Altered microbiota by enhanced T follicular help and hyper IgA results in impaired glucose metabolism

The cross-talk between the epithelial component, gut associated immune system and microbiota ensures the physiological control of energy uptake, immune system activation and microbial commensalism. The P2X7 receptor is an ATP-gated nonselective cationic channel expressed in a variety of cell types. In T cells the dual gating property of the receptor can lead to pro-inflammatory signals or opening of a pore permeable to molecules up to 900 Da and cell death. Mice with deletion of p2rx7 show expansion of T follicular helper (Tfh) cells in Peyer's patches with increased IgA responses. In addition, P2rx7^-/- mice housed in spf facility have increased body weight, blood glucose, insulin levels and fat accumulation. Analysis of gut microbiota revealed a 3-fold increase in the ratio between Firmicutes and Bacteroidetes. We demonstrate that the phenotype of P2rx7^-/- mice could be reproduced by reconstitution of Cd3e^-/- mice with P2rx7^-/- Tfh cells. Reconstituted mice with mutant Tfh cells showed enhanced germinal center reaction, higher concentrations of fecal IgA and impaired glucose metabolism. These observations indicate a causal role of P2rx7^-/- Tfh cells in altered glucose metabolism. Parallel to Tfh cells role we also show that the phenotype of P2rx7^-/- mice could be reproduced by fecal transplant into wild-type animals. Our results emphasize the role of Tfh cells and secretory IgA in the modulation of gut microbiota that ultimately regulates the metabolic balance of the organism.