Bifidobacterium-driven immunoglobulin A production in pediatric patients with IgA deficiency and recurrent respiratory infections
Background: Immunoglobulin A (IgA) deficiency is the most prevalent antibody deficiency underlying recurrent respiratory tract infections (rRTIs) in children, with prevalence rates ranging from 1:4 to 1:65. Previous studies in healthy humans and mice have shown that IgA production is influenced by microbial changes. We investigated the role of the intestinal microbiota in IgA deficiency and induction in children with rRTIs.  Methods: Children below the age of seven years with rRTIs were included in a prospective cohort study. We included 82 children with rRTIs, 38% of whom were IgA deficient. 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. Intestinal microbiota composition was determined by 16S-rRNA sequencing of pre-sorted and sorted high and low IgA coated bacteria. Serum and fecal IgA levels were measured using ELISA, and immunohistochemical staining of B cells from the lung and colon tissues was performed.  Results: The microbiota composition of IgA-deficient children differed from that of the symptomatic controls (PERMANOVA R2 2.4%, p=0.02). In mice, a strong induction of serum and fecal IgA levels after the introduction of microbiota was associated with specific bacterial genera, including several Lachnospiraceae species. Two interbacterial clusters were associated with fecal IgA induction, and a Bifidobacterium interbacterial cluster, consisting of eight bacterial genera, was also associated with higher serum and lung IgA levels and increased lung B-cell density in mice. In children with rRTIs, Bifidobacterium relative abundance was negatively associated with RTI symptom severity.  Conclusions: This study revealed that the intestinal microbiota composition is altered in pediatric IgA deficient patients with recurrent RTIs and demonstrates the dynamics of IgA production using fecal samples from pediatric patients with and without IgA deficiency. We identified a Bifidobacterium interbacterial cluster associated with fecal, serum, and lung IgA induction.