BCCMA: Targeting Gut-Microbiome in Veterans Deployment Related Gastrointestinal and Liver Diseases: Dysbiosis, PTSD, and Epithelial and Immune Biology in Inflammatory Bowel Disease in Veterans

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This Merit Review Project is part of a Collaborative Merit Review Award (CMA), in response to an RFA seeking collaborative projects related to military service exposures and post-traumatic stress disorder (PTSD). Here in CMA2 we focus on the gut microbiome, PTSD, and host features specific to inflammatory bowel disease (IBD) in Veterans. Our overall CMA has 5 projects based on the concept that while emerging evidence supports the importance of the gut microbiome in human diseases, there are no systematic studies focusing on the role of the gut microbiome in deployment-related GI and liver diseases in Veterans. Our overall CMA application, based on the Roadmap developed by our group, proposes to address this knowledge gap. The questions to be addressed include the novel role of the gut microbiome and chronic stress in mechanisms underlying the higher incidence of diarrheal diseases, IBD, and liver diseases in Veterans. A highly collaborative group of high-impact translational projects (3 CSRD & 2 BLRD) will address: CMA1- the role of Gulf War Illness (GWI) and PTSD gut microbiome in susceptibility to diarrheal diseases; CMA2 (this project)- the role of PTSD in increased incidence of IBD/gut inflammation; CMA3- the role of PTSD microbiome in gut-barrier structure and function; CMA4- the role of PTSD and microbiome in liver disease; and CMA5- functional metagenomics in GWl-related gut dysfunctions. The CMA approach is critical as the PIs will collaborate on shared sources of: a) gut microbiome from Veterans; b) metagenomics, metabolomics, and gene expression data; and c) state of the art mouse models and organoid technologies. This CMA2 proposal considers the following concepts. IBD is increasing in the USA and in the VA, and causes morbidity in VA patients. Psychological stress, especially PTSD has been implicated in IBD. PTSD is linked to systemic inflammation and autoimmunity, but specific effects on the gut are unknown. An altered microbiome (dysbiosis) is strongly associated with IBD. Deployment related PTSD in Veterans may be related to dysbiosis, which has been linked to an altered gut-brain axis. More work is needed to determine biological links between PTSD and IBD, which we will study in VA patients. The PI is a gastroenterologist at the VATVHS, and he and his VA GI colleagues can obtain clinical samples for this project, based on our VINCI analysis of the high number of IBD patients at the VATVHS who also have PTSD. Our hypothesis is that PTSD predisposes to and exacerbates IBD in Veterans due to a dysbiotic microbiome, and gut epithelial and immune dysfunction. The Specific Aims are: 1) To test the hypothesis that the dysbiotic gut microbiome in PTSD contributes to IBD pathogenesis in Veterans. We will study the gut microbiome and its function in stool samples and colon tissues. This will be related to deployment history and PTSD assessments. We will utilize: A) metagenomics; and B) metabolomics. The translational goal is to develop strategies to manipulate the microbiome to attenuate PTSD and IBD. 2) To test the hypothesis that PTSD dysregulates intestinal epithelial and immune cell biology and contributes to IBD pathogenesis. We will quantify markers of inflammation established in our Lab at the level of A) mRNA by qPCR; and B) protein, using standard and multiplex immunofluorescence, and Luminex assays. We will conduct C) metabolomics and spermidine studies, based on data from our Lab. The Translational goal is to develop new strategies for diagnosis, prevention, and treatment of IBD in Veterans. 3) To test the hypothesis that human organoids and human microbiota-associated (HMA) mice can be used to validate the causal role of specific microbiome constituents and cellular dysfunction in PTSD and IBD in Veterans. We will use: A) patient-derived organoids from control and IBD patients ± PTSD to establish microbiome constituents and metabolites causing inflammatory responses; and B) germ-free mice humanized with VA patient microbiota studied in colitis models. The Translational goal is to develop a bench to bedside pipeline to guide clinical management of IBD ± PTSD. Together, these studies are expected to improve understanding of IBD and the interaction with PTSD in Veterans and yield new interventions for VA patients.