Ghrelin Signaling Regulates Microbiome-Gut-Brain Axis in Inflammatory Bowel Disease and Post-Traumatic Stress Disorder
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PUBLIC ABSTRACT Topic Area: The proposed studies are in accordance with the objectives of the Fiscal Year 2019 Peer Reviewed Medical Research Program initiatives on Inflammatory Bowel Disease (IBD). IBD is a term for two conditions (Crohn’s disease and ulcerative colitis) that are characterized by prolonged inflammation of the gastrointestinal tract. While the exact cause of IBD is unknown, recent investigations have shown that different conditions such as genetics, diet, or the colonization of pathogenic microorganisms can alter the population status of the gut microbiota. This modification can produce a change from homeostasis to a condition known as imbalance or dysbiosis; however, the role played by microbiota dysbiosis in the different stages of IBD (active flares, remission, and relapse) is not clearly understood. Increasing evidence suggest that post-traumatic stress disorder (PTSD) is associated with a pro-inflammatory activation of the immune system. The current state of the science suggests that there is a bidirectional causal relationship between PTSD and inflammation, which has implications for the development of clinically useful biomarkers and novel treatments. Epidemiological data suggest that patients diagnosed with PTSD are at greater risk for developing IBD. However, whether IBD patients are more vulnerable to develop PTSD or whether prior IBD exacerbates PTSD is unknown. Clinical and preclinical data pin-point inflammation as the main disease condition underlying IBD and PTSD, which predisposes the subject to further inflammatory pathologies. Given the emerging role of gut microbiota dysbiosis in contributing to systemic inflammation in different pathological conditions, the following questions are asked: (a) Does prior IBD lead to gut microbiota dysbiosis, which persists even after remission of the disease? (b) Does prior IBD exacerbate subsequent pro-inflammatory condition/stress, such as PTSD? (c) Can ghrelin, a gut hormone with anti-inflammatory properties, improve IBD-associated microbiota imbalance, thereby attenuate subsequent PTSD? It has been shown that ulcerative colitis-like inflammation, induced by dextran sodium sulfate (DSS), leads to anxiety and depression symptoms in mice during the remission period, 10 to 20 days after the start of inflammation, when local colonic inflammation has receded. In this proposal, an experimental model of IBD (DSS-induced ulcerative colitis) followed by fear conditioning and fear memory behavior testing (PTSD) in mice (referred to as IBD-PTSD paradigm in this application) will be established. Using this model, the gut microbiota and inflammation status in DSS-induced colitis from disease progression to remission, and post-PTSD will be defined in Aim 1, and the ability of ghrelin to ameliorate colitis and restore microbiota balance, thereby attenuating subsequent PTSD will be tested in Aim 2. It is well known that psychological disorders are prevalent in patients with IBD; however, research and clinical gaps exist where psychological diagnoses/considerations are not effectively incorporated into the management of IBD. This interdisciplinary study will provide basic research data for recommendations to enhance cooperation and coordination between gastroenterologists and gastrointestinal psychologists and provide new framework for the bacterial populations and their derived metabolites as potential biomarkers or therapeutic targets for the diagnosis and treatment of IBD. Importantly, new studies are underway that seek to find clues in gut microbiota in Gulf War Veterans that may link to Gulf War illness (GWI), a chronic, multi-symptom health problem that is marked by fatigue, pain, cognitive issues, and gastrointestinal symptoms. The proposed study will provide timely information that are highly relevant to IBD patients from military Service members and Veterans, who may be at greater risk to develop PTSD..........