Oral delivery of Human beta-defensin 2 is reversibly increasing microbiome diversity and is effective in the treatment of experimental colitis

Background: Inflammatory bowel disease (IBD) is a debilitating condition that causes fever, weight loss, loss of appetite, severe abdominal pain, and increased risk for cancer.Crohn's Disease (CD) and Ulcerative Colitis (UC) are the two prototypical examples of IBD.Patients with CD have disproportionately high rates of depression.Given the recently recognized state of systemic inflammation present in depression, it stands to reason that depression and CD are intrinsically linked.The SAMP1/YitFc (SAMP1) mouse is a model of CD that develops spontaneous terminal ileitis.The behavioral of the SAMP1 mouse has never been investigated.The aim of this study was to define a behavioral phenotype for the SAMP1 mouse for use in future studies of CD-associated depression.Methods: To establish a behavioral baseline for our model, we used male SAMP/YitFc (SAMP) mice (n=10) at various ages (together with AKR/J (AKR), C57BL/6, SAMP6, and SAMR1 mice as controls) to perform behavioral tests which included tail suspension (TS), open field (OF), elevated plus maze (EPM), rota-rod, grip strength, Barnes maze, and Y-maze.MRI, histology, IHC, qPCR, and ELISA were performed on intestinal and brain tissue.Results: As expected, gross cobblestoning, elevated MPO activity, and increased histology scores suggested severe ileitis in SAMP compared to AKR mice.Surprisingly, the SAMP mice did not develop depressive or anxiety-like behavior with increasing inflammation (depressive behavior measured with TS and anxiety-like behavior measured with EPM and OF).Conversely, despite the lack of an inflammatory phenotype, the AKR mice demonstrated marked depressive behavior when compared to SAMP (p < 0.0001).The depressive behavior was not due to changes in motor function as demonstrated by non-significant differences in the rota-rod, grip strength, and open field activity (p>0.066,p>0.49, and p>0.085, respectively).Conclusions: The ability of SAMP mice to maintain a constant behavioral phenotype despite their progressive disease state was unexpected.With these results, we now have a model of spontaneous CD that does not naturally develop depressive behavior.In addition, with the AKR mice, we have a model that does not develop intestinal inflammation but has a spontaneous depressive behavior.These powerful models will allow us to manipulate behavior and microbiome to further elucidate the connection between CD and depression.We plan to use these models to investigate the microbiome-gut-brain axis in CD.