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HMOs Might Boost Immune Response via Gut Microbes in Mice

    An image of bacteria. A study suggests that fucose-bearing HMOs affects the infant immune response, gut microbiome, and their gut development.

    Written by: Jyoti Madhusoodanan, Ph.D. | Issue # 122 | 2024

    • Some people, known as secretors, carry a gene that adds the molecule fucose to human milk oligosaccharides (HMOs), altering the cocktail of HMOs an infant receives in mother’s milk.
    • Mice colonized with microbiota from infants fed secretor mother’s milk and non-secretor mother’s milk have distinct gut microbiota. 
    • Dietary HMO has no impact on immune responses of mice with human milk-fed microbiota but offers an immune boost to animals with formula-fed microbiota. 

    Small, sugary molecules known as human milk oligosaccharides (HMOs) are the third most abundant component in a mother’s milk. They are critical players in the development of infant immune response and gut microbiome. HMOs are a diverse group of chemicals, and many factors determine the exact cocktail that a child consumes in milk. One key factor is a mother’s genetics. People with one form of the FUT2 gene produce an enzyme that adds a sugar named fucose to HMOs.  

    Now, a new study suggests that the presence of these fucose-bearing HMOs can have a unique impact on an infant’s developing gut microbiome, and, as a result, affect their gut development and immune system [1]. 

    People with the FUT2 allele are known as secretors, and those who do not are known as non-secretors. In previous studies, researchers have reported that mothers who are secretors and babies who consume their milk have higher levels of Bifidobacterium species in their gut microbiome, known to be a beneficial species [2]. Animal studies suggest that fucosylated HMOs can enhance immunity, reducing the incidence of necrotizing enterocolitis in mice and causing higher levels of antibodies against influenza [3]. “Thus far, no one had looked at whether a mother’s secretor status affected a baby’s gut microbes and thus, their immune system,” said the study’s senior author Laxmi Yeruva, a molecular microbiologist and immunologist at Microbiome and Metabolism Research Unit and Arkansas Children’s Nutrition Center in Little Rock, part of the United States Department of Agriculture-Agricultural Research Service (USDA-ARS). 

    In the new study, Yeruva and her colleagues transplanted gut microbes from infants into germ-free mice. They used three groups of microbes: one from babies who were fed mother’s milk from secretor moms (SMM), another from babies of non-secretor moms (NSM), and a third from babies who were fed formula that was not fortified with HMOs (FM). 

    Each group was then split into two, so one half of each was given supplemental HMOs in their diet. The experiments also included a germ-free control group of animals that did not receive supplements, and groups of mice were colonized with bacterial samples when they were 3 weeks old and again at 4 weeks of age. 

    The researchers examined three factors: the bacterial populations in the animals’ gut microbiota, physical structure of the intestines, and immune differences amongst the various groups of mice.  

    The team found that across all the groups, the gut microbiota in mice was most strongly correlated with the source of intestinal microbes. Supplementary HMOs in the diet had little impact on the gut microbial community. However, the gut microbiome had distinct features depending on whether infants were fed formula or mother’s milk from secretor mothers or non-secretor mothers. Mice with gut microbes from infants fed secretor mother’s milk had a higher proportion of Bacteroides and Bifidobacter species; NSM and NSM + HMOs groups had a higher abundance of Klebsiella, Enterocloster, and other species; FM and FM+ HMO groups had higher levels of Clostridium and Parabacteroides species. 

    The researchers also observed differences in the intestines of each group, such as higher villi, fingerlike projections that help move nutrients into circulation, in the ileum of the NSM microbiome group, and longer cecal glands in the formula group. 

    The group measured immune system differences in spleen samples, which help gauge systemic immunity, and in samples from the mesenteric lymph node, which reveal local immune response within the gut. They found that the SMM group had less inflammation when measured in the spleen. But mice with the HMO-supplemented, formula-based gut microbiota had stronger anti-inflammatory regulatory T-cell expression in the local lymph nodes. “It seems like maybe the response that’s generated in the gut in the formula fed group is not fully circulating in the system,” Yeruva said. 

    Mice that had formula-raised gut microbes and HMO supplementation in their diets had the highest levels of circulatory immunoglobulin A compared to all the other groups. “I was very surprised with that,” Yeruva said. One possible explanation, she added, is that microbiomes from maternal milk-fed infants have already been exposed to HMOs, whereas HMOs are a new food for the formula group. “It’s brand new and they might be producing some specific set of metabolites in response so there is a better immunoglobulin A response.” 

    Still, more work is needed to better understand how fucosylated molecules in human milk might shape the infant gut microbiome and immune system. Although the current study found few differences, Yeruva highlighted some possible explanations. The researchers did not study the secretor status of infants themselves, only the mothers. It’s possible that the transplanted microbiota could have already been influenced by fucosylated glycans produced in the infants’ intestines. Another source of variability is the mice themselves, since mouse intestines are also rich in fucosylated glycans. In ongoing and future studies, the researchers aim to home in on specific HMOs and elucidate the importance of specific molecules. 

    References

    1. Gurung M, Schlegel BT, Rajasundaram D, Fox R, Bode L, Yao T, Lindemann SR, LeRoith T, Read QD, Simecka C, Carroll L., Andres A., Yeruva, L. Microbiota from human infants consuming secretors or non-secretors mothers’ milk impacts the gut and immune system in mice. Msystems. 2024 Apr 16;9(4):e00294-24.
    2. Wacklin P, Mäkivuokko H, Alakulppi N, Nikkilä J, Tenkanen H, Räbinä J, Partanen J, Aranko K, Mättö J. Secretor genotype (FUT2 gene) is strongly associated with the composition of Bifidobacteria in the human intestine. PLOS ONE. 2011 May 19;6(5):e20113.
    3. Good M, Sodhi CP, Yamaguchi Y, Jia H, Lu P, Fulton WB, Martin LY, Prindle T, Nino DF, Zhou Q, Ma C. The human milk oligosaccharide 2′-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine. British Journal of Nutrition. 2016 Oct;116(7):1175-87.