Microbiota-derived polyphosphates govern mucosal immunity through multilevel suppression of STAT/IL-27 signaling (multiome)

The interplay between gut bacteria and mucosal immune cells is crucial for maintaining intestinal homeostasis. Dysregulation of this immune-microbiome axis has been implicated in the pathogenesis of inflammatory bowel diseases, but the mechanisms driving the health-to-disease transition remain unclear. Here, we demonstrate that polyphosphates, a bacterial metabolite, influence mucosal immunity during both homeostasis and inflammation. Germ-free mice were monocolonized with polyphosphate competent Escherichia coli or a ∆ppk E. coli mutant strain deficient in polyphosphate production, affecting subsets of T cells and mononuclear phagocytes. Transfer of lamina propria immune cells into RAG1-/- mice indicated that polyphosphate-experienced T cells induced more severe colitis. Mechanistically, polyphosphate exposure suppressed chromatin accessibility of the Stat1, Stat3 and Il10 genes in CD4+ T cells. Ultra-pure polyphosphates corresponding to the molecular sizes produced by microbes decreased gene expression of STATs as observed by snRNA-seq, antagonized IL-27 production in mononuclear phagocytes through suppression of STAT1, and disrupted IL-27-induced STAT1/STAT3 phosphorylation in naïve CD4+ and CD8+ T cells. IL-27Rα-/- lamina propria immune cells were more aggressive in promoting colitis, suggesting that the paralyzing effects of polyphosphates on IL-27/IL-27Rα signaling are functionally significant. In conclusion, the intestinal microbiota utilizes polyphosphates to disrupt the protective balance of innate and adaptive immune cell networks.