IgA-targeted gut microbiota in altered host metabolism by defective purinergic control of T follicular help

The secretory immunoglobulin A (sIgA) at the mucosal surface of the mammalian gut exerts key roles in host physiology and immune homeostasis by directly modulating gut microbiota composition. Deletion of P2rx7, encoding for the ATP-gated ionotropic receptor P2X7, leads to dysregulated germinal centre reactions and enhanced secretion of intestinal IgA resulting in alterations of the gut microbiota that in turn affects host metabolism. Through amplicon-based 16S rRNA gene sequencing of faecal IgA-coated bacteria (IgA-SEQ) in P2rx7-/- mice, this study defines the intestinal microbial community targeted by IgA and the contribution of sIgA in shaping host-microbiota interactions. We demonstrated that P2rx7-/- mice, which are characterized by an obese-like phenotype, harbour an altered gut microbiota. The enhanced production of sIgA in these mice resulted in the significant enrichment of several bacterial taxa in the IgA+ fraction of faecal microbiota compared to the wild-type C57BL/6 littermate controls. Furthermore, we observed that different members of the IgA+ and IgA- faecal microbiota contributed differently to the obese-like phenotype of P2rx7-/- mice. We showed that alterations of Tfh activity are accountable for the remodelling of the whole intestinal microbial community structure resulting in expansion of secreted IgA reactivity towards different members of the gut microbiota that in turn may contribute to metabolic abnormalities and obesity.