Stress Induced Inflammation and Dysbiosis in a Mouse Model of Crohn's Disease

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PROJECT SUMMARY Psychological risk factors have repeatedly been recognized as integral facets of inflammatory bowel disease (IBD). Stress, in particular, has been repeatedly shown as a strong predictor of flare-ups. Though several studies have attempted to establish a mechanistic relationship between stress and the microbiome-gut-brain axis (MGBA), a satisfying explanation has not been reached. In part, this is due to the reliance on chemically induced models of IBD, particularly Dextran Sodium Sulfate (DSS) colitis. Very little literature exists studying the effect of psychological stress on Crohn’s disease and ileitis. Here, we propose a series of studies to investigate stress and the MGBA in our mouse model of CD-like ileitis, the SAMP1/YitFc (SAMP1). To induce psychological stress, we use restraint stress (RS). Preliminary data from our group has demonstrated that RS is capable of inducing a depressive-like phenotype in addition to raising serum corticosterone levels. Exposure to acute RS resulted in elevated levels of dendritic cells in the mesenteric lymph node and altered cytokine expression in ileal lamina propria. Based on previous literature and our preliminary data, we hypothesize that psychological stress induces a change in the gut microbiome which, in turn, promotes a pro-inflammatory response. To address our hypothesis, we propose the following three aims. Our first aim will validate the ability of stress to worsen intestinal inflammation in our mouse model of CD-like ileitis. To accomplish this aim, we will subject our mice to acute and chronic stress and observe resultant inflammatory changes. Furthermore, we will measure the ability of stress to provoke relapse by inducing remission and subsequently exposing SAMP1 mice to stress. Our second aim will characterize the post-stress immune response and its ability to alter the microbiome. We will make use of our SAMP1ΔCD1-DTR mouse, a selectively inducible dendritic cell knock-out model, to characterize the dendritic cell response to stress. Subsequently, we will generate a bone marrow chimera using harvested marrow from stressed and unstressed mice. In our third aim, we will determine whether the stress-altered microbiome is necessary and/or sufficient to induce an immune response. Germ-free (GF) and specific pathogen free (SPF) mice will receive a fecal microbiome transplantation (FMT) via oral gavage from stressed or unstressed donors. Subsequently, the inflammatory response of the recipient mice will be assessed and the metabolome of the microbiome will be determined. Though stress may be an unavoidable aspect of every CD patient’s life, we believe that our work can lead to therapies that mitigate the harmful effects of stress. Specifically, using our unique mouse model of CD-like ileitis, we hope to discover novel therapeutic strategies, such as pro- or prebiotics, to prevent the inflammatory effects of stress. Future goals of this project include studying the microbiomes of human patients with perceived stress and transplanting into germ-free (GF) mice using our validated human FMT model.