Victoria Niklas, MD is the former VP of Innovation and Medical Communication at Prolacta. She is also a Professor of Pediatrics at the UCLA David Geffen School of Medicine and a practicing neonatologist at the Olive View UCLA Medical Center. She has published research in the area of neonatal gastrointestinal immunology and the role of breastmilk in reducing infections and necrotizing enterocolitis in premature infants.
The full potential of human milk has yet to be realized. Speaking of Human Milk provides healthcare professionals with information on the latest science and clinical research. Each episode features an interview with a thought leader passionate about uncovering the unknown potential of human milk or better understanding the science of neonatal nutrition.
In addition to hosting Speaking of Human Milk, Keli Hawthorne is the director for clinical research for the Department of Pediatrics at the University of Texas Austin, Dell Medical School. In her current role, she trains faculty and staff on effectively executing high-quality protocols for research. She has authored more than 40 peer-reviewed publications on neonatal nutrition.
Keli Hawthorne (KH): Hi y’all, welcome to Speaking of Human Milk, where we give you bitesize episodes on the latest science and innovation surrounding human milk. This podcast is brought to you by Prolacta Bioscience, a company dedicated to Advancing the Science of Human Milk. I’m your host Registered Dietitian Keli Hawthorne. Today, we will be speaking with Dr. Victoria Niklas, a practicing neonatologist and Vice President of Innovation and Medical Communication at Prolacta Bioscience to discuss the topic of human milk oligosaccharides, also known as HMOs, and what researchers are uncovering about how this family of sugars benefit preterm infants fed human milk. Along with working at Prolacta and putting in hours as a neonatologist, Dr. Niklas is also Professor of Pediatrics at UCLA David Geffen School of Medicine in Los Angeles. You wear a lot of hats Dr. Niklas and we are so excited that you were able to take the time to speak with us about HMOs.
Victoria Niklas (VN): I’m happy to be speaking with you Keli!
KH: Let’s start with the basics: What are Human Milk Oligosaccharides?
VN: Thank you Keli. I will start by emphasizing for our listeners that human milk is much more than just nutrition for baby. In fact, I refer to human milk as nature’s best example of a functional food—a brilliant combination of macronutrients, optimized for baby’s growth and development including lactose, proteins and fats and of course micronutrients, but a complete matrix, or even a tissue containing immune cells, enzymes, growth factors and a diverse array of bioactive substances.
Taken together, the matrix of human milk accounts for the significant health benefits observed in preterm infants fed an exclusive human milk diet and, in fact, all newborns that receive human milk. Taken together then, we have to think about human milk not only as nutrition, but also as medicine. Now, among the hundreds of different bioactive factors in human milk, human milk oligosaccharides, or HMOs as they are referred to for short, are a family of structurally diverse sugars or glycans that are highly abundant in, and unique to human milk. In fact, over 200 different HMOs have been identified in human breastmilk.
The spectrum and concentration of HMOs in any individual mother’s milk depends on a variety of factors, many of which are still coming to light, including the mother’s genetics, her diet, her geographic location in the world, the timing after birth are all critical determinants to the mother’s ability to synthesize certain classes of HMOs. So, the concentration and spectrum of HMOs in breastmilk depend on many factors. But Keli, here is fascinating thing, HMOs are the third-most abundant component, following the macronutrients lactose and lipids, in human milk and in fact, HMOs are more abundant than protein!
KH: You said, 200 different HMOs are possible? Sounds complicated, how are they different from each other and why so many different structures?
VN: Yes, at first glance, it sounds complicated, but the basic structure across HMOs is similar. Remember that lactose is the predominant carbohydrate source in breastmilk. Lactose is made up of two building blocks, glucose and galactose. Well, as it turns out, that lactose is in the backbone of all HMOs, but it is the modifications of that lactose backbone that give individual oligosaccharides their unique features. For example, the orientation of the chemical bonds between disaccharide differ as well as the side groups that are added including modifications by the enzymatic addition of acetylglucosamine, fucose, or sialic acid groups. The net result is the wide spectrum of HMOs characteristic of human milk. Although too complicated to discuss today, oligosaccharides range from the very simple and small in size, like 2’ fucoslyllactose or 2FL for short, to the very complex and large, like disialyllacto-N-tetraose (DSLNT) which is one of the largest. So, very different structures are possible. The relationship between the different structures and biological function of HMOs and their contribution to infant health are now just coming to light.
KH: So what do we know about the main role of HMOs concerning infant health?
VN: Scientists recognized that the bacteria in the stool of infants fed breastmilk were different that the stool of infants fed formula. In particular, the stool of breast-fed infants had abundant bacteria, which under the microscope had a unique “bifid” appearance.1
This first led to the proposal that breastmilk contained “bifidus factors” or substances that supported the growth of these bacteria, which we now realize are a large family of Bifidobacterium species important in intestinal health. Although, it was only initially proposed that bifidus-family bacteria were beneficial to gut health, there is now overwhelming data from animal models, microbiological experiments, as well as studies in infants and adults that support the beneficial role of these bacteria in intestinal health. One of the most well-studied functions of HMOs is their role in the growth of beneficial bacteria, an activity broadly known as prebiotic function.2
Prebiotics are substances that support the growth of not only Bifidobacterium, but other commensal or beneficial bacteria such as Lactobacillus species, in the infant’s gut but in adults as well. Prebiotics help the good bacteria in the gut flourish and thrive, counteracting the growth of harmful bacteria. Overall, HMOs result in the establishment of a healthy infant gut microbiota after birth and throughout infancy. This healthy gut microbiome has multiple health benefits, including a reduction in the risk of blood stream infections2 and necrotizing enterocolitis3 as well as have other benefits on neurodevelopment.4
HMOs may in fact be the “secret ingredient” that gives human milk its myriad of health advantages well beyond nutrition!
KH: I am often asked what the difference is between “prebiotics and probiotics.” My answer is that PRO-biotics – with an “O” refers to the health benefits provided by an Organism to the human host – or the beneficial bacterial strain providing a health benefit. And that PRE-biotics – with an “E,” refers to the food that one of these probiotic strains Eats – to support its growth in the baby’s intestine. VN: Oh, that’s a great way to help people remember the difference. There is one other – biotic category we should make our listeners aware of, and that is POST-biotics. Post-biotics are the chemicals that probiotic bacteria synthesize and secrete in the gut that mediate probiotics health benefits that are stimulated by the HMOs or prebiotics. Postbiotics include a family of short chain fatty acids, like acetate, butyrate, and propionic acid that exert effects on the gut epithelium, immune cells, or act in distant sites in the body resulting in optimal outcomes. KH: Besides working as a prebiotic to provide a fuel source to the good bacteria in a baby’s gut, what other functions do HMOs have? VH: Today, we realize that HMOs are far more than just “food for bugs.” HMOs function in several ways to prevent infections and to enhance immune function. HMOs resemble glycan receptors that are used by pathogens to infect the epithelial cells lining the gut and may block the binding of toxins to intestinal cells in the gut through a similar mechanism. In this sense, HMOs act as “decoy receptors,” blocking infections by bacteria and viruses and the action of toxins. HMOs also play an essential role in the maturation of the newborn’s immune system by interacting with various immune cells in the gut and in systemic circulation. And finally, some studies indicate that sialylated HMOs may influence neurodevelopment by functioning as a supplementary source of sialic acid, which is critical for brain development.5,6
KH: Wow, no wonder there is so much interest and research in HMOs. So now that scientists know more about how HMOs function, what are they finding out about how HMOs, or I suppose I could ask how breastmilk feeding, the only natural source for a full spectrum of HMOs, impact a baby’s health and in particular impact the health of an extremely premature infant?
VN: Well, as we highlighted at the beginning of our session, we know that human milk feeding in general and an exclusive human milk diet specifically, which is defined as mother’s milk or donor milk combined with a fortifier made from 100% human milk, results in statistically significant decreases in necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), late-onset sepsis, significant decreases in overall mortality and improved neurodevelopmental outcomes in infants weighing between 500 and 1250 grams. I believe in your previous episode, Dr. Martin Lee reviewed the exciting data behind the clinical benefits of an EHMD.
Based on what we understand about the negative health risks of a disordered gut microbiome, or dysbiosis on infant health, it is more likely than not, that many of the positive health outcomes are related to the collective impact of HMOs shaping a healthy gut microbiome. As dysbiosis is more common in infants fed a cow milk-based diet, which among other things may irritate the intestinal lining, promote the growth of pathogenic bacteria, resulting in increased gut permeability, leading to bacterial invasion and the proinflammatory cascade characteristic of NEC, whereas HMOs have the potential to prevent dysbiosis. The action of HMOs in human milk may therefore be vital in reducing dysbiosis and hence, the risk of NEC, sepsis and other proinflammatory conditions like ROP, CLD and poor neurodevelopmental outcomes.
KH: So do all 200 HMOs participate in preventing dysbiosis or health outcomes like NEC? And is it important to look more specifically at individual HMOs?
VN: Keli this is a very important question and one that is difficult to study. But if we begin with the overwhelming clinical evidence that supports optimal health outcomes in infants fed human milk in general and an EHMD specifically, we can certainly surmise the benefits of a wide spectrum of HMOs and optimal health outcomes. This is supported by recent publications by Dr. Lars Bode7 and in a separate study by Dr. Thomas Abrahamasson.8
Both investigators independently demonstrated that mother’s whose breast milk had low diversity or deficiency of certain HMOs had preterm infants at greater risk for NEC and infections. Numerous animal models and in vitro studies also support these results. Out of all those 200 different types of HMOs that have been identified, the spectrum of HMOs in an individual mother’s milk can vary with a strong association with genetic factors, as well as across the stages of lactation, diet, and time postpartum.
Genetic factors including the ability of the mother to fucosylate, which is deficient in mother’s that lack the FUT2 gene or synthesize a particular linkage to the lactose backbone have notable differences in their HMO profile. Prolacta’s donor milk products are made from donor milk collected from 100 or more donors hence, all products contain a wide spectrum of HMOs, thereby maximizing the various health benefits of HMOs, including those important in establishing a healthy microbiome.
KH: What about a NICU mom who is pumping her milk? Are HMOs damaged or destroyed when a mother freezes and then thaws her expressed milk?
VN: No, as best we and others can tell, HMOs are able to withstand the freeze-and-thaw process that many mothers of NICU babies utilize.
KH: And are HMOs affected by the pasteurization process that donor human milk goes through?
VN: This is an important question and comes into play when mother’s own milk is not available or in short supply, and donor milk is the only next best option. Pasteurization is a mandatory process used (among others’ donor and process specific steps and measures) to ensure a safe supply of donor human milk. Pasteurization, as I am sure our listeners are aware, is a safety measure used to reduce bacteria in human milk that if overgrown would pose a significant health risk to infants. While this benefit of pasteurization outweighs its downsides (also reduces beneficial bacteria found in breastmilk) our work and that of others have shown the HMOs withstand pasteurization so whether a baby gets mother’s milk or donor human milk, the HMOs are unaffected.
KH: Although HMOs have human milk in their name, it’s my understanding that other lactating mammals synthesize oligosaccharides.
VN: Yes, other lactating mammals synthesize oligosaccharides. However, when compared to human milk, they are often present at much lower concentrations and the chemical diversity is reduced or very different. For example, cow’s milk does contain HMOs but at concentrations 100 fold lower than human milk and only a subset of the diverse structures present in human milk.
KH: With all the research currently being done on HMOs, where do you see the science taking us in the future? VN: A great deal remains to be discovered about the precise functions and potential clinical applications of HMOs. One exciting direction may be to discover the lifelong benefits of HMOs, and that their benefits extend beyond infancy into adulthood and across the lifespan. HMOs may one day have a role in treatment of diseases where dysbiosis plays an central role, such as inflammatory bowel disease, diabetes and obesity. Currently, however, our best science reflects that preterm infants born weighing less than 1250 grams should most certainly always receive an HMO-rich exclusive human milk diet.
KH: Thanks, so much Dr. Niklas for your time today discussing HMOs. Do you have anything else that you want to make sure our listeners know about?
VN: Given the spectrum of HMOs in human milk, as well as the myriad factors that support immunity, promote optimal metabolism and growth, it is very unlikely that a few, structurally limited oligosaccharides added to cow milk-based fortifiers or cow milk-derived formulas are a substitute for the extended health benefits afforded by the wide spectrum of HMOs found in Prolacta’s EHMD in preterm infants. Where there is only one chance for the best outcome, any other choice, is not the right choice.
KH: Thanks again for this very informative discussion on HMOs. For our listeners, links to information discussed will be available in the show notes and we look forward to bringing you our future topics on the science of human milk.