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    Issue Date: March 2022

    Extracellular Vesicles from Cow Milk Help with Osteoarthritis

    • Previous research has shown that consuming cow milk is beneficial for people with osteoarthritis, but the mechanism behind how is not well understood.
    • Growth factors and microRNAs in extracellular vesicles (EVs) can have an important role in protecting cartilage from degradation in osteoarthritis.
    • To learn about the mechanism behind how EVs affect arthritis, researchers exposed osteoarthritic knee tissue samples as well as isolated cartilage cells to EVs extracted from cow milk.
    • EVs from cow milk were confirmed to have a protective effect for osteoarthritic cartilage damage.

    Scientists are exploring an exciting new treatment for osteoarthritis, and the source of this new treatment stems from a surprising place: cow milk. Cow milk contains bountiful numbers of extracellular vesicles (EVs)—tiny cellular bubbles that transport lipids, proteins, and nucleotides between cells—and these vesicles are thought to contain components that influence cartilage formation and degradation [1].

    A new study exposed arthritic cartilage samples as well as chondrocytes, or cartilage cells, to EVs extracted from milk and found that growth factors and microRNAs carried within these vesicles reduced both cartilage degradation and inflammation [2]“We wanted to know what the direct roles of these extracellular vesicles from milk were on cartilage,” says Fons Van de Loo, a biologist at Radboud University Medical Center, Netherlands, and lead author of the new paper.

    Many previous studies have shown a beneficial relationship between milk consumption and osteoarthritis prevention [3,4], but the underlying mechanism is little understood. In a previous study, Van de Loo and his colleagues fed arthritic mice EVs from milk and found that it alleviated their arthritis [5], so a natural next step was to study the effect of EVs in human articular joint cells.

    Osteoarthritis is a musculoskeletal disease characterized by degradation of the cartilage in joints, and the CDC estimates that 32.5 million adults in the United States are affected by this condition [6]. Chondrocytes, or cartilage cells, produce collagen and proteoglycans; the former serves as structural scaffolding, whereas proteoglycans act as a shock absorber in joints. In patients suffering from osteoarthritis, enzymes called metalloproteinases break down the proteoglycans. Furthermore, cytokines, proteins with regulatory effects, induce inflammation that further exacerbates the arthritis [7].

    EVs have long been regarded as cellular waste, but in recent years, scientists have become interested in them for their ability to transport various molecules between cells without being broken down [8]. Cow milk is an abundant source of EVs, which carry TGFβ, a type of growth factor, and microRNAs, tiny snippets of non-coding RNA. Both are thought to have important regulatory roles in cartilage growth and maintenance [9,10].

    To test exactly how these EVs and their cargo affect joints and arthritis, Van de Loo and associates had to conduct a multi-stage experiment. First, they used cartilage explants taken from four osteoarthritis donors who were undergoing knee replacements and observed them for three days to see how the cartilage was degrading. Then, they isolated EVs from cow milk and incubated the cartilage samples with the vesicles. After 24 and 48 hours they found a 39% and 34% reduction, respectively, in cartilage breakdown compared with the controls. They then performed genetic analysis to see which metalloproteinases were affected and found a significant reduction in metalloproteinase-1 (MMP-1) [4].

    To study the effects of EVs in more detail, the research team used a chondrocyte cell line and exposed the cells to EVs. Similar to the cartilage explants, Van de Loo found a 90% reduction in MMP-1, as well as reductions in other types of metalloproteinases [4].

    Van de Loo was also interested in the potential effects of EVs on cartilage under inflammatory conditions. Chondrocytes were exposed to interleukin-1-beta, the cytokine that induces inflammation, before treating them with the EVs. Similar to the previous tests, the EVs alleviated the inflammatory effects and inhibited the expression of metalloproteinases [4].

    Lastly, the research team wanted to get a more specific understanding of the roles of TGFβ and microRNAs in preventing osteoarthritis. Van de Loo wanted to know if EVs would still have their protective effects if TGFβ was removed. He used antibodies to remove the growth factor from the EVs and, to his surprise, found a reduction in certain metalloproteinases and some, but not all, inflammatory cytokines. “That was really amazing,” says Van de Loo. “It’s not really just a story about TGFβ and vesicles. It’s really a story about what’s in these vesicles and the microRNAs that could be implicated in this process.”

    Van de Loo says a limitation in the study was the small number of human tissue samples they could secure, and that the explant samples came from patients with late-stage osteoarthritis where the EVs could be absorbed more readily.

    In summation, Van de Loo says that the study’s findings verify that EVs inhibit the metalloproteinases that break down cartilage. “That’s very good news,” he says. “That now opens new avenues for the use of these vesicles in diseases like osteoarthritis.”

    Future studies could work on developing EVs as a treatment for people with osteoarthritis, focusing on how long EV treatments can last or how readily EVs are taken up in the cartilage. Van de Loo’s research brings the research community one step closer towards developing an injectable arthritis treatment made with EVs extracted from cow milk.

    References

    1. Hata T, Murakami K, Nakatani H, Yamamoto Y, Matsuda T, Aoki N. Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochemical and Biophysical Research C 2010 May 28;396(2):528-33.
    2. Pieters BC, Arntz OJ, Aarts J, Feitsma AL, van Neerven RJ, van der Kraan PM, Oliveira MC, van de Loo FA. Bovine milk‐derived extracellular vesicles inhibit catabolic and inflammatory processes in cartilage from osteoarthritis patients. Molecular Nutrition & Food Research. 2021 Dec 29:2100764.
    3. Laird E, Molloy AM, McNulty H, Ward M, McCarroll K, Hoey L, Hughes CF, Cunningham C, Strain JJ, Casey MC. Greater yogurt consumption is associated with increased bone mineral density and physical function in older adults. Osteoporosis International. 2017 Aug;28(8):2409-19.
    4. Lim YS, Lee SW, Tserendejid Z, Jeong SY, Go G, Park HR. Prevalence of osteoporosis according to nutrient and food group intake levels in Korean postmenopausal women: using the 2010 Korea National Health and Nutrition Examination Survey Data. Nutrition Research and Practice. 2015 Oct 1;9(5):539-46.
    5. Arntz OJ, Pieters BC, Oliveira MC, Broeren MG, Bennink MB, de Vries M, van Lent PL, Koenders MI, van den Berg WB, van der Kraan PM, van de Loo FA. Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models. Molecular Nutrition & Food Research. 2015 Sep;59(9):1701-12.
    6. Centers for Disease Control and Prevention. Osteoarthritis (OA). Internet: https://www.cdc.gov/arthritis/basics/osteoarthritis.htm (accessed 16 February 2022).
    7. Chang JK, Chang LH, Hung SH, Wu SC, Lee HY, Lin YS, Chen CH, Fu YC, Wang GJ, Ho ML. Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2009 Oct;60(10):3049-60.
    8. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. Journal of Cell Biology. 2013 Feb 18;200(4):373-83.
    9. Rogers ML, Goddard C, Regester GO, Ballard FJ, Belford DA. Transforming growth factor β in bovine milk: concentration, stability and molecular mass forms. Journal of Endocrinology. 1996 Oct 1;151(1):77-86.
    10. Benmoussa A, Provost P. Milk microRNAs in health and disease. Comprehensive Reviews in Food Science and Food Safety. 2019 May;18(3):703-22.

    Peanut-popping Breastfeeding Moms Help Protect Their Toddlers from Peanut Allergy

    • Peanut allergies in kids can be severe and lack any cure.
    • A recent study finds that breastfeeding lowers the likelihood of peanut sensitization at three and five years of age, as long as the mother consumes nuts.
    • The study also found that introducing peanuts early on once infants start to eat solids reduces the odds of allergy.

    Peanut allergies are among the most common of food allergies, can be severe, and have become increasingly pervasive over time. Recently, evidence has mounted that the early introduction of peanuts into infant diets reduces the odds of affliction. This has led to changes in official guidelines for parents in the United States, Europe, and Australasia [1]. Now, a study that followed the trajectory of allergy development in a large group of Canadian children has found that moms consuming peanuts while breastfeeding further protect their child from developing an allergic response by their fifth birthday. The results are nuanced since the effect is not apparent at one year of age, but becomes so over time. This suggests that antigens or immune complexes in human milk may be involved in programming the gradual development of a child’s immune system.

    The Asthma and Allergy Foundation of America estimates that around 0.6% of US children are allergic to peanuts, and must avoid all forms of the foodstuff [2]. In practice, this is far from easy as all manner of foods from egg rolls to mole sauce can present a source. Moreover, there is no cure for peanut allergy, and reactions can be fatal. Hence any solid data that offers policy advice on how to reduce the likelihood of a child becoming allergic to peanuts has the potential to save lives.

    The Canadian study builds on evidence from a trial that focused only on high-risk kids. The results of that trial were published in the New England Journal of Medicine six years ago and reported that introducing peanuts into the diets of infants as young as 4 to 11 months old helps to lessen the odds of peanut sensitization [3]. Rather than focus on those especially at-risk, the more recent study followed more than 2,700 kids from families drawn from the general population, and hence they were not selected because of a familial tendency towards IgE-mediated allergic diseases [4]. This cohort came from the Canadian cities of Vancouver, Edmonton, Winnipeg, and Toronto, and the electoral district of Morden-Winkler. The moms who enrolled their kids in the trial were asked for how long they breastfed and when their child first tried a peanut, and they completed food questionnaires about their own peanut intake (specifically whether they ate peanut butter, raw peanuts, other nuts or seeds, and how often they did so). The kids were checked over time for peanut sensitivity using standard allergen skin tests.

    As expected from the previous study, the infants in the Canadian cohort who tried peanuts before their first birthday were less likely to become allergic to them. This association was substantial: they were 50–70% less likely to do so throughout childhood. However, what was unusual about this study was its careful assessment of the trajectory of peanut sensitization as the infants grew up. Indeed, if the researchers had stopped testing kids in the cohort at one year of age, their conclusion would have been that breastfeeding has no clear influence on peanut allergy development. This is what some other studies have concluded [5]. However, because the researchers kept assessing the kids over time, and they knew whether moms breastfed and ate nuts, they could look more closely at patterns in the data. They uncovered that when moms didn’t eat peanuts, breastfeeding had no effect. But when they did, the kids who consumed this breastmilk started to show lower odds of peanut allergy when they reached three years old, and the lower odds became more pronounced at the age of five.

    It is unclear exactly why protection against peanut sensitization should develop in this way. The pattern broadly suggests that moms who eat peanuts pass on trace antigens or immune complexes of some sort via their milk, which primes the infant immune system, and that this slow-burn “programming” effect unfolds beyond infancy. An analogous pattern has been reported for egg allergies, whereby if mom’s milk contained detectable levels of ovalbumin, conferred protection against egg allergy started showing up in the data only when the kids reach two-and-a-half years of age [6].

    Taken together, the authors conclude, the recent findings “identify breastfeeding as an important focus for allergy prevention efforts.” This is a broader trend within allergy research. Aside from eggs and now peanuts, as long as moms eat cereals, breastfeeding is also known to influence the development of celiac disease [7]. But the upshot for official guidance to parents concerned about peanut sensitization in their children and future children is simple: it’s not just that moms should continue to eat peanuts early in their infant’s life, and should introduce them early in their child’s diet, but non-allergic breastfeeding moms should be encouraged to eat them.

    References

    1. Chen M., Welch M., Laubach S. Preventing Peanut Allergy. Pediatric Allergy, Immunology and Pulmonology 2018; 31(1), 1-8. doi:10.1089/ped.2017.0826
    2. https://www.kidswithfoodallergies.org/peanut-allergy.aspx Accessed 8 Feb 2022.
    3. Toit G. D., Sayre P. H., Roberts G., Sever M. L., Lawson K., Bahnson H. T., Brough H. A., Santos A. F., Harris K. M., Radulovic S., Basting M., Turcanu V., Plaut M., Lack G. & Immune Tolerance Network LEAP-On Study Team. Effect of Avoidance on Peanut Allergy After Early Peanut Consumption. N Engl J Med 2016; 374(15), 1435-1443.
    4. Azad M. B., Dharma C., Simons E., Tran M., Reyna M. E., Dai R., Becker A. B., Marshall J., Mandhane P. J., Turvey S. E, Moraes T. J., Lefebvre D. L., Subbarao P. & M. R. Sears. Reduced Peanut Sensitization with Maternal Peanut Consumption and Early Peanut Introduction While Breastfeeding. Journal of Development Origins of Health and Disease. 2020; 12, 811-818.
    5. Lodge C. J., Tan D. L., Lau M. X., Dai X., Tham R., Lowe A. J., Bowatte G., Allen K. J. & S. C. Dharmage. Breastfeeding and Asthma and Allergies: A Systematic Review and Meta-analysis. Acta Paediatrica 2015; 104(467), 38-53.
    6. Verhasselt V., Genuneit J., Metcalfe J. R., Tulic M. K., Rekima A., Palmer D. J. & S. L. Prescott. Ovalbumin in Breastmilk is Associated with a Decreased Risk of IgE-mediated Egg Allergy in Children. Allergy 2020; 75(6), 1463-1466.
    7. Persson L. A., Ivarsson A., Hernell O. Breastfeeding Protests Against Celiac Disease in Childhood-epidemiological Evidence. Adv Exp Med Biol 2002; 503,115-123.

    Prehistoric Tartar Deposits Reveal the Earliest Dairy Consumers in Eurasia

    • Tartar deposits on teeth of prehistoric people contain proteins from past meals and can be used to test hypotheses about the origins of dairying.
    • A new study analyzed tartar from burials in and near southwest Russia dating to between 4600 and 1700 BC and found the earliest evidence of dairy consumption at the beginning of the Bronze Age (ca. 3300–2500 BC).
    • This dietary shift is argued to be responsible for population expansions into the Eurasian Steppe environments, which would have been difficult to inhabit without a reliable source of nutrition and fluid.

    Don’t tell your dentist, but tartar can sometimes be a good thing. Prehistoric tartar deposits have become instrumental in helping archaeologists understand when humans first started consuming dairy foods. This crusty mineral build-up (also called dental calculus) acts like a dietary time capsule [1] because it traps and preserves food particles from decades of breakfasts, lunches, and dinners. Archaeologists interested in determining whether dairy foods were included in one of those meals trade in their trowels and screens for dental scalers and mass spectrometers to excavate tartar deposits for proteins specific to dairy, such as ß‑lactoglobulin (BLG). If a prehistoric person ate goat cheese, drank sheep’s milk, or nibbled on cow’s milk yogurt, there is a good chance the proteins from those foods became preserved like a fossil within tartar’s mineral matrix.

    The most recent study [2] to perform these dental excavations—called paleoproteomics—focused on the origins of dairying in the Eurasian steppe. The grassland plains that span from Eastern Europe to Mongolia are arid and difficult for growing crops, and yet archaeological and genetic data suggest widespread human movement into these areas during the Early Bronze Age (ca. 3300 to 2500 BC). A long-standing hypothesis for the rapid expansion in this challenging environment argues that the people must have been pastoralists (or animal herders) that depended on horse traction, wagon transport, and dairy. Archaeologists have found evidence of carts and bridling materials, but there has been no direct evidence to support the use of domesticated horses or dairy consumption during the Early Bronze Age [2].

    To test this hypothesis, researchers performed proteomic analysis on tartar samples collected from 56 individuals dated to between 4600 and 1700 BC from archaeological sites near the Caspian Sea, Kazakhstan, and Russia. Nineteen individuals came from the earliest period (4600 – 4000 BC), but only 11 dental samples had sufficient preservation for analysis. Of these, only one individual’s tartar deposits contained a dairy-specific protein (in this case, a casein protein from a bovine species) [2]. Because BLG is the most commonly recovered dairy protein (and almost always found in tandem with other dairy proteins), dairy consumption could not be confirmed with confidence [2].

    In contrast, 15 of the 16 Early Bronze Age (3300 to 2500 BC) samples and 15 of the 19 Middle to Late Bronze Age (2500 to 1700 BC) samples had unequivocal evidence for dairy consumption. These samples contained BLG along with other dairy-specific proteins. Many of these proteins were genus-specific, allowing the research team to assign the dairy source to Ovis (sheep), Capra (goat), or Bos (cow) [2]. Two of the Early Bronze Age individuals even had milk proteins unique to Equus species (which the researchers attributed to horse milk, as opposed to donkeys, because horses were the only Equus species in archaeological assemblages from this period) [2].

    These findings provide direct evidence for a shift to dairy consumption between 4000 and 3500 BC in this section of the Eurasian Steppe (aka the Pontic-Caspian Steppe). These dates are coincident with both archaeological and genetic data for major expansions into this region, supporting the hypothesis that dairy was a primary driving force of these population movements away from riverine settlements and into the arid plateaus [2]. Dairy would have provided a reliable source of nutrition and hydration in a dry, cold climate where crop cultivation was not dependable, and could have potentially been an important weaning food (and fluid) for infants as well [2, 3].

    The presence of horse milk peptides on teeth dated to the Early Bronze Age was a particularly interesting finding as these proteins provide probable evidence for horse domestication in the Pontic-Caspian steppe region [2]. These are the earliest horse milk proteins identified anywhere in the world, which could indicate that this region was one of the earliest centers for horse domestication [2]. It is not clear whether the horses would have been part of pastoral herds or were ridden (or both). However, by 2000 BC, it is known that people in this region depended heavily on horses as evidenced by horse-pulled chariots in the archaeological record [2].

    Another important unknown is whether these Early Bronze Age dairy consumers were genetically adapted to lactose digestion (via a mutation that allowed for lactase persistence after infancy, hereafter the LP gene variant). Tartar and ancient DNA samples taken from Late Bronze Age (ca. 1380-975 BC) burials from the eastern part of the Eurasian Steppe (Northern Mongolia) indicate a population of dairy consumers who lacked the LP gene variant [4]. Genetic studies suggest that a mutation associated with LP emerged in the Ukraine ca. 4000 BC but only increased in frequency across Europe, not Asia [5]. As a result, the LP gene variant is present in less than 5% of modern day Mongolians despite a subsistence economy that is still highly dependent on dairy [4].

    As was true in other parts of the world [3], the adoption of dairy pastoralism in the Eurasian Steppe may not have been reliant on a genetic adaptation for lactose digestion. These prehistoric populations could have had cultural adaptations to lactose digestion, such as fermenting milk to make yogurt, kefir, and cheese to reduce lactose content. They may also have had alterations to their gut microflora that assisted in lactose digestion. Many modern-day populations without the LP gene variant have higher levels of bifidobacteria that increase the digestion of lactose and thereby reduce symptoms associated with lactose intolerance [6]. Dairy may have been critical for population expansions into the Eurasian Steppe, but contrary to what one might expect, genes for lactose digestion were not.

    References

    1. Metcalf JL, Ursell LK, Knight R. 2014. Ancient human oral plaque preserves a wealth of biological data. Nature Genetics 46(4): 321-3.
    2. Wilkin S, Miller AV, Fernandes R, Spengler R, Taylor WTT, Brown DR, Reich D, Kennett DJ, Culleton BJ, Kunz L, Fortes C, Kitova A, Kuznetsov P, Epimakhov A, Zaibert VF, Outram AK, Kitov E, Khokhlov A, Anthony D, Boivon N. 2021. Dairying enabled Early Bronze Age Yamnaya steppe expansions. Nature 598: 629-33.
    3. Bleasdale M, Richter KK, Janzen A, Brown S, Scott A, Zech J, Wilkin S, Wang K, Schiffels S, Desideri J, Besse M. 2021. Ancient proteins provide evidence of dairy consumption in eastern Africa. Nature Communications 12(1): 1-11.
    4. Jeong C, Wilkin S, Amgalantugs T, Bouwman AS, Taylor WTT, Hagan RW, Bromage S, Tsolmon S, Trachsel C, Grossmann J, Littleton J, Makarewicz CA, Krigbaum J, Burri M, Scott A, Davaasambuu G, Wright J, Irmer F, Myagmar E, Boivon N, Robbeets M, Ruhli FJ, Krause J, Frohlich B, Hendy J, Warinner C. 2018. Bronze Age population dynamics and the rise of dairy pastoralism on the eastern Eurasian steppe. Proceedings of the National Academy of Sciences 115: E11248-55.
    5. Segurel L, Guarino-Vignon P, Marchi N, Lafosse S, Laurent R, Bon C, Fabre A, Hegay T, Heyer E. 2020. Why and when was lactase persistence selected for? Insights from Central Asian herders and ancient DNA. PLoS Biology 18(6): e3000742.
    6. Goodrich JK, Davenport ER, Clark AG, Ley RE. 2017. The relationship between the human genome and microbiome comes into view. Annual Review of Genetics 27: 413-33.

    Scientists Comb Human Genome for Clues to Why Milk Sugars Vary Among People

    • Human milk varies substantially in its content of complex sugars called oligosaccharides.
    • A new study is the first genome-wide association study (GWAS) to look for genes affecting milk oligosaccharide composition in humans.
    • Variants of the fucosyltransferase genes FUT2, FUT3, and FUT6 were significantly associated with concentration of particular milk oligosaccharides.
    • Evolutionary forces seem to be maintaining genetic diversity at the FUT2 gene, which suggests that mutations inactivating FUT2 may be beneficial for mother and/or infant health in some contexts.

    Human milk is loaded with complex sugars that babies can’t digest. Called human milk oligosaccharides (HMO), these indigestible sugars are one of the most abundant components of milk in humans. Rather than feeding the infant, up to 200 different types of HMO nourish helpful bacteria and protect against pathogens. But there is much that scientists still don’t understand about the oligosaccharides in human milk, says molecular geneticist Brenda Murdoch, an associate professor at the University of Idaho.

    For a start, not all human milk is the same. Mothers differ substantially in how much of the different kinds of HMOs they produce, says Janet Williams, a senior research scientist at the University of Idaho who studies milk composition in both humans and cattle. Some of the factors that influence HMO concentrations in humans include season, lactation stage, and genetics. A better understanding of these factors could help untangle how the complex mix of HMOs affects the health of mother and baby.

    In a study of 395 people across eight countries, Williams and her colleagues, in collaboration with Murdoch’s team, have performed the first genome-wide association study (GWAS) of milk oligosaccharides in humans, looking for gene variants that influence levels of 19 HMOs. The results confirm that the gene FUT2 plays a major role in HMO composition and has a complex evolutionary history [1].

    The research is part of a broader study of milk that had previously shown HMO profiles differ among populations around the world [2]. Led by Courtney Meehan of Washington State University and Michelle McGuire of the University of Idaho, the INSPIRE study has explored milk composition, the milk microbiome, milk immune factors, and the infant fecal microbiome at 11 sites in Ethiopia, Gambia, Ghana, Kenya, Peru, Sweden, Spain, and the United States [2–8].

    The new analysis explores genetic contributions to the wide variation in milk HMOs [1]. To find gene variants that affect HMO concentrations, the scientists analyzed the genome of each participant and profiled HMO composition in the participant’s milk sample. For each of the 1.7 million genome locations analyzed, the geneticists used statistical tests to look for particular gene variants that were associated with concentrations of each of the 19 HMOs measured.

    The results confirmed that fucosyltransferase enzymes are central to HMO composition. Fucosyltransferases catalyze a key early step in formation of HMOs, adding a fucose component to the core oligosaccharide structure.

    In this study, variants in FUT2 (which encodes ɑ-1,2-fucosyltransferase) were strongly associated with concentrations of seven HMOs [1]. This was not a surprise; FUT2 variants control a human trait known as “secretor” status that includes effects on HMOs. People with secretor status make milk rich in certain HMOs, whereas these HMOs are vanishingly scarce in the milk of non-secretor individuals. This is thought to be because the FUT2 gene variants of non-secretors don’t make functional ɑ-1,2-fucosyltransferase enzyme [9–11]. The new data support this idea, finding that mutations disrupting or inactivating the encoded enzyme have lower concentrations of particular HMOs.

    The new study also revealed an inverse relationship in how FUT2 variants affect different HMOs. Several of the FUT2 variants were associated with higher levels of three types of HMOs but lower levels of four other HMOs. This observation suggests that a previously observed negative correlation among these groups of HMOs can be explained by genetic variation at FUT2 [2, 12].

    Two other fucosyltransferase genes, FUT3 and FUT6, were associated with concentrations of a particular HMO. FUT3, which encodes ɑ-1-3/4-fucosyltransferase, is known for determining the Lewis blood type and influencing HMO composition [13].

    Mutations that inactivate FUT2 are common in many human populations, and previous studies of FUT2 and FUT3 have found evidence for balancing selection in their evolutionary history [14–18]. Balancing selection occurs when evolutionary forces favor the maintenance of genetic variation at a gene. The most famous example of genetic diversity maintained by balancing selection is the mutation that causes sickle cell anemia. Inheriting this mutation from both parents causes sickle cell anemia, but inheriting a mutated copy from one parent and the non-mutated version from the other parent does not normally cause anemia symptoms and has the added bonus of providing protection against malaria. These opposing selective forces have maintained the disease-associated allele in areas where malaria is common [19].

    The new study looked at patterns of genetic diversity and found evidence of balancing selection for FUT2 but not FUT3. This suggests that there is some evolutionary advantage to maintaining genetic diversity in FUT2. But what is that advantage? Like sickle cell anemia, the boost probably relates to disease—many studies have found secretor status is linked to increased susceptibility to some pathogens and increased resistance to others [20].

    However, the story is further complicated by the fact that the same fucosyltransferases that make milk oligosaccharides are needed for making many other sugars important for health, including blood group antigens in the mucus layer of the gut lining and respiratory system. There is even a link between FUT2 and FUT6 gene variants and blood plasma vitamin B12 status [21]. A selective advantage of the FUT2 mutation could relate to any of these biological roles or to some combination.

    There is much more to learn about genetic variation in HMOs, the researchers say. For example, although there was not much evidence for genetic influences on HMOs outside of fucosyltransferases, Williams points out that even when you discount the major effects of FUT2 by considering just secretors (or just non-secretors), HMO profiles still vary a lot among women—so there may well be more genetic factors to find.

    Additional genes might be linked to more HMOs in the future by including more participants and analyzing additional genomic locations and variant types. “Milk is one of the first and primary food sources,” says Murdoch. “We really don’t know as much about it as we should.”

    References

    1. Williams, J. E., McGuire, M. K., Meehan, C. L., McGuire, M. A., Brooker, S. L., Kamau-Mbuthia, E. W., Kamundia, E. W., Mbugua, S., Moore, S. E., Prentice, A. M., Otoo, G. E., Rodríguez, J. M., Pareja, R. G., Foster, J. A., Sellen, D. W., Kita, D. G., Neibergs, H. L., and Murdoch, B. M., 2021. Key genetic variants associated with variation of milk oligosaccharides from diverse human populations. Genomics. 113: 4. 1867–1875, doi: 10.1016/j.ygeno.2021.04.004.
    2. McGuire, M. K., Meehan, C. L., McGuire, M. A., Williams, J. E., Foster, J., Sellen, D. W., Kamau-Mbuthia, E. W., Kamundia, E. W., Mbugua, S., Moore, S. E., Prentice, A. M., Kvist, L. J., Otoo, G. E., Brooker, S. L., Price, W. J., Shafii, B., Placek, C., Lackey, K. A., Robertson, B., Manzano, S., Ruíz, L., Rodríguez, J. M., Pareja, R. G., and Bode, L., 2017. What’s normal? Oligosaccharide concentrations and profiles in milk produced by healthy women vary geographically. The American Journal of Clinical Nutrition. 105: 5. 1086–1100, doi: 10.3945/ajcn.116.139980.
    3. McGuire, M. K., Randall, A. Z., Seppo, A. E., Järvinen, K. M., Meehan, C. L., Gindola, D., Williams, J. E., Sellen, D. W., Kamau-Mbuthia, E. W., Kamundia, E. W., Mbugua, S., Moore, S. E., Prentice, A. M., Foster, J. A., Otoo, G. E., Rodríguez, J. M., Pareja, R. G., Bode, L., McGuire, M. A., and Campo, J. J., 2021. Multipathogen analysis of IgA and IgG antigen specificity for selected pathogens in milk produced by women from diverse geographical regions: The INSPIRE Study. Frontiers in Immunology. 11, doi: 10.3389/fimmu.2020.614372
    4. Pace, R. M., Williams, J. E., Robertson, B., Lackey, K. A., Meehan, C. L., Price, W. J., Foster, J. A., Sellen, D. W., Kamau-Mbuthia, E. W., Kamundia, E. W., Mbugua, S., Moore, S. E., Prentice, A. M., Kita, D. G., Kvist, L. J., Otoo, G. E., Ruiz, L., Rodríguez, J. M., Pareja, R. G., McGuire, M. A., Bode, L., and McGuire, M. K., 2021. Variation in human milk composition is related to differences in milk and infant fecal microbial communities. Microorganisms. 9: 6. 6, doi: 10.3390/microorganisms9061153.
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