Breast milk calibrates neonatal immune responses to gut bacteria in mice

Fred Hutchinson Cancer Center reports that maternal immunoglobulin G (IgG), ingested in the first week of life, restrained microbiota-dependent adaptive immune responses weeks later, after weaning in mice. Investigators identified a critical early-life window when ingested IgG tunes responses to commensal microbes and dietary antigens.

For mammals, the postnatal window is a critical phase of immune development, when properly calibrating responses to newly encountered microbes and other environmental antigens is essential to health.

Breast milk shapes gut mucosal immunity by supplying the infant gut with living microbes, bacteria-selecting oligosaccharides, maternal cells, and immune mediators—including antibodies.

Multiple antibody classes, including IgA, IgG, and IgM, are present in breast milk. Previous work has focused on IgA in adult mucosal defense, but neonatal gut physiology differs from adults. IgG is abundant in milk, yet its role in neonatal immunity has remained unclear.

In the study, “Breast milk IgG engages the mouse neonatal immune system to instruct responses to gut antigens,” published in Science, researchers developed a strategy to dissect the specific contributions, timing, and function of breast milk antibodies during the postnatal period.

Researchers raised newborn mice either with or without maternal antibodies. Some pups were cross-fostered to mothers at birth or later, to control the timing of antibody exposure. Small amounts of purified IgG, taken from milk or blood, were fed directly to pups during the first week of life.

Germ-free conditions and antibiotics were used to test whether the presence of gut bacteria mattered. Investigators compared different forms of IgG and tracked which subclasses bound to bacteria in the gut. Mice missing key receptors that normally sense antibodies or complement proteins were also tested. Finally, pups were challenged in disease models that included chemically induced colitis and food allergy responses.

Receiving maternal antibodies in the first week of life prevented exaggerated immune reactions later on. Without early antibodies, young mice developed overactive T follicular helper cells and B cells in gut tissues after weaning. Gut microbes were required for the exaggerated immune responses in gut tissues.

Feeding purified IgG alone during the first week was enough to restore control, even at very low doses. IgG bound directly to bacteria in the neonatal gut, most strongly through IgG2b and IgG3 subclasses. Antibodies did not significantly alter the types of microbes present or the integrity of the gut barrier.

Complexes formed between IgG and microbes activated neonatal antibody-sensing receptors and complement proteins. Removing both sensing systems eliminated the protective effect. Mice that received early IgG were also more resistant to colitis and had fewer allergic responses to dietary proteins.

The researchers conclude that maternal IgG serves as an active instructor of immune development. By forming complexes with commensals during the first postnatal week, IgG calibrates tolerance mechanisms that reduce the risk of inflammatory or allergic disease. Findings suggest that maternal antibodies not only protect neonates from pathogens but also provide critical instruction for long-term gut immune health.

While mice are a common model for biology that may translate to humans in research, it should be noted that mouse milk has proportionately higher IgG content than human milk.

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