Chronic inflammatory diseases affect millions of Americans each year, and have a significant medical, psychosocial, and economic impact on both the patient and on society. Multiple sclerosis is a chronic, degenerative neurological disorder involving immune-mediated inflammatory demyelinating processes, and is significantly exacerbated by comorbid conditions, such as stress and anxiety. Despite this knowledge, the mechanisms by which this occurs are not yet well understood. The studies in this proposal will test the highly novel and integrative hypothesis that the intestinal microbiota are involved in stressor-induced enhancement of systemic inflammation that leads to symptom exacerbation in an animal model of multiple sclerosis. We have made the exciting discovery that the intestinal microbiota are necessary for stressor-induced increases in splenic IL-1? to occur. This is important, because IL-1 plays a central role in the development of many chronic inflammatory diseases, including multiple sclerosis. How the microbiota lead to increased IL-1 during stressor exposure, as well as the effects on chronic inflammatory diseases, is not well understood. During repeated social defeat, commensal microbes can translocate from their primary niche to the interior of the body. Because there is accumulating evidence that neuroendocrine hormones, such as sympathetic nervous system-derived catecholamine hormones, can impact microbial populations, Aim 1 will test whether stressor-induced activation of the sympathetic nervous system leads to translocation of commensal microbiota. As further confirmation that microbial translocation is necessary for stressor-induced immunoenhancement to occur, Aim 2 will test the hypothesis that stressor-induced increases in splenic IL-1? are dependent upon both macrophage pattern recognition receptor signaling and inflammasome formation. Finally, to determine whether the microbiota contribute to stressor-induced exacerbation of a chronic disease, a widely used animal model of multiple sclerosis, namely experimental autoimmune encephalomyelitis (EAE) will be employed. The effects of repeated social defeat on EAE progression will be determined in germfree mice (i.e., mice that have never come into contact with commensal microbes) and conventional mice. By integrating the results of Aims 1, 2, and 3, we will identify novel mechanisms by which stressor exposure can exacerbate a chronic inflammatory disease. These findings would ultimately facilitate the rational design and use of microbiota-targeting therapeutics to treat chronic disease.
Stress and anxiety are well known to exacerbate chronic inflammatory diseases, but the mechanisms by which the stress response can enhance immune system activity are not well understood. Our studies demonstrate that exposure to a well characterized social stressor results in increased circulating cytokines and primes splenic macrophages for enhanced reactivity upon stimulation. This R21 proposal will test the novel hypothesis that stressor-induced sympathetic nervous system activity leads to the translocation of commensal microbiota from their natural niche to the interior of the body where they trigger the production of IL-1?; it is further hypothesized that the IL-1? leads to symptom exacerbation in an animal model of multiple sclerosis.
| Maltz, Ross M; Keirsey, Jeremy; Kim, Sandra C et al. (2018) Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short Chain Fatty Acid Levels and Receptors. J Pediatr Gastroenterol Nutr : |
| Mackos, Amy R; Maltz, Ross; Bailey, Michael T (2017) The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation. Horm Behav 88:70-78 |
| Lafuse, William P; Gearinger, Rachel; Fisher, Sydney et al. (2017) Exposure to a Social Stressor Induces Translocation of Commensal Lactobacilli to the Spleen and Priming of the Innate Immune System. J Immunol 198:2383-2393 |
