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Milk is an emulsion of water, protein, and fat globules. The fat globules have been extensively studied in recent years because of their bioactive function. These complex spherical structures act as a source of energy and nutrients, help shape the gut microbiome, and support our immune systems.

The globules vary widely in structure and size, ranging from 0.1 to 15 μM [1]. The core is made of triglycerides enclosed in a three-layered membrane consisting of phospholipids and proteins. The size of the globule and the presence of its surrounding membrane have been shown to affect digestion [2] and may contribute to infant growth and development [3].

Studies have also found that they affect interactions between milk and naturally occurring bacteria; however, it was unclear whether this was due to the chemical composition, i.e., the triglycerides and phospholipids, the size of the milk fat globules, or both [1]. 

In a new study, published in Food Chemistry, researchers at the Hebrew University of Jerusalem found that the size of milk fat globules plays a critical role in modulating interactions between milk and bacteria. Indeed, the size of the globule seems to be more important than the chemical composition. Smaller fat globules are better at promoting the growth of beneficial bacteria compared to larger globules [4]. 

To determine the effect of structure and composition on bacteria growth, the researchers cultured different strains of bacteria with small or large milk fat globules that had been separated from raw milk or produced in vitro by mammary epithelial cells [4]. 

The team found that regardless of whether the milk fat globules were isolated from raw milk or produced by the cell model, good bacteria, namely Bacillus subtilis and Lactobacillus plantarum, preferred small milk fat globules compared to large globules. Small globules promoted bacterial growth, while large globules triggered biofilm formation, a protective mechanism that usually signifies stress. Interestingly, the harmful bacteria, i.e., S. aureus and E. coli, did not have a preference [4]. These results indicate that the structure and size of the globule are more important than the chemical composition. 

The researchers further supported these data with metabolomics. They incubated B. subtilis with small and large fat globules isolated from the mammary epithelial cells and isolated the metabolites. There was a significantly greater number of metabolites produced after treatment with the small fat globules. For example, metabolites associated with the citric acid cycle were elevated. The data suggest that small fat globules support more metabolic activity [4].

The differences in bacteria growth, biofilm formation, and metabolites can be attributed to the milk fat’s surrounding membrane. Small milk fat globules have a relatively greater surface area of membrane and can provide more nutrients and energy, specifically to the commensal bacteria. There may be protective mechanisms in place that provide a competitive advantage over pathogenic bacteria.   

This study provides greater insight into the interactions between milk fat and bacteria, which can have important implications for our understanding of milk nutrition and food safety.

References

1. Raz C, Paramonov MM, Shemesh M, Argov-Argaman N. The milk fat globule size governs a physiological switch for biofilm formation by bacillus subtilis. Frontiers in Nutrition. 2022 2022-August-11;9.
2. Garcia C, Antona C, Robert B, Lopez C, Armand M. The size and interfacial composition of milk fat globules are key factors controlling triglycerides bioavailability in simulated human gastro-duodenal digestion. Food Hydrocolloids. 2014 2014/03/01/;35:494-504.
3. Schipper L, Bartke N, Marintcheva-Petrova M, Schoen S, Vandenplas Y, Hokken-Koelega ACS. Infant formula containing large, milk phospholipid-coated lipid droplets and dairy lipids affects cognitive performance at school age. Front Nutr. 2023;10:1–11.
4. Raz C, Tzirkel-Hancock N, Shemesh M, Argov-Argaman N. The role of structure in the interaction between bacteria, mammary epithelial cells and milk fat globules from raw or “cultured” milk. Food Chem. 2025 Mar 1;467:142244.

In the largest single study to correlate diet and cancer risk, researchers found that the boost of calcium contained in milk, dairy products, and other foods can cut the risk of colorectal cancer by as much as 17 percent [1]. 

Colorectal cancer is the third most common cancer, with nearly 2 million cases reported globally in 2022. The disease is most prevalent in high-income countries including the US, Europe, Japan, and Australia. Rates are lower, albeit on the rise, in low and middle-income countries. Diet and lifestyle are strongly associated with the risk of colorectal cancer. 

In a 2018 report [2] from the World Cancer Research Fund & American Institute for Cancer Research, experts concluded that consuming more than two alcoholic drinks per day and eating processed meat or red meat increased the risk of colorectal cancer, and eating fiber-rich foods and dairy likely reduced the risk. But strong connections between many foods and colorectal cancer have been elusive – in part because it is difficult to measure various elements of people’s diets over long-running, large studies. 

For the new study, researchers tracked how 97 dietary factors were associated with colorectal cancer rates in more than 500,000 women in the U.K over a total of about 16 years. During that time, 12,251 women were diagnosed with the condition. The researchers found that women who developed colorectal cancer were older than the overall cohort. They were also more likely to have a family history of bowel cancer and had more adverse health behaviors, such as smoking. 

The research team found that diets with higher amounts of calcium-rich foods, such as milk and yogurt, were linked to a lower risk of developing colorectal cancer. Other nutrients, such as magnesium, potassium, and riboflavin, were also protective — likely because they’re also abundant in calcium-rich foods, the authors wrote in the study.  Other calcium-rich foods, such as dark leafy greens, were also linked to lower risk of cancer. 

Precisely why calcium is so beneficial was not examined in this study. But evidence from other research offers clues: studies in rats and other models, for example, have shown that calcium can bind bile acids in the intestine and protect the mucosal lining from damage; prevent DNA damage and promote programmed cell death, which can clear away aging or pre-cancerous cells. In a press release, nutritional epidemiologist Keren Papier of the University of Oxford, who led the work, said these possibilities might explain calcium’s benefits. “It’s suggested that calcium might protect against bowel cancer by binding to bile acids and free fatty acids to form a type of a harmless ‘soap’, which stops them from damaging the lining of our gut,” Papier said in a press release. 

All dairy products – except cheese and ice cream – were linked to the benefits of calcium-rich foods. In addition to calcium, other chemicals in milk and dairy products may confer additional protection. Experiments in animal models have shown that butyric acid and sphingomyelin, which are also present in many dairy products, may block cancer-causing chemicals from triggering the disease.  

Other studies, using data from the UK Biobank [3] and the Nurses’ Health Study II [4], have found similar links between dietary calcium and a lower risk of colorectal cancer. But a study using data from the China Kadoorie Biobank found an opposite effect: in that work, where 3350 cases occurred among more than 500,000 participants, researchers reported that milk consumption increased cancer risk by about eight percent. “It is possible that the association between dairy milk and colorectal cancer risk might differ in populations where a large majority cannot digest lactose,” the authors wrote in the study. 

Overall, the study’s results confirm well-established correlations between alcohol, red meat and processed meats with colorectal cancer risk. The data also reveals a strong protective role for calcium-rich foods, including milk and other dairy products, but more work is needed to understand the overall benefits and risks of dietary calcium. 

References

1. Papier K, Bradbury KE, Balkwill A, Barnes I, Smith-Byrne K, Gunter MJ, Berndt SI, Le Marchand L, Wu AH, Peters U, Beral V. Diet-wide analyses for risk of colorectal cancer: prospective study of 12,251 incident cases among 542,778 women in the UK. Nature Communications. 2025 Jan 8;16(1):375.
2. World Cancer Research Fund International. Diet, nutrition, physical activity and cancer: a global perspective: a summary of the Third Expert Report. World Cancer Research Fund International; 2018.
3. Bradbury KE, Murphy N, Key TJ. Diet and colorectal cancer in UK Biobank: a prospective study. InternationalJjournal of Epidemiology. 2020 Feb 1;49(1):246-58.
4. Kim H, Hur J, Wu K, Song M, Wang M, Smith-Warner SA, Zhang X, Giovannucci EL. Total calcium, dairy foods and risk of colorectal cancer: a prospective cohort study of younger US women. International Journal of Epidemiology. 2023 Feb 1;52(1):87-95.

The human newborn’s immune system has the challenging task of learning to distinguish harmful pathogens from harmless environmental antigens. Mounting the appropriate response—attack or tolerate—without prior experience is like building the airplane while flying it. But here’s where human milk comes in. In addition to providing infants with mom’s experienced antibodies, human milk contains a multitude of ingredients that provide on-the-job training for the infant’s naïve immune system. 

Previous research on how this “training” influences the activity or function of infant immune cells has largely  focused on identifying an association between human milk intake and infant health outcomes (e.g., comparing the incidence of asthma between infants fed human milk or formula) or investigating the function of specific milk components in animal models. Surprisingly, research on the association between human milk intake and human infant immune profiles— the molecules and mechanisms that regulate immune responses—has received less attention [1]. 

A new observational study [1] addressed this blind spot by investigating the association of human milk feeding practices with the concentration of 76 serum immunological markers.  The study participants were part of the long-running Canadian CHILD Cohort Study, which followed (and continues to follow) over 3,000 infants from birth through adolescence. From this larger cohort, 605 infants had sufficient data to be included in the final analyses. Thorough data on environment, health, family, and diet for each participant were collected from questionnaires and clinical visits during the second trimester and at birth, three months, six months, one year, and three years of age. Blood samples were drawn at the one year visit. This large and comprehensive dataset allowed the research team to control for factors other than human milk that can influence serum biomarkers, such as maternal age, household pets, parental allergy history, and age at introduction to formula or solid foods [1]. After taking all these other factors into account, does human milk feeding explain the variation among infants in serum biomarkers?

Current milk feeding status was significantly associated with the concentration of seven of the 76 biomarkers. Six of the biomarkers (CCL20, CD244, CXCL6, FGF-21, IL-10, and TRAIL) were significantly higher and one (EN-RAGE) was significantly lower in infants that were receiving human milk at the time of the blood draw (n=258) compared with those that were not receiving human milk (n=347). Five of these seven biomarkers (CCL20. CD244, CXCL6, FGF-21, and EN-RAGE) were also found to be significant predictors of current infant human milk feeding status [1]. 

One obvious explanation for the significantly higher quantities of serum CCL20, CD244, CXCL6, and FGF-21 in infants currently receiving human milk is that the biomarkers came directly from human milk. Although they are found in human milk, this study was not able to determine if the biomarkers measured in infant serum were made by the mother (and passed along in milk) or by the infants [1]. It also is unknown whether these biomarkers can cross the intestinal barrier (where they would end up if provided by milk) and enter the infant’s circulation (where they were measured). Moreover,  numerous biomarkers measured in infant serum also present in milk  did not have a significant association with milk feeding. 

An alternative (and not mutually exclusive) explanation is the production (whether it be to make more or make less) of these biomarkers by the infant was regulated by other ingredients provided by human milk. For example, the researchers highlighted how milk fatty acids can stimulate liver cells to produce FGF-21 (a peptide hormone) [1]. 

Similar biological functions among these five biomarkers further suggest that their increased (or decreased) levels are not solely related to their inclusion (or exclusion) in the infant’s diet. Higher levels of FGF-21 in animal models have been associated with promoting maturation of B and T cells and reducing the production of pro-inflammatory molecules. CD244 is a surface protein expressed on many types of immune cells, including T cells, and has immunoregulatory functions. Depending on which type of immune cells they are expressed, CD244 protein receptors can either activate or inhibit an immune response. CCL20 and CXCL6 both help to promote a more anti-inflammatory gut environment. EN-RAGE—the only biomarker that was found to be significantly lower in infants receiving human milk at the 12-month blood draw—is a pro-inflammatory cytokine. Lower concentrations of EN-RAGE along with higher concentrations of CCL20 and CXCL6 suggest a lower degree of gut inflammation associated with human milk feeding [1]. Taken together, these findings suggest infants currently receiving human milk have more anti-inflammatory immune cells than those not receiving human milk [1].

Human milk feeding history, specifically the duration of human milk feeding, was only significantly associated with one biomarker, IL-7, but this protein is also functionally similar to the previously highlighted biomarkers. Physiologically, IL-7 influences the function and activity of naïve T cells (one type of white blood cell), including increasing their proliferation (T cells dividing and increasing in number) and differentiation (T cells becoming specialized cells, such as CD8+ cells). The researchers suggested that IL-7 provided by human milk may therefore be responsible for the previously reported positive association [2] between human milk feeding duration and the quantity of different types of T cells, including regulatory T cells (T regs), CD4+ T cells and CD8+ T cells [1]. The association of this biomarker with feeding duration but not feeding status suggests that this biomarker may remain elevated in infants for months after human milk feeding ends. This hypothesis is supported by this study’s finding that IL-7 concentrations were lower among infants who stopped receiving human milk more than five months prior to the blood draw [1].  

The biomarkers highlighted by this study represent potential mechanisms by which human milk “trains” the infant immune system to suppress inflammation and tolerate harmless antigens. Whether this training happens by directly providing critical bioactive proteins as milk ingredients or by increasing (or suppressing) their production by infant cells through the presence of other milk ingredients, or both, is not known. Indeed, this study [1] was the first to identify an association between these biomarkers (except for FGF-21) and current human milk feeding. 

And that is the purpose of observational studies—to look for associations among variables and generate hypotheses to test in experimental studies. This study does that in spades, identifying at least five potential pathways for regulating the development of the infant immune system. Expanding this research with experimental studies will not only help bolster the current recommendations by the World Health Organization to encourage human milk feeding up to two years but also can potentially identify mechanisms that can improve health outcomes of formula-fed infants. 

References

1. Ames SR, Lotoski LC, Rodriguez L, Brodin P, Mandhane PJ, Moraes TJ, Simons E, Turvey SE, Subbarao P, Azad MB. Human milk feeding practices and serum immune profiles of one-year-old infants in the CHILD birth cohort study. The American Journal of Clinical Nutrition. 2025 Jan 1;121(1): 60-73.
2. Wood H, Acharjee A, Pearce H, Quraishi MN, Powell R, Rossiter A, Beggs A, Ewer A, Moss P, Toldi G. Breastfeeding promotes early neonatal regulatory T‐cell expansion and immune tolerance of non‐inherited maternal antigens. Allergy. 2021 Aug;76(8): 2447-60.

Scientists have created bioengineered plants that can produce more than 12 types of human milk oligosaccharides (HMOs) in a single leaf [1]. The study lays the groundwork for producing infant formula that more closely approximates human breast milk. It may also enable researchers to manufacture HMOs in large enough amounts to test their therapeutic potential in adults. 

“We were shocked by how easy it was,” says Patrick Shih, a plant and microbial biologist at the University of California, Berkeley, who led the work.  The study “represents, to our understanding the most HMOs ever produced in a single organism,” he adds. 

HMOs are complex sugars that are among the most abundant components found in human breast milk. Human breast milk contains more than 200 HMOs, and although babies can’t digest them, they are known to support the development of the babies’ gut microbiomes [2]. 

Researchers have been able to reliably produce two to five different types of HMOs by inserting the genes encoding them into the DNA of bacteria called Escherichia coli [3].  With commercial production so limited, Shih says, “if we think the diversity of HMOs is key to unlocking aspects of gut health, we are currently missing the vast, vast majority of them.”

Engineering bacteria to produce specific biological molecules is a complex and costly industrial process that involves growing the bacteria in a fermentation tank and then extracting the molecules. For some types of molecules, such microbial production works well, but its efficiency for HMOs has been low. 

That’s because many microbes, including E. coli, have relatively simple sugar metabolism.  Getting them produce HMOs “is an uphill battle,” Shih explains. “With E coli, you’re trying to force it to do something it doesn’t want to do, so you have to do a lot of hard metabolic engineering.” 

Plants, on the other hand, produce complex sugars for a living, with the help of photosynthesis. “They are essentially sugar producing factories because they have diverse branches of sugar metabolism,” Shih says. Collin Barnum, a graduate student in his lab, experienced an “aha moment” when he realized plants’ potential.  The team set out to use a plant called Nicotiana benthamiana, a cousin on the tobacco plant, to create a platform that can expand the diversity of biosynthesized HMOs and can also scale up the amount of HMOs produced. 

The team altered the plants’ genomes to encode pathways that biosynthesize HMO, homing in on a winning combination of genes that produced more than a dozen different HMOs at once. Among these HMOs was lacto-N-fucopentaose 1 (LNFP1), a particularly complex but abundant HMO that microbial processes cannot make but known to be nutritionally important [4]. They then purified their plant-synthesized HMOs and fed them to bifidobacteria, a type of “good” bacteria that are present in the infant gut microbiome. They found that the bacteria were able to metabolize the HMO.

The team also conducted an economic analysis that showed that producing complex HMOs in plants at an industrial scale would be more cost-effective than doing so via microbial engineering. “If you have an engineered plant, all you have to do is put a seed in the ground, give it water and sunlight, and then the carbon dioxide from photosynthesis gets fixed to produce these sugars,” Shih says. “That’s certainly more sustainable” than microbial production. 

The current work is a proof of concept  that it’s possible to optimize a pathway and create a stable line of plants that produces multiple HMOs. The group is now working on making a larger number of these sugars. “If you could make one product that you could grind up and add to infant formula to approximate the HMO profile in breast milk, that would potentially be a game changer for the industry,” Shih says. 

One limitation, however, is that many of the enzymes and genes that produce HMOs are still unknown, so they cannot be engineered into a plant. The team is also exploring how to increase the yield of HMOs that the plants can produce. Some preliminary evidence suggests that HMOs may also be helpful for treating conditions in adults such as irritable bowel disease [5]. But microbial processes do not produce enough material to test their efficacy. 

Additionally, says Shih, Nicotiana benthamiana is a plant species used in laboratories, but not one that is widely cultivated, which also limits the production potential. “If we imported the gene pathways we constructed into a more agronomically relevant crop species, would you maintain the same production level? That’s a big question mark,” Shih says. 

References

1. Barnum CR, Paviani B, Couture G, Masarweh C, Chen Y, Huang YP, Markel K, Mills DA, Lebrilla CB, Barile D, Yang M, Shih PM. Engineered plants provide a photosynthetic platform for the production of diverse human milk oligosaccharides. Nat Food. 2024, 5(6):480-490. 
2. 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. 
3. Bych K, Mikš MH, Johanson T, Hederos MJ, Vigsnæs LK, Becker P. Production of HMOs using microbial hosts – from cell engineering to large scale production. Curr Opin Biotechnol. 2019. 56:130-137.
4. Hani G, Hoeflinger JL, Heiss BE, Masarweh CF, Larke JA, Jensen NM, Wickramasinghe S, Davis JC, Goonatilleke E, El-Hawiet A, Nguyen L, Klassen JS, Slupsky CM, Lebrilla CB, Mills DA. Fucosylated Human Milk Oligosaccharide Foraging within the Species Bifidobacterium pseudocatenulatum Is Driven by Glycosyl Hydrolase Content and Specificity. Appl Environ Microbiol. 2022. 88(2):e0170721.
5. Tribarren C, Magnusson MK, Vigsnæs LK, Aziz I, Amundsen ID, Šuligoj T, Juge N, Patel P, Sapnara M, Johnsen L, Sørensen N, Sundin J, Törnblom H, Simrén M, Öhman L. The Effects of Human Milk Oligosaccharides on Gut Microbiota, Metabolite Profiles and Host Mucosal Response in Patients with Irritable Bowel Syndrome. Nutrients. 2021. 13(11):3836.