The role of breastmilk IgA in infant gut microbiota and immune development

The gut microbiota is highly dynamic in the first year of life and plays a pivotal role in immune development. Dysbiosis in the gut microbiota during this period has been linked to later development of numerous immune-mediated diseases, including allergies and asthma, but the specific host-microbe interactions that contribute to this phenomenon are still being uncovered. Secretory IgA (SIgA) is the most abundant antibody in the gut, and a key determinant of gut microbiota composition. During the first months of life, infants are not yet able to produce SIgA, receiving it instead through breastmilk. Breastmilk SIgA is known to protect infants against infections previously encountered by the mother. However, the effects of this antibody on infant gut microbiota composition, and thus immune development, have not been defined. This thesis investigates the role of breastmilk SIgA in guiding microbe-mediated immune imprinting in early life. Chapter 2 uses a mouse model of SIgA deficiency to show that maternal milk SIgA targets and limits the immunostimulatory microbe Segmented Filamentous Bacteria (SFB) in the neonatal murine gut, preventing premature activation of the intestinal Th17 cell responses and protecting against Th17-mediated asthma. Chapter 3 characterizes the human breastmilk SIgA repertoire in mothers enrolled in the CHILD Cohort Study, a longitudinal birth cohort in Canada, demonstrating a relationship between breastmilk SIgA-bacteria binding patterns and infant gut microbiota composition. This chapter identifies the bacterium Erysipelatoclostridium ramosum as an immunologically important target of breastmilk SIgA in the infant gut, and a potential human analogue to the well-studied and disease-relevant mouse pathobiont, SFB. Chapter 4 takes advantage of the techniques developed throughout Chapters 2 and 3 to elucidate the relationship between the maternal gut microbiota, breastmilk SIgA, and bacterial colonization dynamics in the offspring. This chapter confirms the ability of SIgA to mediate mother-to-offspring microbiota transfer. In summary, using in vivo models, human samples, longitudinal human health data, and cell culture, this work defines a significant role for breastmilk SIgA in guiding early-life gut microbiota and immune maturation, with important implications for future developments in preventative medicine and infant nutrition.