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Human milk is a rich cocktail of nutrients, antibodies and other molecules that nourish babies, guide the development of their gut microbiota, and protect them from infections. Now, a new study reveals that another component of maternal milk may play a key role in infant gut development and immunity: human milk-derived extracellular vesicles (HMEVs) [1]. 

Extracellular vesicles are little membrane-encased capsules of proteins, microRNAs, and other molecules that play many important roles in the human body. Although they’re common in milk, their role is one that “researchers have only scratched the surface of understanding,” says epidemiologist Ardythe Morrow of the University of Cincinnati. “Extracellular vesicles have been studied in human milk before, but there’s a really limited literature.”  

Although antibodies in maternal milk are well known to confer immune protection, this shield is relatively short-lived and passive – and antibodies alone don’t completely explain the long-term advantages of mother’s milk. “We know that breastfeeding has long term benefits and is involved with epigenetic modulation, so we suspected that extracellular vesicles are a significant player in milk,” said pediatrician and immunologist Somchai Chutipongtanate, who led the new study. 

Morrow and Chutipongtanate were curious to learn whether HMEVs might help protect infants from viral infections such as influenza. But they ran into a hurdle when they launched their study in early 2021, as, due to the COVID-19 pandemic, rates of flu infections were unusually low. The team turned their sights to SARS-CoV2 instead. 

The researchers used human milk samples and data from a cohort of mothers who had experienced COVID-19 infections during pregnancy from mid-2021 to early 2022 and compared them to COVID-free participants. In the third trimester of pregnancy, the researchers confirmed the participants’ history of COVID-19 infections by checking for the presence of antiviral antibodies in serum, a well-established marker of recent infection. 

Researchers collected milk samples from nine women who had experienced COVID-19 infections and six control participants at two weeks of lactation (about 10 days postpartum). None of the participants were vaccinated against COVID-19. The researchers isolated HMEVs from milk and compared the vesicles’ cargo in the two groups. 

The team found no significant differences in the microRNA content of HMEVs from the control group and participants who had experienced COVID-19 infections, suggesting the microRNA payload of vesicles is carefully controlled by maternal cells. “At first we expected to see differential expression of microRNAs between the groups, but that was not the case,” Chutipongtanate said. “That might indicate that microRNA packaging in HMEVs is highly regulated, so that the long-term benefits of EVs in human milk are not changed after an infection.” 

The team found 52 proteins that significantly differed from vesicles from mothers with past COVID-19 infections compared to those from uninfected mothers. Based on their sequence and potential functions, these proteins are likely involved in mucosal epithelial development and immune functions. Some also showed the potential to modulate B-cell activation and the humoral immune response against bacteria. “What we are seeing is the effects of [an infection] that would have happened anywhere from a month prior to several months prior,” Morrow said. “It’s even more remarkable that there’s a durability that the proteins are exhibiting.” 

Unlike antibodies or secreted proteins, vesicles are effectively tiny packages formed directly from cells. As such, extracellular vesicles are a “really important conveyor of cargo and messages from maternal cells to infant cells,” Morrow said, with the “potential to have really profound immediate and long-term effects.” 

Still, there’s much to be discovered about HMEVs. The authors added that further studies are needed to understand whether maternal vaccination or the timing of an infection might alter microRNA levels in HMEVs. The precise role of differently expressed proteins also needs further study. Nonetheless, the data highlight the multi-dimensional nature of protection that maternal milk provides an infant, Morrow said. “It’s more than just blocking a virus,” she said. “What I’d like people to understand is that mother’s milk is providing multiple lines of defense and communicating how to handle the environment through milk to the baby.” 

References

1. Chutipongtanate S, Kongsomros S, Cetinkaya H, Zhang X, Kuhnell D, Benefield D, Haffey WD, Wyder MA, Kwatra G, Conrey SC, Burrell AR. Prenatal SARS-CoV-2 Infection Alters Human Milk-Derived Extracellular Vesicles. Cells. 2025 Feb 15;14(4):284.

A combination of human milk oligosaccharides (HMOs) may significantly modulate the microbiome, according to a recent study of gut bacteria collected from young children and grown in a dish [1]. However, adding just one synthetic HMO – specifically, 2-fucosyllactose (2’FL), which is most often added to infant formula today [2] – has a substantially smaller effect on the microbiome. 

Human milk contains more than 200 types of different HMOs. Human cells cannot digest HMOs, and researchers believe they primarily support the infant’s gut microbiome [3].

Scientists studying how bacteria in the microbiome utilize HMOs have generally focused on a group of bacteria called bifidobacteria, which are known to be probiotic [4]. But here, the team set out to explore HMOs’ effects on a much larger swathe of gut bacteria. “No one has really thought much about other microbes in the gut, because they are kind of hard to culture,” says Emma Allen-Vercoe, a simicrobiologist and microbiome researcher at the University of Guelph who led the work. “But the paper actually found that there is an enormous diversity of microbes that can utilize human milk oligosaccharides – and that they all do it in slightly different ways.” 

The researchers studied stool samples from 7 children 18-24 months old who were part of the DIABIMMUNE birth cohort. The cohort follows children from infancy through adolescence to determine how exposure to microorganisms in early childhood affects the risk of developing Type 1 diabetes. Although Allen-Vercoe and her colleagues initially aimed to explore the link between HMOs and diabetes, they ended up focusing more narrowly on how HMOs affect bacteria cultured from the children’s stool samples. 

The first step was to culture a diverse population of bacteria from each sample. Because bacterial species from the gut microbiome tend to be finicky, they used a specialized bioreactor called the RoboGut, which is designed to mimic conditions that the bacteria would experience naturally [5]. They were able to culture more than 400 species, says Simone Renwick, a postdoctoral researcher at the Mother-Milk-Infant Center of Research Excellence at the University of California, Davis and the study’s first author. 

Next, the researchers added either a single HMO, synthetic 2’FL, or a mixture of 150-200 pooled HMOs, taken from milk samples of several women, to the bacterial cultures that were derived from the children’s stool. They compared the changes they observed to control cultures to which nothing was added.

Cultures to which they added the pooled HMOs quickly changed their microbial composition. Several types of bacteria expanded in number while others shrank. In contrast, cultures to which they added 2’FL barely changed, remaining similar to the control cultures. 

In subsequent experiments, the team profiled the metabolic activity that occurred in response to adding either the pooled HMOs or the 2’FL, measuring how bacteria under each set of conditions broke down the HMOs, which are complex sugars. They quantified 47 different metabolites – some of which were upregulated and some of which were suppressed – when the pooled HMOs were added. However, they observed almost no change in metabolite composition after adding 2’FL. Only the bacterial community of one child noticeably shifted its metabolic activity after the single HMO was added. 

The researchers tested how the cultures metabolized 19 of the most common and abundant HMOs produced by women and found that the cultured bacteria could make metabolic use of all of them. 

Finally, the researchers probed how each of 330 different strains of bacteria in the samples, which belonged to 157 different species, changed its growth pattern in response to the addition of HMOs. Overall, many different types of bacteria utilized HMOs and there was a high degree of individual differences among infants in which species were able to do so. 

The study used microbiome samples from a just small number of children, and the researchers only added the HMOs to the cultures once.  Nonetheless, the findings suggest that HMOs likely have an enormous effect on shaping a young child’s microbiome in still largely unknown ways, says Renwick. They also point to the need for exploring a wide range of HMOs beyond 2’FL.  

“Our research really underscores the importance of providing infants with a diversity of HMO structures,” says Renwick. “And I think there’s more research on this now, and more interest, than ever before.”

References

1. Renwick S, Furst A, Knip M; DIABIMMUNE Study Group; Bode L, Danska JS, Allen-Vercoe E. Modulating the developing gut microbiota with 2′-fucosyllactose and pooled human milk oligosaccharides. Microbiome. 2025. 13(1):44. 
2. Vandenplas Y, Berger B, Carnielli VP, Ksiazyk J, Lagström H, Sanchez Luna M, Migacheva N, Mosselmans JM, Picaud JC, Possner M, Singhal A, Wabitsch M. Human Milk Oligosaccharides: 2′-Fucosyllactose (2′-FL) and Lacto-N-Neotetraose (LNnT) in Infant Formula. Nutrients. 2018;10(9):1161.  
3. Walsh C, Lane JA, van Sinderen D, Hickey RM. Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health. J Funct Foods.2020. 72:104074. 
4. 1: O’Callaghan A, van Sinderen D. Bifidobacteria and Their Role as Members of the Human Gut Microbiota. Front Microbiol. 2016;7:925.
5. Gianetto-Hill CM, Vancuren SJ, Daisley B, Renwick S, Wilde J, Schroeter K, Daigneault MC, Allen-Vercoe E. The Robogut: A Bioreactor Model of the Human Colon for Evaluation of Gut Microbial Community Ecology and Function. Curr Protoc. 2023;3(4):e737.

In 2023, approximately 32 million people worldwide were estimated to be living with Alzheimer’s disease [1]. There are currently no pharmacological treatments for delaying or reversing disease progression. Instead, researchers have turned to food, or “nutraceuticals,” as a potential therapeutic option for prevention. 

In a new study published in the American Journal of Clinical Nutrition, researchers at Wuhan University in China found that whey protein powder containing milk fat globule membrane (MFGM), vitamins B6 and B12, and taurine improved cognitive function in older adults with minor cognitive impairment [2]. The data suggest that this whey protein powder and the additional nutrients may prevent cognitive decline. 

In this 12-month, randomized, double-blind, placebo-controlled study, adults over 55 years of age with mild cognitive impairment received whey protein powder or a placebo daily. The researchers evaluated the participants’ cognitive function at 0, 6, and 12 months using various tests that assessed short- and long-term memory, orientation, attention, language, and visuospatial and executive functioning [2]. 

Participants who consumed whey protein powder had significantly improved cognitive function after 12 months compared to the placebo group. Interestingly, the treatment group also had improved muscle mass, suggesting that whey protein powder can help combat muscle loss in older adults [2].

The researchers noted that they were not surprised by these results. Their whey protein powder consisted of vitamins B6 and B12, which promote phospholipid synthesis [3]; taurine, which increases neurogenesis and synaptic function [4]; and MFGM, which supports neurodevelopment and cognitive function by providing a rich source of phospholipids to the brain [5]. However, the researchers did not directly test the mechanism of action of their whey protein powder, so it is unclear how it biochemically affects the brain.

Additional studies are needed to support these findings. A longer intervention period would be beneficial. In addition, the authors proposed performing additional cognitive tests and collecting more objective data, such as blood markers or brain scans. 

Regardless, these data are consistent with previous studies in both mice and humans [5]. Mice genetically predisposed to Alzheimer’s disease perform better on learning and memory tests, have lower levels of amyloid beta and tau proteins, and have decreased inflammation after consuming chow supplemented with whey protein powder and MFGM for 3 months. Similarly, in humans, a recent study has shown that the consumption of buttermilk enriched with MFGM led to better short- and long-term memory in female adults aged 65 years or older compared to the control, skim milk [6].

MFGM has been extensively studied over the years because it is a rich source of phospholipids, and it is abundant in industrial byproducts, such as buttermilk and cheese whey [5]. It is often added as a supplement in infant formula to support the baby’s immune system and neurodevelopment. 

Javier Fontecha, a researcher at the Institute of Food Science Research in Spain and an outside expert on this subject, says that this knowledge should be used for the development of similar formulas, but for the senior population. This “may have an impact on slowing cognitive decline in older people.”

This research adds to the growing body of knowledge that food and nutritional supplements can have a significant impact on cognitive function [2].

“Considering that there is no pharmacological solution to prevent or avoid cognitive decline during aging,” he adds, “the availability of a well-characterized dietary supplement with sufficient support and science evidence to prevent this pathology would be very important.” 

References

1. Gustavsson A, Norton N, Fast T, Frölich L, Georges J, Holzapfel D, et al. Global estimates on the number of persons across the alzheimer’s disease continuum. Alzheimer’s & Dementia. 2023;19(2):658-70.
2. Li F, He R, Yue Z, Yi H, Lu L, Zhang L, et al. Effect of a 12-mo intervention with whey protein powder on cognitive function in older adults with mild cognitive impairment: A randomized controlled trial. Am J Clin Nutr. 2025 Feb;121(2):256-64.
3. van Wijk N, Hageman R, Kamphuis P, Broersen L, Sijben J. Specific nutrients to increase availability of components involved in neuronal membrane synthesis. Alzheimer’s & Dementia. 2011 2011/07/01/;7(4, Supplement):S665-S6.
4. Chen C, Xia S, He J, Lu G, Xie Z, Han H. Roles of taurine in cognitive function of physiology, pathologies and toxication. Life Sciences. 2019 2019/08/15/;231:116584.
5. Luque-Uria A, Calvo MV, Visioli F, Fontecha J. Milk fat globule membrane and its polar lipids: Reviewing preclinical and clinical trials on cognition. Food Funct. 2024 Jul 1;15(13):6783-97.
6. V. Calvo M, Loria Kohen V, Díaz-Mardomingo C, García-Herranz S, Baliyan S, Tomé-Carneiro J, et al. Milk fat globule membrane-enriched milk improves episodic memory: A randomized, parallel, double-blind, placebo-controlled trial in older adults. J Funct Foods. 2023;111.

A healthy sugar might sound like an oxymoron, but not all sugars were created equal. The milk sugar lactose evolved as an energy source for infant mammals, and many of its attributes that benefit infants also extend to adult consumers. Although lactose is probably best known for causing digestive issues in some adults, growing evidence [1-3] for health benefits of moderate lactose consumption—even in individuals who might be genetically predisposed to lactose intolerance—suggests it could be time to rebrand milk’s main carbohydrate as a nutritional good guy rather than a digestive villain. 

Origin Story

Lactose is a disaccharide exclusively made by mammary glands. During milk synthesis, the milk protein alpha-lactalbumin acts as an enzyme and binds together one glucose molecule and one galactose molecule. Mammalian milk expert Olav Oftedal proposed two evolutionary advantages that may explain why mammary glands synthesize lactose rather than passing along glucose and galactose as monosaccharides [4,5]. First, more is better: one lactose molecule has half the osmotic concentration of two monosaccharides. As a result, lactose exerts less osmotic pressure per unit mass than glucose (or galactose) and most mammalian milks end up having the same ion concentration as the mother’s plasma. This supports optimal milk production. Second, it’s good to be unique: glucose is prevalent in nature, as are the bacteria that feast on glucose. Only bacteria that evolved the ability to digest lactose could colonize milk. Synthesizing a novel sugar may have protected the mammary gland and infant digestive tract from a large number of microbes. 

The very attributes that made lactose evolutionarily advantageous for ancestral mammalian mothers and infants—being complex and novel—are also what make many modern-day adults avoid milk and other dairy foods. Lactose needs to be broken down into its simple sugars during digestion. This is accomplished by the digestive enzyme lactase, made by cells that line the human infant’s small intestine. After infancy, these cells stop making lactase (presumably because it is energetically inefficient to produce an unneeded enzyme). However, shifts in the human diet to include animal milks approximately 10,000 years ago acted as a selective pressure to keep lactase turned on. Today, roughly one third of all modern-day adults have one or two copies of the lactase persistence (LP) gene and the ability to continue to make lactase throughout their lifetime. 

The Break Down

In the other two-thirds of adults (who stop producing lactase), lactose passes through the small intestine undigested into the colon, where bacteria ferment and break it down. Some of the gut microbes that dine on lactose produce hydrogen, carbon dioxide, and methane as by-products. These by-products cause the gas, bloating, and discomfort commonly associated with lactose intolerance. 

However, intolerance is not the inevitable fate of life without lactase. Research suggests that most lactase non-persistent (LNP) people can handle 12 grams of lactose without noticing symptoms [3], which is roughly equivalent to the lactose content of an eight-ounce glass of cow’s milk. Moreover, not all gut bacteria produce gas because of lactose metabolism. Some gut bacteria can metabolize lactose into lactic acid and short-chain fatty acids. These byproducts do not cause painful side effects, and production of short-chain fatty acids can even have beneficial effects on gut health and immune function, including increasing the integrity of the gut barrier and reducing inflammation in the gut [6, 7]. 

The ability of undigested lactose to “feed” lactic acid bacteria (e.g., Bifidobacteria), promote their growth, and produce metabolites that improve human health indicates lactose can act as a prebiotic in LNP individuals. Some researchers [3,8,9] have called it a “conditional” prebiotic because these actions depend on the quantity of lactose consumed and the microbe populations present in the gut. There is also evidence suggesting that LNP individuals can shift their gut microbe populations toward those that produce short-chain fatty acids and away from those that cause symptoms of lactose intolerance simply by adding small amounts (<12 grams) of lactose to their daily diet [10-13]. As contradictory as it might sound, prolonged lactose consumption could reduce the incidence of lactose intolerance and turn lactose from a gut-disrupting sugar to a health-promoting prebiotic. 

Importantly, the prebiotic actions of lactose may not be exclusive to LNP individuals. In healthy LP individuals, some lactose may resist being broken down by lactase in the small intestine and could reach the colon if the amount of lactose consumed exceeded the individual’s lactase activity [1,3]. Data to support this hypothesis primarily come from infants, making extrapolations to older consumers difficult. Additional research on lactose digestion among LP children, adolescents, and adults is needed to fully understand the prebiotic potential of lactose across all human consumers.

Sugar Without the Spike

Whether you are LP or LNP, lactose must be broken down into smaller, easier to absorb simple sugars so the body can use them for energy and building blocks for molecules such as glycoproteins [1-3]. So much of the focus on lactose digestion is on how the disaccharide is broken up that the when is often overlooked. Complex molecules like lactose take longer to digest than simple molecules. As a result, glucose and galactose are released more slowly into the bloodstream than if they were delivered as monosaccharides. 

Lactose has a lower glycemic index (GI, a measure of how quickly a carbohydrate raises blood glucose levels) than glucose. (For reference, the GI of glucose is 100 whereas the GI of lactose is 46)  [1-3]. Carbohydrates with a slower release of glucose into the bloodstream offer several health benefits including improving blood sugar control, lowering the risk of diabetes, and potentially contributing to weight management by helping the consumer feel fuller for a longer period. 

Lactose may also help consumers feel full by regulating the concentration of the hormone ghrelin, often referred to as the “hunger hormone” because its production tells the brain that it is time to eat [1,3]. Although much of milk’s satiating effects have been attributed to its protein content, studies have found that consuming lactose reduces ghrelin levels and appetite more than consuming glucose [1]. Apart from experimental studies like these, lactose is not usually consumed as a single ingredient but instead as part of the milk matrix. The observed satiating effects of milk likely result from multiple nutrients, including whey and casein proteins and potentially even lactose.

Bone of Contention

Milk’s matrix also includes essential minerals, such as calcium. Compared with other foods, calcium from milk (and other dairy) has high bioavailability, meaning that much of the calcium that is present in milk can be absorbed and used by the body. Again, milk proteins (particularly casein) may be partly responsible for this effect, but lactose may also have a hand in increasing calcium uptake.

There are two possible mechanisms that could explain lactose’s influence on calcium absorption. First, lactose digestion is associated with a decrease in the pH of the digestive tract. This more acidic environment increases the solubility of calcium, which in turn can increase the passive uptake of this mineral by the intestines [1-3. 14]. Another (not mutually exclusive) possibility is that lactose’s influence on the composition of the gut’s microbe population could lead to increases in intestinal absorption of calcium [14]. 

Many older adults are in negative calcium balance, meaning they lose more calcium (in urine or stool) than they absorb and deposit into their skeleton. Foods with high bioavailability would be especially important to aging adults looking to maintain strong bones. Although studies from human infants and non-human animals suggest lactose does increase the intestinal absorption of calcium [1-3, 14, 15], whether or not lactose has this effect in humans beyond infancy is a point of contention across researchers [1-3, 14]. Although some studies have found that lactose intake increased calcium absorption among adult study subjects, many have found no effect and others have even reported that lactose impairs calcium absorption [16]. There are also arguments that lactose consumption may increase calcium intake in LNP individuals more so than LP individuals as a result of its prebiotic effect on the gut microbiome [3, 16], providing one more reason why moderate consumption of lactose among LNP adults could be nutritionally beneficial.  

No Need to Be Lactose-Free

With the growing popularity of plant-based milks and low-carbohydrate diets, it is important for consumers to understand that lactose is unique among sugars. Whereas some sugars can promote the growth of harmful gut bacteria and increase blood sugar levels, lactose has opposite effects. Consuming too much sugar, especially those found in sugar-sweetened beverages, can negatively impact bone health by increasing calcium excretion. But drinking one glass of lactose-containing milk a day could improve bone health by increasing calcium absorption. Individuals with LNP may be avoiding lactose because of the digestive issues it can cause, but emerging research suggests that they may reap more health benefits and can avoid many of the distressing symptoms by consuming small amounts throughout the day. Lactose may have evolved to provide energy for growing mammalian infants, but it provides a nutritional advantage beyond infancy. 

References

1. Anguita-Ruiz A, Vatanparast H, Walsh C, Barbara G, Natoli S, Eisenhauer B, Ramirez-Mayans J, Anderson GH, Guerville M, Ligneul A, Gil A. Alternative biological functions of lactose: a narrative review. Critical Reviews in Food Science and Nutrition. 2025 Feb 22:1-4.
2. Romero-Velarde E, Delgado-Franco D, García-Gutiérrez M, Gurrola-Díaz C, Larrosa-Haro A, Montijo-Barrios E, Muskiet FA, Vargas-Guerrero B, Geurts J. The importance of lactose in the human diet: Outcomes of a Mexican consensus meeting. Nutrients. 2019 Nov;11(11):2737.
3. Schaafsma G. Lactose and lactose derivatives as bioactive ingredients in human nutrition. International Dairy Journal. 2008 May 1;18(5):458-65.
4. Oftedal O.T. 2013. Origin and evolution of the major constituents of milk. In: McSweeney PLH, Fox PF (Ed.) Advanced Dairy Chemistry Volume 1A: Proteins, 4th Edition, Springer: New York, pp. 1–42.
5. Oftedal O.T., Iverson S.J. 1995. Comparative analysis of nonhuman milks: phylogenetic variation in the gross composition of milks. In: Jensen RG (Ed.) Handbook of Milk Composition. Academic Press, San Diego, pp. 749–788.
6. Li M, van Esch BC, Wagenaar GT, Garssen J, Folkerts G, Henricks PA. 2018. Pro-and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. European Journal of Pharmacolog 831: 52-9.
7. Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJ, Faber KN, Hermoso MA. 2019. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Frontiers in Immunology 10: 277.
8. Gänzle MG. Lactose—a conditional prebiotic?. In: Lactose 2019 Jan 1 (pp. 155-173). Academic Press.
9. Venema K. Intestinal fermentation of lactose and prebiotic lactose derivatives, including human milk oligosaccharides. International Dairy Journal. 2012 Feb 1;22(2):123-40.
10. Brown-Esters O, Mc Namara P, Savaiano D. Dietary and biological factors influencing lactose intolerance. International Dairy Journal. 2012 Feb 1;22(2): 98-103.
11. Kable ME, Chin EL, Huang L, Stephensen CB, Lemay DG. Association of estimated daily lactose consumption, lactase persistence genotype (rs4988235), and gut microbiota in healthy US adults. The Journal of Nutrition. 2023 Aug ;153(8): 2163-73.
12. Szilagyi A. Adaptation to lactose in lactase non persistent people: Effects on intolerance and the relationship between dairy food consumption and evaluation of diseases. Nutrients. 2015 Aug 13;7(8): 6751-79.
13. Forsgård RA. Lactose digestion in humans: intestinal lactase appears to be constitutive whereas the colonic microbiome is adaptable. The American Journal of Clinical Nutrition. 2019 Aug 1; 110(2): 273-9.
14. Kwak, HS, Lee WJ, Lee MR. Revisiting lactose as an enhancer of calcium absorption. International Dairy Journal. 2012 Feb 1;22(2):147-51.
15. Guéguen L, Pointillart A. 2000. The bioavailability of dietary calcium. Journal of American College of Nutrition 19: 119S-136S