Bifidobacterium-driven immunoglobulin A production in pediatric patients with IgA deficiency and recurrent respiratory infections

Background: Immunoglobulin A (IgA) deficiency is the most common primary antibody deficiency and a key factor contributing to recurrent respiratory tract infections (rRTIs) in children, with prevalence rates ranging from 1:4 to 1:65. Previous studies in healthy humans and animal models have shown that the gut microbiota significantly influences IgA production. We investigated the role of the intestinal microbiota in IgA deficiency and its potential in promoting IgA induction in children with rRTIs. Results: Children under seven years of age with rRTIs were enrolled in a prospective cohort study. Serum and feces were collected for IgA level measurement using ELISA and to determine the composition of the intestinal microbiota by 16S-rRNA sequencing. We included 82 children with rRTIs, 38% of whom were IgA deficient. The microbiota composition of IgA deficient children differed from that of symptomatic non-IgA deficient children (PERMANOVA R2 2.4%, p=0.02). Feces from a subgroup of children with and without IgA deficiency was used to inoculate germ-free mice. At baseline and after 3, 8, 12, and 16 weeks, serum and fecal samples were collected from the mice for measurement of IgA levels and microbiota composition. We also collected B-cells from the lung and colon tissues for immunohistochemistry. The introduction of microbiota in germ-free mice was related to a strong induction of serum and fecal IgA levels and associated with the abundance of specific bacterial genera, including several Lachnospiraceae species. Two community clusters were associated with fecal IgA induction, and a Bifidobacterium cluster, consisting of eight bacterial genera, was also associated with higher serum and lung IgA levels and increased lung B-cell density in mice. Furthermore, in children with rRTIs, Bifidobacterium abundance was negatively associated with the severity of RTI symptoms. Conclusions: This study shows that children with IgA deficiency and recurrent respiratory tract infections harbour a distinctly altered intestinal microbiota. Using faecal transfers from paediatric donors into germ-free mice, we demonstrate robust induction of IgA across mucosal sites. Notably, a Bifidobacterium-dominated community cluster was linked to stronger IgA responses in stool, serum, and lung, highlighting a microbiota–mucosal immunity axis with translational potential.