Abstract
The secretory immunoglobulin A (SIgA) in mammalian gut protects the organism from infections and contributes to host physiology by shaping microbiota composition. The mechanisms regulating the adaptive SIgA response towards gut microbes are poorly defined. Deletion of P2rx7, encoding for the ATP-gated ionotropic P2X7 receptor, leads to T follicular helper (Tfh) cells expansion in the Peyer’s patches (PPs) of the small intestine, enhanced germinal centre (GC) reaction and IgA secretion; the resulting alterations of the gut microbiota in turn affects host metabolism. Here, we define gut microbiota modifications that correlate with deregulated SIgA secretion and metabolic alterations in P2rx7−/− mice. In particular, Lactobacillus shows enhanced SIgA coating in P2rx7−/− with respect to wild-type (WT) mice. The abundance of SIgA-coated lactobacilli positively correlates with Tfh cells number and body weight, suggesting Lactobacillus-specific SIgA response conditions host metabolism. Accordingly, oral administration of intestinal Lactobacillus isolates from P2rx7−/− mice to WT animals results in altered glucose homeostasis and fat deposition. Thus, enhanced SIgA production by P2X7 insufficiency promotes Lactobacillus colonization that interferes with systemic metabolic homeostasis. These data indicate that P2X7 receptor-mediated regulation of commensals coating by SIgA is important in tuning the selection of bacterial taxa, which condition host metabolism.
Highlights
Mice are characterized by altered fat distribution[20]. In these mice, dysregulated T follicular helper (Tfh) cells activity with consequent enhanced germinal centre (GC) reactions and secretion of high affinity IgA affects microbiota composition resulting in altered glucose homeostasis and fat deposition[15,16]
In the IgA− microbiota of P2rx7−/− mice, we observed a significant increase in the relative abundance of Lachnospiraceae, Bilophila and Clostridia (LEfSe, p < 0.05, Wilcoxon rank-sum test, linear discriminant analysis (LDA) > 2.0; Fig. 3b), whereas the presorted faecal microbiota of P2rx7−/− mice was depleted of bacterial taxa important for intestinal homeostasis, e.g. Barnesiella, Ruminococcaceae, Clostridium cluster IV26,27 (LEfSe, p < 0.05, Wilcoxon rank-sum test, LDA > 2.0; Fig. S2c)
IgA coating identifies bacterial taxa with the potential ability to interact with the host and colonize the intestinal mucosa; in addition, it can influence bacterial gene expression, metabolism and ability to colonize different intestinal ecological niches[8,9]
Summary
T follicular helper (Tfh) cells in PPs are essential for SIgA affinity maturation that in turn modulates the structure and function of the intestinal microbiota[11]. The altered control of Tfh cells by defective sensing of microbiota derived ATP leads to enhanced secretion of T cell dependent IgA and increased frequency of replacement mutations in the IgVH1 family’s complementarity determining region (CDR) 2 suggesting enhanced affinity maturation of IgA responses[15]. The alteration of the gut microbiota due to the lack of P2X7 mediated control of Tfh cells results in dysregulated metabolic homeostasis, consistent with the central role of SIgA in regulating host-microbiota interactions and host physiology[16]. A number of studies in mice and humans have demonstrated that obesity is associated with alterations of the gut microbiota. The characterization of the faecal microbiota targeted by SIgA in P2rx7−/− mice allowed us to identify the enhanced SIgA coating of Lactobacillus as a possible mechanism contributing to the observed metabolic disturbance
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