The role of IL-1ß-inducing pathobionts in the pathogenesis of Crohn’s disease

: Recent studies have demonstrated that potentially pathogenic commensal populations, namely pathobionts, are enriched in inflammatory bowel disease (IBD) and contribute to the pathogenesis of both Crohn’s disease (CD) and ulcerative colitis (UC). However, the identity of pathobionts and how these pathobionts trigger and/or exacerbate intestinal inflammation remains incompletely understood. The long-term goal of this proposal is to unravel the mechanisms by which IBD-associated pathobionts contribute to inflammatory processes in the gut. In our preliminary experiments, we identified pathobionts that can potently induce secretion of the pro-inflammatory cytokine IL-1 from host mononuclear phagocytes. Such IL-1-inducing pathobionts (hereafter called IBIPs) are selectively enriched in CD patients, and the colonization by IBIPs may be linked to the colitogenic capacity of the gut microbiotas. Strikingly, the persistent gut colonization, but not short-term exposure, to IBIPs predisposes the host to exacerbated dextran sulfate sodium (DSS)-induced colitis. Notably, adaptive immunity (T and B lymphocytes) is not required for this “pathogenic training” of the host, suggesting that the persistent colonization of IBIPs may imprint inflammatory memory in innate immune cells or non-immune cells, such as epithelial cells. We demonstrated that the persistent colonization by IBIPs results in myelopoiesis in the bone marrow (BM). Moreover, we found that IBIPs adhere to the colonic epithelium and cause a pore formation. Based on these preliminary results, our central hypothesis is that persistent gut colonization by IBIPs results in a leaky gut and subsequent BM-mediated trained innate immunity through systemically circulated IBIPs or inflammatory mediators induced by IBIPs, such as IL-1. We will test this hypothesis through the following two specific aims: In Aim 1, we will define the impact of IBIPs on the induction of trained innate immunity. We will examine the function and epigenetic modulations of myeloid cells (macrophages and neutrophils) in the colonic mucosa and the BM. Also, we will test the importance of IL-1b in this process. In Aim 2, we will determine the impact of IBIP colonization on colonic epithelial integrity. We hypothesized that IBIP colonization could cause epithelial damage, leading to the dissemination of luminal bacteria and/or bacterial factors, which, in turn, imprints pathogenic trained immunity. The rationale for the proposed research is that identifying the precise mechanisms of pathobiont-driven inflammatory responses in IBD will result in new and innovative ways to treat IBD.