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Molecules in Human Milk Boost Immunity Even in the Absence of Milk-digesting Bacteria

    fucosyllactose human milk HMO

    Written by: Jyoti Madhusoodanan | Issue # 111 | 2022

    • Human milk oligosaccharides (HMOs) promote the growth of beneficial gut bacteria and modulate immune responses.
    • In germ-free mice, HMOs boosted immune responses both in intestinal cells and the rest of the body.
    • Future studies could reveal a therapeutic use for HMO supplements in pills or infant formula.

    In 2013, Laxmi Yeruva was not just a researcher—she was also a new mother trying to figure out the best foods for her baby. Like many parents, Yeruva breastfed her infant and supplemented his diet with formula. The personal experience fueled her wonder about the chemistry of human milk.

    As a molecular microbiologist and immunologist at Arkansas Children’s Nutrition Center in Little Rock, part of the United States Department of Agriculture-Agricultural Research Service (USDA-ARS), Yeruva homed in on one component: human milk oligosaccharides, also known as HMOs. These short, complex carbohydrate molecules are the third-most abundant component in human milk, preceded only by lactose and fats. More than 160 different HMOs have been identified thus far. “But only a handful have been extensively studied,” Yeruva said in an interview.

    In previous studies, researchers found that HMOs promote the growth of beneficial bacteria in the intestines of animal models and studies of infants. These chemicals also block pathogens from binding to immune cells and can thereby reduce infection rates in the GI tract. In addition to boosting the growth of the gut microbiome, HMOs also appear to modulate immunity, such as by improving responses to the influenza vaccine in a study conducted in mice [1].

    But all these studies were conducted in the presence of gut bacteria, Yeruva said. Could HMOs have direct effects on the immune system in the absence of bacteria?

    In a recent study, Yeruva and her colleagues set out to identify the effects of HMOs in the absence of bacteria by studying these molecules in germ-free mice [2]. The team treated 21-day-old germ-free mice with a pool of HMOs isolated from human milk—not just a subset of these molecules. The team fed mice a 15 mg/day HMO dose each day for either 7 or 14 days and then euthanized them either 28 or 35 days later. Another set of mice were kept alive for 50 days. In addition to the HMOs, the mice had unlimited amounts of food and water. For each time span studied, the researchers also maintained a control group of animals as a comparison to understand the effects of HMOs.

    When they ended the treatment, the researchers studied the physical development of intestinal tissues and changes in gene expression that resulted from feeding the HMOs. The intestines of animals fed the HMOs had shallower folds and glands. It’s still a mystery why HMOs in the absence of microbes appear to have this effect, Yeruva says. “I’m still trying to understand what this means.”

    In the intestinal tissue, the presence of HMOs triggered the expression of genes necessary for their transport, absorption, and secretion. The researchers also found that HMOs had a strong impact on the immune response even in the absence of microbes—not just within the gastrointestinal tract but affecting immune cells such as T-regulatory cells and macrophages in the bloodstream. “HMOs truly impact the whole body’s immune response, and their presence could help with responding to vaccines,” Yeruva says.

    The data suggest that the impact of HMOs is not solely because of their effects on gut bacteria. These milk molecules affect intestinal metabolism and the immune system even in the absence of the microbiome. “I was pleasantly surprised to see this direct effect without microbiota,” Yeruva says. “I’m excited to see there’s a potential benefit.”

    If future studies continue to reveal a strong role for HMOs, they could eventually be used as supplements for sick or immunocompromised children to improve their health, Yeruva says.



    1. Xiao L, Leusink-Muis T, Kettelarij N, Van Ark I, Blijenberg B, Hesen NA, Stahl B, Overbeek SA, Garssen J, Folkerts G, van’t Land B. Human milk oligosaccharide 2′-fucosyllactose improves innate and adaptive immunity in an influenza-specific murine vaccination model. Frontiers in Immunology. 2018 Mar 9;9:452.
    2. Rosa F, Sharma AK, Gurung M, Casero D, Matazel K, Bode L, Simecka C, Elolimy AA, Tripp P, Randolph C, Hand TW, Williams KD, LeRoith T, Yeruva L. Human milk oligosaccharides impact cellular and inflammatory gene Expression and immune response. Frontiers in Immunology. 2022;13.