The inflammatory bowel diseases (IBD, including Crohn's disease and ulcerative colitis) involve disrupted homeostatic interactions between the microbiota and the mucosal immune system as a result of multiple genetic and environmental factors. A major environmental factor that is well recognized to increase the severity of IBD is psychosocial stress. However, the biological mechanisms linking stress to disrupted homeostatic relationships between the microbiota and the mucosal immune system are not well understood. This proposal will test the novel hypothesis that intestinal epithelial cells represent a mechanistic link between stress, alterations of the gut microbiota, and pathogen-induced colitis. Our preliminary data demonstrate that exposing mice to a well characterized and widely used social stressor, called social disruption (SDR) reduces the abundance of commensal Lactobacillus reuteri in the colon. Upon oral challenge with the murine colonic pathogen Citrobacter rodentium, which induces colonic histopathology with similarities to human IBD, mice exposed to SDR (and thus having lower levels of L. reuteri) had a significant increase in pathogen-induced colitis as indicated by a significant increase in colonic histopathology, chemokines (e.g., CCL2), cytokines (e.g., TNF-?), effector molecules (e.g., iNOS), and macrophage infiltration. Importantly, preventing the stressor-induced reduction in L. reuteri by feeding L. reuteri to the mice during stressor exposure abrogated the effects of the stressor on C. rodentium-induced colitis. Like its human homologue (i.e., enteropathogenic E. coli), C. rodentium induces colonic inflammation by colonizing the colonic epithelium. Thus, the use of C. rodentium is an ideal model to determine whether the colonic epithelium is critical in the link between stress, the microbiota, and exacerbation of colitis. This proposal will test the novel hypothesis that when L. reuteri are decreased due to stressor exposure, colonic epithelial cells overproduce chemokines (particularly CCL2) that increase the recruitment of inflammatory macrophages to the colon where they ultimately exacerbate colitis.
The first aim will examine the role of CCL2 as a novel primary mechanism (pathway) mediating the effects of stress on colonic inflammation, by assessing the effects of stress-induced alterations of L. reuteri on CCL2 production by colonic epithelial cells and by using CCL2 knockout mice. In the second aim, we will use adoptive transfer experiments to test whether peripheral inflammatory monocytes, which we show are increased in the circulation of stressed mice, traffic to the colon in response to the elevated CCL2, where they can exacerbate colitis through an overproduction of TNF-? and iNOS. Finally, in the third aim, we will determine whether the ability of L. reuteri to affect chemokine production by colonic epithelial cells is dependent upon L. reuteri colonizing the colon, and/or due to the production of immunomodulatory factor(s). This proposal will identify novel mechanism(s) that may lead to new therapeutic targets in the treatment of IBD.
The stress response exacerbates colitis, both in experimental animals and in patients with inflammatory bowel disease, but the biological mechanisms by which this occurs are not well understood. Our studies demonstrate that stressor-induced reduction in commensal Lactobacillus reuteri is involved with the observed increase in colonic histopathology in mice challenged with Citrobacter rodentium during exposure to a well characterized and widely used social stressor. This proposal will test the novel hypothesis that the stressor-induced reduction in L. reuteri leads to an overproduction of chemokines, particularly CCL2, and cytokines by colonic epithelial cells, ultimately resulting in the recruitment of TNF-?-producing inflammatory macrophages that exacerbate colitis.
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|Mackos, A R; Galley, J D; Eubank, T D et al. (2016) Social stress-enhanced severity of Citrobacter rodentium-induced colitis is CCL2-dependent and attenuated by probiotic Lactobacillus reuteri. Mucosal Immunol 9:515-26|
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|Galley, Jeffrey D; Yu, Zhongtang; Kumar, Purnima et al. (2014) The structures of the colonic mucosa-associated and luminal microbial communities are distinct and differentially affected by a prolonged murine stressor. Gut Microbes 5:748-60|
|Galley, Jeffrey D; Bailey, Michael T (2014) Impact of stressor exposure on the interplay between commensal microbiota and host inflammation. Gut Microbes 5:390-6|
|Galley, Jeffrey D; Nelson, Michael C; Yu, Zhongtang et al. (2014) Exposure to a social stressor disrupts the community structure of the colonic mucosa-associated microbiota. BMC Microbiol 14:189|
|Mackos, Amy R; Eubank, Tim D; Parry, Nicola M A et al. (2013) Probiotic Lactobacillus reuteri attenuates the stressor-enhanced severity of Citrobacter rodentium infection. Infect Immun 81:3253-63|
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