Development of the gut microbiota and mucosal IgA responses in twins and gnotobiotic mice

Immunoglobulin A (IgA), the major class of antibody secreted by the gut mucosa, is an important contributor to gut barrier function(1–3). The repertoire of IgA bound to gut bacteria reflects both T cell-dependent and -independent pathways(4,5), plus glycans present on the antibody’s secretory component(6). Human gut bacterial taxa targeted by IgA in the setting of intestinal barrier dysfunction are capable of producing intestinal pathology when isolated and transferred to gnotobiotic mice(7,8). A complex reorientation of gut immunity occurs as infants transition from passively acquired IgA present in breast milk to host-derived IgA(9–11). How IgA responses co-develop with assembly of the microbiota during this period remains poorly understood. Here, we (i) identify a set of age-discriminatory bacterial taxa whose representations define a program of microbiota assembly/maturation during the first 2 postnatal years that is shared across 40 healthy USA twin pairs; (ii) describe a pattern of progression of gut mucosal IgA responses to bacterial members of the microbiota that is highly distinctive for family members (twin pairs) during the first several postnatal months then generalizes across pairs in the second year; and (iii) assess the effects of zygosity, birth mode and breast feeding. Age-associated differences in these IgA responses can be recapitulated in young germ-free mice, colonized with fecal microbiota obtained from two twin pairs at 6 and 18 months of age, and fed a sequence of human diets that simulate the transition from milk feeding to complementary foods. The majority of these responses were robust to diet suggesting that ‘intrinsic’ properties of community members play a dominant role in dictating IgA responses. The approach described can be used to define gut mucosal immune development in health and disease states and help discover ways for repairing or preventing perturbations in this facet of host immunity.