah, because mothers are variable—mothers, or something called secretors, have an abundance of this molecule called 2’-FL. But there is about a quarter of moms who don’t have this. So again, we just see that in nature, and we have certain core similarities, but there is—there is individuality. And that individuality is perfectly great. In fact, it is a healthy part of being human.

So it’s fine to have moms with different oligosaccharides in them. But it is, regardless, a very important component of human milk. I think that was a part—and that the oligosaccharide fraction, including 2’-FL and other oligosaccharides, have a way of helping shape a healthy microbiota towards Bifidobacteria and other healthy microbes as a community, but also inhibiting pathogens so they don’t—oligosaccharides don’t support the growth of disease-causing organisms, so pathogens. And it also helps modulate the immune system towards an immune system that has positive benefits of short-chain fatty acids and small organic acids.

DR. MICHAEL CABANA: Well, it’s certainly an exciting development to go from FOS and GOS, which seem like very nonspecific substances, to human milk oligosaccharides. It’s interesting to think also what’s actually happening in the gut in terms of what 2’-FL was doing, or human milk oligosaccharides. What do we know about the mechanism of how these are working?

DR. PHILIP SHERMAN: Well, there’s great interest in understanding shaping of the host immune system, the innate and adaptive arms of the immune system. And there’s increasing evidence that the composition of the microbiome early in life impacts the immune system for the rest of one’s life.

DR. ARDYTHE MORROW: Yeah, very important.

DR. PHILIP SHERMAN: So some of those very powerful studies in animal models, rodent models in particular supporting that. But there’s 2 human studies in babies looking at the composition of their microbiome at 3 months of age and then again at 6 years of age.

It turns out the composition of the microbiome at 3 months of age, how biodiverse that microbiome is, predicts those children that will have reactive airway disease like asthma—the biodiversity less pronounced in those who end up getting asthma later in life, whereas their microbiome at the time of the illness, at 6 years of age, isn’t different. So there’s something about that early composition and why the issue about antibiotics and breastfeeding early in life, its impact on the immune system isn’t just for the time of exposure, but it’s for the rest—probably for the rest of one’s life.

DR. MICHAEL CABANA: It seems like it’s a combination of 3 different things, your genetic susceptibility, having the right exposure, but also the timing of the exposure seems like it makes a difference within that—at least in this study—this 3-month window as well.

14


DR. PHILIP SHERMAN: They say timing is everything.

DR. MICHAEL CABANA: Timing. Timing is everything, yeah. Any other thoughts about mechanisms for human milk oligosaccharides and how that might be working?

DR. ARDYTHE MORROW: Well, I would just emphasize one thing, I think, and then we can talk about many other things, although this is my favorite topic. Right? So, you know, my initial work, and along with my colleagues, David Newberg and Larry Pickering and Guillermo Ruiz-Palacios, and so on, we had NIH funding around pathogen-binding inhibition.

And this is the thing that makes it, perhaps, most different than other forms of so-called prebiotic carbohydrates or oligosaccharides that are out there, like FOS and GOS.

Because of the similarity with the gut oligosaccharide, an incoming pathogen that might want to attach to that gut-carbohydrate receptor, instead with mother’s milk having this abundant source of oligosaccharide, if it’s in the gut lumen then it can instead attach to the mother’s milk oligosaccharide structure and blunt the edge of whatever would have attached at the gut surface.

DR. MICHAEL CABANA: Are there specific pathogens that it’s protecting against? Or is this nonspecific.

DR. ARDYTHE MORROW: Remember that there are all these different oligosaccharides and they all have different structures. Right?

So for the oligosaccharide that I’ve done the most work on, and is the first one to come out commercially, 2’-FL, we found that that was important in terms of enteric infection or diarrheal disease. Moderate to severe diarrheal disease seemed to be reduced by having more—[an] abundance—of that structure or related structures, and then specifically Campylobacter diarrhea, norovirus diarrhea, and potentially rotavirus.

And there’s some nice work from—again preclinical work or bench science that—indicating mechanisms besides pathogen-binding inhibition that are immune-related. So it’s a very sophisticated, multidimensional system.

15


DR. MICHAEL CABANA: Okay, super. Great. So we talked about establishing the microbiome through different things: how a baby is born; how you feed a baby, specifically through breastfeeding.

But one of the other ways to potentially influence the microbiome is through probiotics or probiotic interventions. And probiotics are defined by the World Health Organization as live microorganisms when ingested in adequate amounts that confer a beneficial effect to the host.

Probiotics to me encompass many different types of strains and many different types of mechanisms. Phil, you’ve done a lot of work in this area. How do probiotics work, or is it possible to even summarize that in one—in one little sentence or two?

DR. PHILIP SHERMAN: Well, as we heard about human milk oligosaccharides, life is complicated. And it turns out that beneficial microbes work in multiple different ways. And that is the case for these beneficial microbes; mostly bacteria, mostly gram-positive bacteria, but including gram-negative bacteria and some yeast also. And they act in different ways to have different effects. And it’s very strain-specific. That’s the interesting thing.

So it’s not—probiotics is an inclusive term for a lot of different organisms that work in a lot of different ways. So, for example, there are some bacteria that work like Ardythe just described for milk oligosaccharides, where there’s competition for receptor-binding sites. And so that’s called colonization resistance, when one beneficial microbe outcompetes a pathogen, for example.

Other probiotic strains that don’t have that effect impact human health by promoting the immune system. Some organisms increase—secrete IgA, for example. Other organisms increase goblet-cell mucin—innate trefoil factors. Other organisms tighten up the epithelial barrier in the gut, making it more resistant to macromolecular uptake, and other organisms impact on more distal sites in the immune system: for example, inflammatory cells in the lamina propria underlying the gut epithelia.

16


So it might be that one strain does have all of those effects, but it’s much more likely that you need multiple strains, or that you target for an anti-inflammatory disease a probiotic strain that has anti-inflammatory effects. For an antipathogen effect, you target—you use a probiotic strain that’s selective for antipathogen effects.

DR. MICHAEL CABANA: One of the concepts is this idea of bacterial diversity is dysbiosis. So is it possible to address dysbiosis with one specific intervention? It seems like it’s just one bacterium and you’re trying to affect a whole community. Can that really happen?

DR. ARDYTHE MORROW: First of all, this is—maybe we should say what is dysbiosis. Right?

DR. MICHAEL CABANA: Okay, sure.

DR. ARDYTHE MORROW: You know, I had one of my senior colleagues say, “There is no such word”—and, you know, a very learned pediatrician. So I want to say that this is a relatively new word, and it’s being used a lot. But it really, in my opinion, tends to mean the idea of imbalance in the microbial community, which perhaps—and appears to also have an influence on the imbalance and the functionality of that microbial community. Would you agree with that definition?

DR. PHILIP SHERMAN: Absolutely.

17


DR. MICHAEL CABANA: So not just reduced diversity, but reduced diversity affecting the function—

DR. ARDYTHE MORROW: Exactly.

DR. MICHAEL CABANA: —of the microbiome.

DR. ARDYTHE MORROW: And oftentimes, even—in the studies that I’ve done at Cincinnati Children’s and at [the] University, I have seen in many different communities the dominance of one thing, rather than a nice, even kind of balance of sharing communities. So that’s one feature of dysbiosis.

DR. MICHAEL CABANA: So, a probiotic intervention to address bacterial diversity or an imbalance?

DR. PHILIP SHERMAN: Yeah. So it is part of a therapeutic armamentarium that’s available to us. So as Ardythe mentioned, normally the colon has 500 to 1,000 bacterial species. So one concept is that you can— if you’re missing or have far fewer than 500 to 1,000, why not transfer in from your spouse or your mother or your colleague or a donor 500 to 1,000 species? And that’s called a fecal microbial transplant.

And in some settings, that is—does work. The amazing therapies that have been shown in clinical trials are in elderly folks with recurrent Clostridium difficile infection, where there is a real loss of biodiversity and you can enhance it by giving a transplant.

Now it turns out with that transplant, the bioactive ingredient may not be the bugs. It actually might be phages contained in the transplant.

DR. MICHAEL CABANA: Interesting.

18


DR. PHILIP SHERMAN: So that’s kind of interesting. That can be, instead of using 500 to 1,000—and other things being in it like phages and maybe retroviruses—it’s possible to use a more select number of strains. That has been up to—and in clinical studies—up to 30 strains; in commercial use up to 8 beneficial microbe strains in a cocktail of microbes.

Others believe that it’s better to use a single strain. For me, the word is not yet—final word is not yet in on whether one should use a combination or a single strain. Both are available in the marketplace.

And if one knew the actual bioactive compound present on a single strain, one could extract and use that. That’s called a postbiotic. That is not available at present. That is a conceptual thought for consideration down in the future. An inflammatory molecule, for example, derived from a probiotic strain, could be delivered to a very premature baby where you’re worried about using viable organisms.

But available today is single strains, multiple strains, and in very, very select cases—not for most common use, I would say—would be—or in the setting of a clinical trial—a fecal microbial transplant.

DR. MICHAEL CABANA: That seems like a very extreme type of intervention that you might use in very extreme cases. Ardythe?

DR. ARDYTHE MORROW: Yeah. I think under evidence-based situations, it seems like it’s a very appropriate thing to do. I was struck by the concept that, you know, years ago—because I started as an infectious disease epidemiologist—is that microbes are bad. And now we’re tending to transition to thinking, “Well, microbes are good.”

I think what we have is, instead, really the idea of trying to understand the balance between what human beings need to thrive and the microbial community that’s a healthy one for us, because there are certainly still pathogens, and we don’t really know what all of these organisms, phages or fungi, et cetera, might actually be doing. So this is why, in my opinion, anyway—and see what you think about that, Phil—is that why we have to be careful with things like fecal transplant because we don’t yet know about what we’re—all of the ramifications. Right?

So all of these things are still interesting and under study and may be very important. But we also have to kind of follow evidence-based guidelines and follow over time to see ultimately. Do you agree?

DR. PHILIP SHERMAN: Yes. And amen.

DR. MICHAEL CABANA: Well, I think, you know, from the previous discussion about all the factors that affect the microbiome, to do a clinical trial there would be so many variables to try and control and to manage in terms of making sure that everyone has a similar diet. It would be hard to know what type—other type of exposures there are, what other types of activities, environments. So—

DR. PHILIP SHERMAN: That is true. Clinical research is challenging. Having said that, I do believe it’s highly appropriate to do so. Evidence-based medicine helps direct the right therapies...including that they’re safe and efficacious.

I would say a well-designed trial should use the right strain at the right dose in the right setting. And that’s easier said than done. Those are the complexities in designing a trial, making sure that the patient population is homogenous enough to get a result that is impactful and yet diverse enough that it’s relevant to the practitioner. And that’s the complexity of clinical research.

DR. MICHAEL CABANA: Yeah.

DR. ARDYTHE MORROW: Can I ask you about synbiotics? Because this has been said about human milk, for example, as a model—that it’s the combination of the carbohydrates that help feed the beneficial microbes and the microbes themselves. So what do you think about synbiotics?

19


DR. PHILIP SHERMAN: So the definition, as described, is the combination of a live organism [and] a probiotic plus either an HMO [human milk oligosaccharide] or a prebiotic—a synthetic oligosaccharide. And there is much less evidence out there, but there is increasing evidence that that may be the way to go.

So I think you’re absolutely right to bring this up as a very interesting point. I think for the practitioner, more evidence is still required before we go that route. But it’s certainly on the radar screen for evaluation.

DR. MICHAEL CABANA: So combining a prebiotic and a probiotic—

DR. PHILIP SHERMAN: It’s called a synbiotic.

DR. MICHAEL CABANA: —it’s a synbiotic. Yeah. Okay, great. You talked about specific strains used in specific situations at specific doses. There might be some examples of that already in the literature.

It’s nice to see the literature growing. It’s been growing very quickly. But these clinical trials are now being published, and there is some indication that we have good evidence for probiotic interventions. Anyone—do you want to talk about [this]?

DR. PHILIP SHERMAN: Well, as a group we’ll discuss a few. There are very—there are many areas that are evolving right now, so we’re just choosing a couple.

So one example that’s relevant to folks who look after healthy little babies, and really relevant to parents and grandparents too, Ardythe, of little babies, is the issue of colic. So colic is irritable babies. They’re otherwise healthy. They do grow out of it. But it’s a real stress for the babies, and it’s a real stress for the mamas.

And it turns out when evaluated—not in great numbers, but when it’s been evaluated, there is a dysbiosis, an altered composition in those babies compared to age-matched controls in the same community, fed the same diet.

20


And there are a number of studies undertaken around the world, including here in North America; level 1, randomized controls looking at an active probiotic agent against placebo, showing that the irritability—as a treatment strategy, the probiotic is more effective in reducing irritability in those babies.

DR. MICHAEL CABANA: So this is treatment—treatment, not prevention, of colic.

DR. PHILIP SHERMAN: So the multiple studies that have been done around the world, including North America, are treatment strategies. There is, however, an additional study undertaken in Italy. As far as I’m aware—and you might know more about this Michael—I think there is only one study from Italy using the same probiotic strain and the same doses as a prevention strategy, and also showing a beneficial effect.

I think there is more room to work in this area to show that it works in both prevention and treatment—how long, how much. And, you may ask, how does it work—?

DR. MICHAEL CABANA: Yeah, well—

DR. PHILIP SHERMAN: —because—

DR. MICHAEL CABANA: It’s—it’s—

DR. ARDYTHE MORROW: It’s what everybody wants to know.

DR. MICHAEL CABANA: That’s what everyone wants to know. You know, as a primary care pediatrician, if there is a patient with colic on my schedule, I know that’s going to take a lot of time to explain. So it’s great that there is potentially some sort of treatment.

The one thing that puzzles me is that you’ve described it as a potential dysbiosis, but anecdotally when we’ve seen changes, and when you look at the clinical trials, it seems like there are changes occurring within the first week. So it seems like a short time period to have such dramatic change.

Can you really change a microbiome, or the intestinal microbiome, in less than a week?

DR. PHILIP SHERMAN: Yeah. So an excellent question, for which we don’t have the total answer. I think the short answer is, “Yes, we can within a week,” but is that the explanation for why [a] probiotic might work in the setting of colic? Maybe. Maybe not. How is that for a definitive answer?

So yes, it might be working through altering the microbiome. But the interesting thing is that this probiotic strain, in particular, has other effects—so, for example, direct effects on nerve channels that relate to visceral hyperalgesia, so pain sensation in the gut.

Those pain channels are turned from the open state to the closed state by probiotics and culture supernate is derived, so secreted out from the probiotic strain that directly impact the local milieu.

In addition, there is more and more evidence accumulating that those effects of probiotics are not only local in the gut, but also distant in the brain.

DR. MICHAEL CABANA: So there is a gut-to-brain axis.

DR. PHILIP SHERMAN: So exactly.

DR. ARDYTHE MORROW: Very exciting.

21


DR. PHILIP SHERMAN: And it’s bidirectional: brain-gut axis, and gut-to-brain axis. And it’s mediated hormonally and probably neurally. And we know this from animal models where transecting the vagal nerve abolishes the beneficial effects distally of probiotics locally.

And it turns out, hot off the press is a paper showing that there is a brand-new cell type, [an] enteroendocrine cell called a neuropod that senses microbial products and transmits them to nerves that go up to your brain. So there is now a biologic explanation for the microbial gut-brain axis.

DR. ARDYTHE MORROW: Very cool. Very cool.

DR. MICHAEL CABANA: Yeah, interesting.

DR. ARDYTHE MORROW: Are there any negatives/downsides for taking probiotic? I have often heard on the adult side that some people take it and say that they feel more GI disturbance than they do—

DR. PHILIP SHERMAN: Yeah. It might relate to dose. It might relate to if there is a synbiotic the sugar content. Many of the studies that have been done so far in humans are limited in numbers and quite short-term.

So in the doses taken in foods and in food supplements, there is a long history; very, very safe, very few side effects. In the larger concentrations of single strains that are used in human subjects as therapeutics, short-term we think they’re safe. But we need to follow those people long-term, especially when it’s given to babies.

We need to know not is it safe this year—but how is it in your 40s, 50s, 60s and 70s? So we’re going to have to do a lot of surveillance in the long run. So short-term, I think we would say it’s safe in otherwise healthy individuals. There is some concern—because probiotics are viable organisms—in the very immunosuppressed individuals. Evidence to date suggests it’s probably safe; single strains [and] lower doses [are] probably safer than high strains delivered locally into the gut.

DR. MICHAEL CABANA: We have used probiotics for healthy newborn infants, and I know reviewing the literature, some of the complications occur when there is central line access or contamination. So you’re right. It’s a live organism, and you have to be very careful about potential contamination.

DR. MICHAEL CABANA: So one other curious thing about the probiotic literature with colic, if you look at the different studies, there is one study in Australia that showed a different result. Maybe it goes back to geography, but the other thing that was different about that group was all the other studies dealt with babies who were exclusively breastfed.

DR. MICHAEL CABANA: So an interesting thing that it didn’t—the probiotic did not seem to have an effect with formula-fed babies. I wonder if there is—

DR. ARDYTHE MORROW: So again, this may—speculation here, but this may, again, be that synbiotic concept. You know, everybody eats, including bacteria, and what they eat and what they produce when they eat—and it gets back to that sensing. And again, the concept that Phil mentioned, which is it’s not only what’s there, but what functionality.

So the idea that there is this oligosaccharide substrate that’s available to these organisms, which otherwise may not be. And that could through—you know, in vitro work would suggest that this is changing the ability to create short-chain fatty acids and small organic acids that actually help benefit the gut.

So, you know, not all the dots are connected yet, but that’s how I—I imagine that we will eventually, as we’re doing more research on this, thinking about the functionalities, what’s actually being done, and that could be influenced by diet.

22


DR. MICHAEL CABANA: I think that’s why these clinical trials are so important. The more clinical trials we have, we just learn more about the other possible variables that might affect the effectiveness of these probiotic interventions.

One area that’s been really well-covered is diarrhea and probiotics. I know you’ve been involved in international organizations in terms of summarizing that. Probiotics for diarrheal disease—so one would be treatment of infection and the other one [for] antibiotic-associated diarrhea. But what’s been your experience with treatment of infectious diarrhea?

DR. PHILIP SHERMAN: Well, we need to hear from you too, Michael, because I know you’ve been involved in these studies.

DR. MICHAEL CABANA: Yeah, sure.

DR. PHILIP SHERMAN: But my experience has been—there [have] been lots of meta-analyses...looking at trials and their effects of probiotics, various strains, as interventions to reduce the duration of diarrhea.

The interesting thing for me is it doesn’t matter which probiotic strain is used. They all show the same results. The summary of all of these meta-analyses is that you reduce the duration of diarrhea by about a day; statistically significant when you reduce the duration of diarrhea by about a day.

What’s interesting is how the experts in the field can look at that and have completely different interpretations of what that data means. So in the global context, it’s been said 1 day doesn’t cut it. That’s not good enough. It distracts from the important primary therapeutic intervention, which is oral rehydration therapy, which saves lives for severe diarrheal disease.


23


DR. PHILIP SHERMAN: So there is no question about that. So it’s not been added, probiotics, as an adjunct to manage diarrheal disease in the global setting. However, if you’re the mama or papa of a child who you want to get back in daycare and they’re not allowed to go back until the diarrhea is settled, 1 day can make a difference. So there is a difference of opinion of evaluating the same data. And I would be interested in your consideration.

DR. MICHAEL CABANA: Yeah. I think you have to work with parents to understand what their needs are and work together to develop a decision. But there’s definitely a science, but there is also an art to applying the science that we know.

So even—we talk about needing more trials, but even with a lot of trials, you get some of these ambitious situations as well too.

DR. ARDYTHE MORROW: Right. Right, exactly. Very interesting.

DR. MICHAEL CABANA: The other issue is probiotics for antibiotic-associated diarrhea as well, too. So that seems to be—when I prescribe an antibiotic, there is always the chance of antibiotic-associated diarrhea. And the evidence is actually pretty good that it can reduce the risk of antibiotic-associated diarrhea. But here is one of those situations as well.

Every time you complicate the regimen, if I go from having you give one therapy to two therapies—when you complicate it, it decreases the potential adherence to the regimen. And you also want to be able to work with parents to make sure that’s something that they can include and work with as well, too.

So good evidence that it can prevent antibiotic-associated diarrhea, but not all kids are going to develop that, and not all parents or families are willing to go through that additional step as well too. So once again, matching the science with the art of medicine as well, too.

DR. ARDYTHE MORROW: That’s an important point.

DR. MICHAEL CABANA: Right.

DR. MICHAEL CABANA: So one of the other interesting areas in pediatrics is the use of pediatric interventions for the prevention of necrotizing enterocolitis [NEC]. It’s not something we see in primary care. It’s, you know, with premature infants in the neonatal intensive care unit. But a very devastating illness.

Here is one thing that I have always been interested in. It seems like there are several studies that show a potential positive effect in prevention with probiotic interventions. What are your thoughts on that?

DR. ARDYTHE MORROW: Also with oligosaccharide.

DR. MICHAEL CABANA: Okay.

DR. ARDYTHE MORROW: The human milk oligosaccharide. But you want to talk about the probiotic first?

DR. ARDYTHE MORROW: Well, in general, the most effective intervention we know for prevention of necrotizing enterocolitis is providing an exclusive human milk diet.

DR. MICHAEL CABANA: Okay.

DR. ARDYTHE MORROW: And that also means then you’re also providing human milk oligosaccharide. And there has been work on that showing predominantly the most—the strongest effect seems to be an oligosaccharide that we hadn’t talked about yet, which is something called DSLNT.

DR. MICHAEL CABANA: DSLNT?

24


DR. ARDYTHE MORROW: Right. It’s an oligosaccharide that [has] been shown through both in vitro and in vivo work, and then in an epidemiologic study, to be associated. The higher the level, it appears to be protective against the occurrence of necrotizing enterocolitis.

And mechanisms around this, again, are under—still under investigation. But it would seem to have an anti—important anti-inflammatory and so immune-modulator modulation and microbial modulation.

And one of the things about NEC is, I think, for my money, that it’s very much tied into the microbiota. What we see is dysbiosis. And it may be coming in various guises and types. But one of the...meta-analyses showed that babies are at increased risk of NEC if there is a kind of increase in the Enterobacteriaceae, which includes a whole family of gram-negative organisms that are most common in the preterm infant, E coli, klebsiella, so and on—and if those are surging, that tends to be associated with NEC. So that’s important. But oligosaccharide, particularly DSLNT, seems to be a helpful preventative.

DR. MICHAEL CABANA: So these are observational studies or clinical trials that have—

DR. ARDYTHE MORROW: No clinical trials, for example, for DSLNT—and that’s one of the issues. It gets to where we are in the science and how long and frustrating that can be.

DSLNT—my colleague Lars Bode has worked on this particularly. It’s a complex molecule. And we do not yet know how to synthesize it. Therefore, there is no way to do a trial. And even if we could synthesize [it], it would take a while to get the FDA regulatory—so what is best? Well, mother’s milk right now.

DR. MICHAEL CABANA: Okay. Okay.

DR. ARDYTHE MORROW: And then eventually we may have the opportunity to test DSLNT.

The molecule I also talked about, 2’-FL, has perhaps an adjunctive benefit. There is some work showing that it’s helpful for gut repair or recovery, but it’s probably not as primary a preventive as DSLNT might appear.

So the story is more that every oligosaccharide has a function, and the timing of it in terms of its trajectory through lactation actually changes. Like how abundant it is. And so we’re still working on the science of all of that.

DR. MICHAEL CABANA: Do you see more of that specific human milk oligosaccharide for mothers who have...premature infants? Are they more likely to produce that specific human milk oligosaccharide?

DR. ARDYTHE MORROW: In our data, it tends to be more abundant with less-mature infants. So that is to say [in] early lactation it’s higher, and that’s probably an indicator of its importance in very early life.

DR. MICHAEL CABANA: Okay. That’s fascinating with the timing.

DR. ARDYTHE MORROW: Yes.

DR. MICHAEL CABANA: And the shift in HMO.

DR. ARDYTHE MORROW: Right. HMO shift definitely over lactation.

DR. MICHAEL CABANA: Okay. So maybe when you go to the breast-milk bank, you might want to find out when that milk was produced?

DR. ARDYTHE MORROW: So this is another area of work that needs ultimately to be done because that’s a hard thing for milk banks to be—I mean, they can do it one-on-one, but it’s in general challenging. And most of the donor milk banks have milk that’s coming from later lactation.

25


DR. MICHAEL CABANA: I’m going to switch gears a little bit, but not really. Ardythe and Phil, potential side effects or safety issues with prebiotic exposure. Are there any potential side effects with too much prebiotics? Can you have too much of a good thing?

DR. ARDYTHE MORROW: So...the mother’s situation of breastfeeding, well this is just as nature has it, and there are no side effects there that are negative, unless the mother is HIV-infected, or HTLV-1-infected, or something like that. But that’s not what we’re talking about.

When we’re starting to give oligosaccharide, human milk oligosaccharide structures in formula, they have to be tested. So far, there have been a lot of safety tests preclinically. So far so good. But it’s also about dose.

So when the formula is being tested, and there have been 2 trials, they have also shown safety. But there is always a consideration of what dose level and not getting above and beyond what would have been given in human milk. So that’s the way—but so far, safety looks quite good.

DR. MICHAEL CABANA: Can you go to the local drugstore and buy some GOS off the shelf and take some GOS?

DR. ARDYTHE MORROW: I think you can buy GOS. That’s the way I pronounce it. But in nutrition stores, for example. Maybe—I don’t know about the local physician.

DR. MICHAEL CABANA: So can you overdose on GOS?

DR. ARDYTHE MORROW: I think you can overdose on anything. For example, you take anything in the diet. You can—if it’s not in balance, you could; but not—you would immediately have GI symptoms. You know, if you were going way above and beyond.

DR. MICHAEL CABANA: Can you elaborate on the GI symptoms? Diarrhea, flatulence, or—

DR. ARDYTHE MORROW: Yes, all of the above that way. You can get kind of osmotic diarrhea. That would happen.

DR. MICHAEL CABANA: Yeah, it seems like it would be—yeah.

DR. ARDYTHE MORROW: But you know, those dosings are specified when they’re being made commercially. And thinking about on the infant side, it will be tested formula by formula. You know, different companies will have different products. And then it’s just—then the burden is for them to show safety.

DR. MICHAEL CABANA: So Phil mentioned that it’s important to know what you’re looking for when you’re looking for safety issues. Is there anything that you’d be looking for that you think—?

DR. ARDYTHE MORROW: Growth is a big one, of course. And all of the formulations; for example, in the US, the FDA [is] always making sure that growth would be appropriate to and equivalent to—and ideally to—a breastfed baby. But certainly at least as good as formulations without oligosaccharide in them.

And tolerance—we would be looking at things like colic, which Phil mentioned. All of those things are part of evaluating an infant formula.

DR. MICHAEL CABANA: And when you mention growth, there can be too much growth or not enough growth? So failure to thrive or obesity?

DR. ARDYTHE MORROW: That is true.

DR. MICHAEL CABANA: What are we worried about?

26


DR. ARDYTHE MORROW: So one could be concerned about either one for anything that you add to infant formula. So you’re really just looking at the growth curves and looking for anything anomalous to that normal growth pattern.

DR. MICHAEL CABANA: Okay. So the bottom line to date, no serious side effects documented?

DR. ARDYTHE MORROW: No. With the—given the studies that have been done so far, all is looking quite good. But when anybody is looking at formula, we would have to look at the evidence for a particular formulation actually. That’s important.

DR. MICHAEL CABANA: Phil, what are your takeaway messages, or what—Ardythe?

DR. PHILIP SHERMAN: Well, I hope that we’ve conveyed to folks that are listening, and thank you for listening, that this is an exciting and emerging new field. It’s clear from what we’ve talked about that we don’t have all the answers yet, but there is very promising evidence that human milk oligosaccharides, potentially prebiotics, and potentially probiotics, are going to have an impact on the gut microbiome, on the function of the gut microbiome, [and] its impact on the host, both in the setting of health and in promoting and preventing disease.

DR. MICHAEL CABANA: Ardythe?

DR. ARDYTHE MORROW: I agree. I am totally with that. I would just add also that mothers who are breastfeeding are already promoting their infant gut health, and then that this is an exciting and emergent area. Someone more than 10 years ago noted that the gut microbiota was like the missing organ that we didn’t know that we had in our...development.

I think that is a guiding concept and that we should recognize that the science is going to continue to emerge and develop and become more sophisticated, and we’ll have more and more of an armamentarium—[that] is a word you used and I agree with—and that we will have more options.

It seemed not long ago that the only option was [an] antibiotic and that we were overusing it. And now we have these more beneficial strategies to balance out the armamentarium, and that will continue to develop.

Even in the HMO world, for example, this is—we are starting with one or two, and we’ll continue to study and figure out what the right complement of things are for mothers who can’t breastfeed and what their babies need.

DR. MICHAEL CABANA: Well, as a pediatrician who does clinical trials, this has certainly reinforced for me why it’s so difficult to do some of these clinical trials because there are so many factors that affect the microbiome. And there are so many ways you can influence [it].

But simple things like what we choose to do, how we feed our infants, and what we choose not to do—for example, antibiotic exposure—and then using very carefully specific interventions like probiotics, there is a place for them as well too.

So it’s been a great discussion. Thanks.

DR. ARDYTHE MORROW: Thank you, Michael.

DR. PHILIP SHERMAN: Thank you.

DR. ARDYTHE MORROW: Thank you, Phil.

evolution of the intestinal microbiome

Documents