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

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.