INNATE MEMORY IMPRINTED BY ORAL INFLAMMATION DRIVES PERSISTENT GUT INFLAMMATORY SUSCEPTIBILITY

Abstract Oral conditions such as periodontitis are associated with extra-oral diseases, including inflammatory bowel disease (IBD). Approximately 50% of IBD patients present with oral manifestations, which correlate with worse clinical outcomes. However, the persistence of oral inflammation-imprinted risk remains poorly understood. Here, we investigated the long-term impact of oral inflammation on IBD susceptibility and the mechanisms linking oral-gut mucosal inflammation. Oral inflammation was induced in mice using ligature-induced periodontitis (LIP). After ligature removal and recovery (LIP-R), mice remained more susceptible to DSS-induced colitis than controls, indicating that not only active but also past oral inflammation confers persistent susceptibility to gut inflammation. This inflammatory memory response persisted in Rag1-deficient mice, which lack adaptive immunity. Analysis of immune alterations revealed increased bone marrow (BM) myelopoiesis in LIP mice. Consistently, BM transplantation from LIP mice transferred colitis susceptibility to naïve recipients, demonstrating that oral inflammation imprints memory in BM myeloid progenitors. Moreover, colonization by the oral pathobiont Klebsiella aerogenes was required to recall this memory in the gut and exacerbate colitis. To investigate mechanisms of recall specificity, we performed single-cell RNA sequencing of mononuclear phagocytes (MNPs) from a competitive BM transfer model. LIP-derived MNPs displayed upregulation of interferon (IFN)-responsive genes. Functionally, while monocytes from control and LIP-R mice responded similarly to LPS alone, IFN-γ priming selectively amplified LPS-induced pro-inflammatory cytokines in LIP-R monocytes. Importantly, gut colonization by K. aerogenes increased mucosal IFN-γ levels. Thus, pathobiont-induced IFN-γ appears essential for recalling oral inflammation-imprinted memory in the gut. Together, our findings reveal that oral inflammation imprints long-lasting innate immune memory in BM myeloid progenitors. This memory persists after resolution of oral disease and can be reactivated in the gut mucosa by IFN-γ-inducing pathobionts such as K. aerogenes. These results provide new mechanistic insights into the oral–gut axis in IBD pathogenesis.