A review of the multifunctional benefits of prevalent HMOs and the implication for infant health

FEATURING: David R. Hill, PhD 

 TRANSCRIPT

 Amie: Human milk oligosaccharides are fascinating and here at Abbott Nutrition Health Institute we’re excited to continue to learn more about their benefits and how they impact infant health.

Amie: I'm Amie Heap with Abbott Nutrition Health Institute, and I've invited a Power of Nutrition Podcast regular, Dr. Karyn Wulf, the Abbott Medical Director and a practicing pediatrician, to today's discussion. We're also honored to host Dr. David Hill, Senior Research Scientist at Abbott to discuss his recent review publication “Multifunctional Benefits of Prevalent HMOs: Implications for Infant Health.”

Amie: Dr. Hill and Dr. Wulf, thanks for joining us. 

Dr. Hill: Thanks for the invitation. 

Dr. Wulf: Thank you for inviting me again.

Amie: I’ll note that Dr. Wulf will conduct today's interview and provide her insights as well. Dr. Wulf, the microphone is yours.

Dr. Wulf: Thank you, Amie. Dr Hill, before we start can you please tell us a little bit about yourself, like your current role, background, and how you came to focus your career on nutrition?

Dr Hill:  Thank you, Dr. Wulf. Well as Amie mentioned I am a Senior Research Scientist here at Abbott Nutrition. That means that my job is to conduct basic science research to understand how we can improve our products and deliver new and enhanced nutrition and other health benefits for our consumers. 

So, my training and background before I came to Abbott, absolutely informs my current work. I majored in Biology at Kent State University and after that I enrolled at Case Western Reserve University in Cleveland Ohio for my graduate work. While I was there, I studied the role of breastmilk carbohydrates in promoting intestinal development and immune defense in newborn infants. And I graduated with a PhD in the topic of Molecular Medicine in 2013. So I went on to do a postdoctoral fellowship Boston College where I worked on human milk oligosaccharides. After about a year in Boston I made my way to the University of Michigan and I spent nearly six years there developing model systems to study the role of the microbiome and nutrition in human gastrointestinal development. And along the way I’ve done some teaching in Immunology, Evolutionary Biology, and Statistics. 

So when I look back, each and every one of these experiences contributes in one way or another to the work that I do now. I’m excited to work in nutrition applications primarily because of the tremendous reach that nutrition has, and the potential to impact people’s lives. Millions of people use these products every day and so it’s a real privilege that I get to be one of the people works on them. If I can make improvements to a product that helps a family get off to a good start or helps somebody manage a chronic health condition then that’s is time well spent in my view.

Dr. Wulf: Thank you so much Dr. Hill, that’s quite an impressive pedigree. We’re excited to have you with us today. So let’s start at the beginning. First, what are HMOs and why are they so important for infant nutrition?

Dr Hill:  Yea so essentially all HMOs are modified forms of lactose, which is the main carbohydrate in milk. So collectively, all the HMOs together make up the 3rd most abundant component of breastmilk so they represent a very substantial investment of maternal resources, and really you’re diverting the calories contained in lactose into an alternate form that can’t be directly metabolized. So this implies that HMOs must have non-nutritional functions that are highly adaptive and beneficial to the developing infant. So let’s take 2’-fucosyllactose or 2’-FL I think it’s a good example of an HMO. In 2’-FL we have a lactose is modified by the addition of another carbohydrate called fucose that’s attached to a very specific position by specialized enzymes. On paper when you see the chemical structure it seems like a very small change but in practice it has a really dramatic effect on the function of the carbohydrate. So this modification takes a fairly standard carbohydrate, like lactose and, converts it into a highly specialized prebiotic that can support a healthy microbiome.  Preclinical research has shown that this 2’-FL reduces pathogen adhesion and interacts with immune cells.  There’s also evidence from breastfed infants that 2’FL in human milk even supports cognitive development in ways that would be different from lactose or fucose alone. 

Dr. Wulf: That’s very interesting – Could you expand upon the term core HMO’s and are there any HMO’s that are more abundant than other in human milk?  

Dr Hill: That is a really great question, and one that I think scientists will continue to chip away at for some time. We approached this in the paper with a figure that summarizes the evidence for different types of benefits for each of 5 major HMOs. And I think what comes across in that figure is that some benefits seem to apply to all HMOs while other benefits may be specific to individual structures. This is at least in part due to the emerging nature of this science right – there’s many HMO structures that exist in nature that we haven’t yet been able to study in the labratory. For example, all 5 of the HMOs that we looked at had been shown to promote the growth of beneficial microbes. The specific nature of this benefit varied a bit from one structure to another, for example with some microbes seem to prefer fucosylated HMOs or sialyated HMOs, but generally all HMOs seem to have prebiotic potential. In other areas like intestinal motility, for example, in animal models that have examined this, only fucosylated HMOs have been shown to have any benefit. Likewise, sialylated HMOs have been more widely studied for their effects on brain development relative to say acetylated HMOs. So ss the years go by continuing research begins to pile up I think we’ll develop a more complete picture of both the specific and the common functions of different HMO structures. And I think what we’ll see in the end is that many HMOs serve as prebiotics, but that certain types of structures will be more potent in delivering certain immune or other developmental benefits.

Dr. Wulf:  That’s very interesting. Could you expand upon the term core HMOs and are there any HMO’s that are more abundant than others in Human Milk?

Dr Hill: Right so, In writing a review paper, you know I didn’t want to simply recite just a litany a book report of scientific findings but to also produce some new interpretation of the current evidence that might be useful to other researchers in this field. So the idea of Core HMOs was to resolve a key question in pediatric nutrition. So we know that HMO composition is highly variable from one mother to the next, yet all breastfed babies tend to do very well regardless of mom’s unique HMO pool. No one type of breastmilk seems to be obviously better than another. And so as long as there remains a need for infant formula, we really should strive to recapitulate the HMO benefits that are delivered in breastmilk. But which HMOs you know, should be a priority for fortification in infant formulas? How do you decide which HMOs to add to formula? And so we proposed that researchers should aim to define the most important functions of HMOs and then compose formula fortification strategies that address all of those essential functional benefits. So then a set of HMOs that delivers on all of the benefits of HMOs seen in breastmilk could be called “Core HMOs”. We proposed as a starting point a set of 5 HMOs that represent all 3 major classes so, fucosylated, sialylated, and acetylated HMOs and these all can be readily produced for formula supplementation, they’re present in most breastmilk, and they may have the potential to deliver benefits in the areas of digestive health, immunity, and cognition.

Dr. Wulf: So you mentioned that HMOs are a prebiotic, can you tell us a little more about the concept of prebiotics and what the role of HMOs are as a prebiotic? .

Dr Hill:  Sure, so there’s really two key features that make something a prebiotic. First, it’s something that’s utilized by a microbe that confers a health benefit and second, that that structure is selective for that microbe. So, we can take the HMO 2’-FL as an example. So, we already talked about how 2’-FL is two very common carbohydrates, fucose and lactose, put together in a unique way. And so, as it turns out, only a few bacteria have actually evolved the enzymes that are needed to utilize fucose and lactose put together in this structure, and nearly all the bacterias that know how to do this are beneficial members of the infant microbiota. So, what does that mean in practice? Well it means that if you’re a Bifidobacteria one of these beneficial gut microbes, floating around in the developing infant gastrointestinal tract, you now have this one particular nutrient resource all to yourself. – so you don’t have to share or compete with anybody else, not even the host. And this means that those beneficial bacteria have a very significant advantage in this highly competitive environment and as a result they’ll grow very quickly and become permanently established in that developing ecosystem. 

Dr. Wulf: So Dr. Hill, in your review you discuss several essential functions of HMOs, can you elaborate more on how HMOs impact digestive health? 

Dr Hill:  Yea, Absolutely. So, HMOs deliver both direct and indirect benefits for digestive health. And we’ve already talked a bit about the indirect benefits to digestive health: so they serve as important prebiotics that influence the assembly of a microbial community in the developing gut. And then those microbes go on to perform a whole host of beneficial functions like, supporting the immune system, processing dietary nutrients, and generating beneficial metabolites that can even circulate throughout the body. So those are the indirect benefits. But HMOs also have direct benefits on gut function that are not necessarily dependent on the microbiota. So several HMOs can stimulate production of mucins that protect the intestinal surface and strengthen the bonds between the cells that line the digestive tract. There’s also research done in mice that suggests that fucosylated HMOs in particular can help to normalize the intensity and frequency of intestinal contractions in the gut, which might go a long way towards improving comfort and satiety for the infant But this is based on animal models. 

Dr. Wulf: Absolutely fascinating. In your review, you also mention the potential role of HMOs for immune health. Can you tell us a little bit more about that?

Dr Hill:  Yea, This is a really big topic and an area of research that’s rapidly evolving, but, in general there are two big ideas though that I would like to highlight: receptor decoy activity and shaping the immune response. So, The receptor decoy hypothesis proposes that HMOs mimic the structures that pathogens look for in a potential host cell. So Instead of attaching to its intended receptor on a host cell and causing infection, the pathogen binds to one or more HMOs and drifts away harmlessly without establishing an infection. And this fits with the epidemiological evidence showing that higher levels of HMO in breastmilk are associated with a reduced risk of infection. 

So at some point researchers (including scientists here at Abbott) realized that, while the receptor decoy hypothesis was compelling and well supported, there were more immune benefits to HMOs that couldn’t be explained by receptor decoy activity alone. So we now know that HMOs can interact directly with immune cells in the gut and elsewhere and that these interactions change the behavior of the immune cells. A good example is a study done by my colleague Karen Goehring and our team here who looked at how immune cells from babies who were breastfed or given a formula containing 2’-FL responded to challenges in the laboratory compared to immune cells from babies who received formula without HMO. So we saw that immune cells from babies receiving breastmilk or 2’-FL containing formula tended to have a more measured and less inflammatory response to common viruses. So that suggests I think that HMOs may actually contribute to an environment that shapes the programming of the developing immune system.

Dr. Wulf: So in addition to the gastrointestinal benefits and the immune health development, your paper also mentions the role of HMO in the management and reducing the risk of allergy.  Could you talk a little more about what you studied in this area? 

Dr Hill:  Yea so This is another emerging area of research and I think it builds off of the way the HMO shapes the immune response in infancy. And the way we put it in the paper is that the first two years of life represent a critical window for immune education. You have your first exposure to microoorganisms the introduction of foods and these present challenges to the developing immune system. So there’s now research to suggest that the way HMOs shape the immune response in infancy might change the developmental trajectory in ways that are beneficial, so maybe promoting tolerance to dietary antigens or reducing excessive inflammation. So preclinical work shows that HMO feeding reduces diet induced anaphylaxis in mice. And there have been some incidental findings of reduced eczema in infants using HMO fortified formula compared to formula without HMO. It is kind of inherently difficult to study the effects of HMOs on allergy development later in life simply because of the time it takes to start to observe allergies in infants. But now that HMOs are becoming increasingly available in infant formula this is an area where I would expect to see exciting work in the years ahead.

Dr. Wulf: How do HMOs impact cognitive development?

Dr Hill: Yes so epidemiologists have examined levels of HMOs in breastmilk and there’s now several studies that have demonstrated that HMOs, and sialylated HMOs in particular, are associated with improved language skills, cognitive skills, and even motor skills out to 12,  18, or 24 months of age. So similar to the digestive health benefits, I think that there are likely both direct and indirect mechanisms that contribute to these findings. So a theme that keeps coming up is that HMOs are highly effective prebiotics, and the microbial community that develops as a result of the presence of HMOs produces all of these beneficial metabolites that circulate throughout the body. It doesn’t appear that HMOs themselves are absorbed by the brain but we have some evidence that microbes that consume HMOs turn those HMOs into other structures that can cross into the central nervous system. On the other hand if we think about possible direct evidence and direct mechanisms of action there is some evidence that HMOs may stimulate the vagus nerve, which is this direct connection between the enteric nervous system and the central nervous system. So a former colleague of mine, Dr. Enrique Vazquez and his team in Granada showed that mice exhibit improved learning following consumption of 2’-FL, but this benefit disappears entirely in the absence of that neural connection between the gut and the brain.

Dr. Wulf: So are you saying that if the vegus nerve is cut you no longer see those benefits?

Dr Hill: That’s exactly right. It was really a very clean experiment and very strong evidence for the role of the vegus nerve.  

Dr. Wulf: As you’re going through this work, and you’ve made your life’s work looking at HMOs and these human milk oligosaccharides, and other nutrition impact in infants, is there anything that still surprises you as your studying HMOs?  

Dr Hill: Yea I think you know to work in science is you’re constantly surprised. And if we knew how everything worked then we wouldn’t need to do all these experiments and write all these papers. Working on HMOs, I am constantly struck by the degree of interconnectedness in the system. So, HMOs support these good microbes, but they also help the immune system to tolerate those microbes. The microbes in turn support digestion, and healthy development of the immune system and even cognition. It’s this mutually beneficial relationship where cooperation and the synchronized effort of the infant, mom, and microbes produces this result where everyone flourishes.

Dr. Wulf: It certainly seems that human milk was evolved for a very specific purpose and you’re just beginning to unravel some of that important purpose. 

Dr Hill: Yea absolutely, we have so much work to do to really learn from the system and you know as a scientist here at Abbott it’s again just a privilege to be able to work on something so interesting but also so relevant to so many people’s lives. Yea I’m really excited about the progress we’ll make in the years to come. 

Dr. Wulf: Excellent, well Dr Hill, thank you so very much for your time today, and for helping us to build awareness and better understand this important topic. 

Dr Hill: Thank you very much.

Amie: Thank you both.  

Amie: Before we close, Dr. Wulf, based on the information Dr. Hill shared and your role as a Pediatrician, in what ways do you think clinicians can take this information and apply it to practice?

Dr. Wulf: <<Reply>>>> That’s an interesting question Amie, Pediatricians know that human milk is the gold standard for infant nutrition, and we certainly encourage breast feeding whenever possible. And it’s been a little while since I was in medical school,l but I remember learning in medical school that breast milk contains factors that support the infant’s immune system and cognitive development, but I didn’t receive a lot of education on what all of these factors in human milk actually were, or how exactly they worked. This research on human milk oligosaccharides is truly fascinating – Dr. Hill did a wonderful job highlighting the specific mechanisms of action of HMOs. And I think this just reinforces how important human milk is to infant nutrition, and how scientific advances can bring some of these human milk benefits to infant formulas for those babies who can’t get human milk. 

Amie:  Thank you Dr. Wulf and Dr. Hill for your insights with us today.

Amie: For our listeners. If you’re looking for more podcasts, we have dozens across a variety of different nutrition science topics, and you can find them on ANHI.org by clicking RESOURCES at the top of the page, then PODCASTS & VIDEOS. 

As I said in the introduction to this recording, HMOs are a favorite topic among the ANHI team, and we have a host of other HMO resources on our site. In fact, we also created a short four-minute video summarizing this review. Simply visit anhi.org, click RESOURCES at the top of the page, click PODCASTS AND VIDEOS, and scroll down or search to find the video titled, Multifunctional Benefits of Prevalent HMOs: Implications for Infant Health.

Thanks for listening today. Stay healthy and safe.