Gut microbiota perturbation in IgA deficiency is influenced by IgA-autoantibody status

Immunoglobulin A (IgA) exerts its primary function at mucosal surfaces where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One-third of individuals with IgA deficiency (IgAD) suffer from recurrent mucosal infections, possibly related to an altered microbiota. We here aimed to delineate the impact of IgA deficiency and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from IgAD subjects and IgA sufficient household members (n = 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria and strain level analyses. We supplemented the dataset with 32 IgAD subjects and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. The IgAD gut microbiota exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multi-drug and antimicrobial peptide resistance, virulence factors, and Type III and VI secretion systems. These functional changes are largely attributed to E. coli, but were independent of E. coli strain variations and most prominent in IgAD subjects with IgA-specific autoreactive antibodies. The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier-perturbing events. This phenotype is especially pronounced in IgAD subjects with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify IgAD subjects with increased risk for gastrointestinal implications.