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Human Milk SIgA Shapes a Protective Gut Microbiome

    A baby in a crib. As infants cannot produce enough secretory immunoglobulin A on their own, they rely on human milk sIgA to bind to invading bacteria.

    Written by: Lauren Milligan Newmark, Ph.D. | Issue # 128 | 2025

    • The human milk antibody sIgA selectively binds bacteria in the infant’s gut and contributes to the establishment of a healthy, balanced gut microbiome.
    • A new study identified the gut bacterium E. ramosum as an important target of human milk sIgA.
    • Cell culture models demonstrated that binding by human milk sIgA to the microbe E. ramosum limited the microbe’s ability to attach to the intestinal lining and trigger inflammatory immune responses.
    • SIgA-driven regulation of E. ramosum may be one mechanism by which human milk protects against allergy, asthma, or other chronic conditions. 

    Secretory immunoglobulin A (sIgA) is the most abundant immune protein in human milk and likely the hardest working. From its first day on the job, this antibody actively  protects infants from acute infections. Unable to produce enough sIgA to effectively fight on their own, infants rely on sIgA provided by human milk to bind to invading bacteria and viruses and prevent their attachment to mucosal surfaces, including the digestive tract [1, 2]. 

    SIgA is also the most abundant antibody in the human gut [1]. In addition to its role of targeting infection-causing pathogens in the digestive tract, milk sIgA selectively binds beneficial and harmful gut bacteria. This binding influences bacterial growth and thus the types and quantities of microbes that make up the infant’s gut microbiota [3-5]. 

    Human milk sIgA’s role in immediate infection protection is well established, but the long-term health impacts of its interactions with gut microbes are still emerging [1-3, 5, 7, 8]. Recent research aims to understand how milk sIgA may prevent early gut imbalances, which are linked to chronic conditions like inflammatory bowel disease, asthma, and allergies [8-11]. 

    A new paper [1] by a team of microbiologists and immunobiologists from the University of British Columbia, Vancouver (UBC) explored how human milk sIgA’s ability to bind gut bacteria may reduce inflammatory immune responses, particularly those involving T helper 17 (Th17) cells. The UBC team’s previous research [7] found mouse milk sIgA limited the colonization of segmented filamentous bacteria (SFB), a bacteria known to trigger Th17 responses in the mouse infant’s gut and lungs. The restriction of SFB growth by mouse milk sIgA during early life correlated with decreased Th17 activity in lungs and reduced susceptibility to asthma [7].

    Encouraged by this novel finding, the UBC researchers then turned their attention to human milk sIgA and human infant gut bacteria to look for a counterpart to mouse SFB. They examined previously collected data for the CHILD cohort study, a longitudinal study following thousands of Canadian infants and their mothers from pregnancy through adulthood. Three hundred mother-infant dyads were selected from this larger population. All infants were fed human milk for at least three months. Mothers provided a milk sample at three months, an infant fecal sample at three months, and an infant serum sample at one year of age [1]. The CHILD cohort dataset also included the atopic status (i.e., having a sensitive immune system that is prone to allergies) of mothers and infants, allowing the researchers to test hypotheses regarding milk sIgA binding and the development of allergies.

    Total milk sIgA levels at 3 months did not significantly differ between atopic and non-atopic mothers or between atopic and non-atopic infants. However, serum samples collected at one year did correlate with milk sIgA concentration at three months [1]. Infants who received less total milk sIgA at three months of age had significantly higher levels of immune markers associated with a Th17 (or pro-inflammatory) response. This finding suggested that, just as the UBC team had observed in their mouse model [7], sIgA delivered in human milk in early infancy may have long-lasting impacts on infant immunity. 

    The next step in the study was determining the mechanism by which sIgA delivered from milk helps keep a Th17 immune response in check. For this, the researchers compared binding capabilities of milk sIgA with the proportion of specific microbes in the infant gut (estimated from fecal samples).

    Milk sIgA originates from plasma cells in the mother’s gut-associated lymphoid tissue (GALT). Antibodies then migrate from the mother’s GALT to the mammary gland during lactation, and the sIgA passed in milk represents the mother’s microbial and pathogen experience.  

    “We believe that shifts in the mother’s microbiome can cause shifts in the sIgA in milk,” explains Dr. Katherine Donald, a Postdoctoral researcher in UBC’s Department of Microbiology and Immunobiology and lead author of this study. “The assumption is that if the mother makes sIgA directed at a bacterium, this sIgA was derived from the maternal gut where the mother herself had this bacterium,”

    Looking at sIgA’s specific targets, the researchers found high amounts of sIgA binding were associated with a higher concentration of the majority of microbes [1]. For these bacteria, the binding action of milk sIgA is believed to have resulted in their proliferation. There was one notable exception; Erysipelatoclostridium ramosum was the only microbe in the infant gut whose concentration had a negative correlation with targeted milk sIgA [1]. More milk sIgA did not result in more E. ramosum, it resulted in less. Why might milk sIgA limit the growth of this bacteria?

     “E. ramosum is a consistent marker of allergy development…it has the most consistent association with allergies in studies from all across the world,” says Donald. “E. ramosum is consistently present in infant guts.” Across the entire CHILD cohort (both infants with and without allergies), E. ramosum levels were higher in one year old infants compared with three month olds [1]. “It is just that if this bacterium blooms too early in infant gut maturation, it could predispose the infant to allergies.” 

    To observe milk sIgA and E. ramosum’s interactions, the UBC team created an in vitro model of the epithelial cells that line the human infant’s intestines. Before the addition of human milk sIgA, E. ramosum adhered to the epithelial cells. This adherence was associated with a subsequent increase in the cells’ production of markers of inflammation consistent with a Th17 response [1]. In contrast, when sIgA (purified from 20 milk samples with high E. ramosum sIgA binding capacity) was added to the cell culture, adherence was reduced and Th17-associated responses were dampened [1].

    “We found that sIgA gets in the way of [E. ramosum’s] colonization,” says Donald. “Some bacteria were helped by sIgA to adhere to cell walls while others were inhibited, but not fully prevented. It wasn’t that sIgA stopped E. ramosum from growing completely, it just slowed that growth.”

    Based on these study results, you might think E. ramosum is a bacteria you don’t want in your gut microbiome. But as Donald explains, “ E. ramosum isn’t a pathogen.” Instead, E. rasomum is considered a pathobiont [1]; under certain conditions (e.g., there is too much of it in the infant’s gut, too early in the infant’s life) it can contribute to the development of diseases. “It is all about timing and balance,” says Donald. “At one year of age, is it believed that having E. rasomum at 1 – 2% of total [gut] bacteria is optimal, but at three months it should be low or undetectable.” 

    SIgA has always been considered a critical human milk ingredient for its ability to neutralize infection-causing pathogens. Its potential to control the development of the human infant gut microbiome provides yet another compelling reason to encourage and support mothers in providing their infants with human milk. At the same time, makers of infant formula should take note of these study results. If milk sIgA directed at E. ramosum can provide protection against the development of chronic diseases, including allergies, then infant formula developers might consider exploring ways to incorporate similar immune-modulating components or design formulas that otherwise support the establishment of a beneficial gut microbiome, potentially reducing the risk of allergies and other long-term health issues in formula-fed infants.

    Human milk feeding is consistently linked to a reduced risk of chronic diseases and sIgA-mediated control of E. ramosum may be one mechanism by which human milk protects against allergy, asthma, or other chronic conditions. That a similar mechanism was found in a mouse model suggests that milk sIgA’s actions in the infant gut to prevent inflammatory responses in early life could be a shared adaptive mechanism across mammals [1]. If true, that could mean milk sIgA has been hard at work for over 65 million years. 

     

    References

    1. Donald K, Serapio-Palacios A, Bozorgmehr T, Ma M, Garcia MA, Petersen C, Mandhane P, Subbarao P, Moraes TJ, Simons E, Turvey S. Human milk IgA promotes normal immune development by limiting Th17-inducing Erysipelatoclostridium ramosum in the infant gut. Proceedings of the National Academy of Sciences. 2025 Jul 15; 122(28): e2501030122.
    2. Rio-Aige K, Azagra-Boronat I, Castell M, Selma-Royo M, Collado MC, Rodríguez-Lagunas MJ, Pérez-Cano FJ. The breast milk immunoglobulinome. Nutrients. 2021 May 26;13(6): 1810.
    3. Pabst O, Slack E. IgA and the intestinal microbiota: the importance of being specific. Mucosal Immunology. 2020 Jan 1;13(1):12-21.
    4. Rogier EW, Frantz AL, Bruno ME, Wedlund L, Cohen DA, Stromberg AJ, Kaetzel CS. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proceedings of the National Academy of Sciences. 2014  Feb 25;111(8): 3074-9.
    5. Donald K, Petersen C, Turvey SE, Finlay BB, Azad MB. Secretory IgA: linking microbes, maternal health, and infant health through human milk. Cell Host & Microbe. 2022 May 11;30(5):650-9.
    6. Akagawa S, Kaneko K. Gut microbiota and allergic diseases in children. Allergology International. 2022;71(3):301-9.
    7. Donald K, Serapio-Palacios A, Gerbec Z, Bozorgmehr T, Holani R, Cruz AR, Schnupf P, Finlay BB. Secretory IgA in breast milk protects against asthma through modulation of the gut microbiota. Cell Reports. 2024 Oct 22;43(10).
    8. Guo J, Ren C, Han X, Huang W, You Y, Zhan J. Role of IgA in the early-life establishment of the gut microbiota and immunity: Implications for constructing a healthy start. Gut Microbes. 2021 Jan 1;13(1):1908101.
    9. Sarkar A, Yoo JY, Valeria Ozorio Dutra S, Morgan KH, Groer M. The association between early-life gut microbiota and long-term health and diseases. Journal of Clinical Medicine. 2021 Jan 25;10(3):459.
    10. Arrieta MC, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, Kuzeljevic B, Gold MJ, Britton HM, Lefebvre DL, Subbarao P. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Science Translational Medicine. 2015 Sep 30;7(307):307ra152
    11. Donald K, Finlay BB. Early-life interactions between the microbiota and immune system: impact on immune system development and atopic disease. Nature Reviews Immunology. 2023 Nov;23(11):735-48.