Some Human Milk Oligosaccharides May Temper Asthma Risk

Written by: Alla Katsnelson, Ph.D | Issue # 123 | 2024

Human milk oligosaccharides (HMOs) are a key component of breastmilk—and one which infants, ironically, cannot digest. A given person’s breastmilk contains varying proportions of about 200 different kinds of these sugar molecules [1], and the lineup helps shape infants’ gut microbiomes. 

A new study shows that breastmilk containing high levels of a specific type of HMO can protect babies with a genetically heightened risk for asthma. [2]. The study,  the largest to date to explore the role of individual HMOs on children’s respiratory health, identified variants in the maternal genome that regulate the HMO makeup of breastmilk. The findings add to the growing body of knowledge about the health effects of HMOs and may help scientists develop systems for synthesizing HMOs in the lab, the authors say. 

“There is an incredible diversity of HMOs in human milk, and we are starting to uncover what’s driving that diversity in terms of human genetics” says Meghan Azad, a professor of pediatrics and child health at the University of Manitoba, who co-led the work. 

The current study builds on the researchers’ previous work on maternal genetics and HMOs. In a 2018 publication, they analyzed maternal genetics and breast milk samples from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort study, a birth cohort of 3500 families started in 2010 [3]. They found enormous variation in HMO concentrations across mothers.

In the new work , the researchers again analyzed data from  the CHILD cohort, this time analyzing the variation in the 19 HMOs present at greatest concentrations along with genetic data from 980 mothers and their children. Rather than thinking about breastmilk as a single variable, they focused on the interactions within what researchers term the mother-milk-infant triad [4]. “The mothers’ genetics, the babies’ genetics, the HMOs – they all interact,” says Azad. Those interactions are dynamic: the milk consists of various components, and those components not only vary across mothers, but also change over time, due to both environmental factors and changing needs of the developing infant. 

The strongest association to emerge from the data, which had been previously identified, linked several variants in the gene encoding fucosyltransferase 2 (FUT2) with whether a mother’s HMO mix included certain HMOs tagged with a sugar called fucose [5]. Most mothers in the study – 73% — carried variants of FUT2 that maintained its function, and a high proportion of their HMOs was fucosylated. Mothers with FUT2 variants that incapacitated both copies of the gene carried more HMOs without fucose. Mothers who had one particular FUT2 variant almost completely lacked three fucosylated HMOs, and overall, their HMO makeup tended strongly toward non-fucosylated HMOs.

The researchers then examined how different HMO combinations in breastmilk affected whether or not infants in the study developed asthma as they got older.  Breastmilk containing high concentrations of certain fucosylated HMOs mitigated asthma risk, but only in children who carried gene variants that raise the risk for developing asthma. “It’s a complicated relationship – which, as a milk scientist doesn’t surprise me,” Azad says. “The story is going to be different depending on the children’s own genetics.” 

The researchers are continuing to follow children from the study as they get older. They are also using the CHILD study cohort to investigate how HMOs consumed in infancy might affect other conditions, such as diabetes and  attention-deficit/hyperactivity disorder.  Additionally, Azad and her colleagues are currently studying whether donor milk banks should sort their supplies based on which FUT2 gene variants donors carry. Babies whose mothers have functioning FUT2 genes may benefit from donor milk from mothers with the same FUT2 status, she says. 

In addition to linking HMOs to respiratory disorder, the current study also identified known and novel variants in FUT2 and in other genes that play a role in synthesizing HMOs. “That gives some new information to people who are trying to find ways of making these HMOs for therapeutic applications,” Azad says. 

Although formula companies have begun adding a few of the easiest-to-synthesize HMOs to formula, Azad notes that the study’s findings underscore how difficult it is to artificially replace HMOs. “Even if you could make all the HMOs that breastmilk contains and put them in formula, we’ve clearly shown that each mom has a different make-up of HMOs,” she says. 

Considering that HMOs are known to affect the gut microbiome, synthesized versions may have benefits beyond breastmilk and formula. For example, they may help people with inflammatory bowel disease regulate their microbiome, Azad says. “I think there are probably lots of lessons we can learn from HMOs and human milk that can be applied to other life stages and conditions.” 

References

1. Bode L. Human milk oligosaccharides: prebiotics and beyond. Nutr Rev. 2009; 67 Suppl 2:S183-91. 
2. Ambalavanan A, Chang L, Choi J, Zhang Y, Stickley SA, Fang ZY, Miliku K, Robertson B, Yonemitsu C, Turvey SE, Mandhane PJ, Simons E, Moraes TJ, Anand SS, Paré G, Williams JE, Murdoch BM, Otoo GE, Mbugua S, Kamau-Mbuthia EW, Kamundia EW, Gindola DK, Rodriguez JM, Pareja RG, Sellen DW, Moore SE, Prentice AM, Foster JA, Kvist LJ, Neibergs HL, McGuire MA, McGuire MK, Meehan CL, Sears MR, Subbarao P, Azad MB, Bode L, Duan Q. Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children. Nat Commun. 2024;15(1):7735. 
3. Azad MB, Robertson B, Atakora F, Becker AB, Subbarao P, Moraes TJ, Mandhane PJ, Turvey SE, Lefebvre DL, Sears MR, Bode L. Human Milk Oligosaccharide Concentrations Are Associated with Multiple Fixed and Modifiable Maternal Characteristics, Environmental Factors, and Feeding Practices. J Nutr. 2018;148(11):1733-1742. 
4. 1: Bode L, Raman AS, Murch SH, Rollins NC, Gordon JI. Understanding the mother-breastmilk-infant “triad”. Science 2020;367(6482):1070-1072.
5. Bode L. The functional biology of human milk oligosaccharides. Early Hum Dev. 2015;91(11):619-22.

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