This Collaborative VA Merit application (CMA) is being submitted as part of a group of 5-linked CMAs from nationwide VA experts in gastrointestinal (GI) and liver diseases, who have formed a national steering committee after participating in a successful field-based meeting in San Diego in May 2019 (funded by VA ORD). The roadmap developed at this meeting was published in Gastroenterology (1). Specifically, this proposal is part of a cluster of CMAs that are aimed at advancing our knowledge about the emerging role of gut microbiome for a better understanding of the pathophysiology of Veterans service and deployment related GI and liver diseases including the more prevalent disorders associated with the GWI and PTSD, and to develop potential biotherapeutics to alleviate the disease symptoms. In this regard, the importance of an altered diversity of the gut microbiome in the development and progression of gastrointestinal diseases including inflammatory bowel disease (IBD) is supported by a range of evidence including patient-based studies and mouse modelling of the disease. The overall incidence of IBD among Veterans has increased 2-3 folds however the underlying mechanism(s) are unclear. The Veterans’ health care system has noticed a similar rise in the cases of the PTSD and GWI. An association of the altered gut microbiota has also been reported in the Veterans suffering from PTSD and GWI. However, there are no systematic studies focusing on the role of the gut microbiome in service and deployment-related increases in IBD risk in the Veterans. Our hypothesis in this CMA is that, in Veterans, PTSD-associated gut microbiota synergizes with gut barrier dysfunctions to promote risk for IBD and/or disease severity. A collaborative approach using the gut microbiome from Veterans with PTSD, metagenomics, and state-of-the-art mouse models and technologies will be employed to test this hypothesis in following proposed studies: Aim-1. To examine whether PTSD-associated Gut dysbiosis in a humanized mouse model promotes susceptibility to colitis and/or disease severity; Aim-2. To investigate if mouse models mimicking barrier protein defects, as seen in preliminary data, are at higher risk of developing PTSD & associated risk of colitis, and possible mechanisms; and Aim-3. To determine the causal link between PTSD-associated gut microbiota and mucosal injury/repair in specific contexts of epithelial intrinsic and in vivo settings of colitis. Specific role of gut barrier proteins will be examined in ‘pore’ and ‘leak’ pathways and colitis associated injury/repair. The outcome from proposed studies should help establish the causal relationship between PTSD-associated microbiome and an increased risk for IBD in Veterans and thus may aid in development of novel strategies in mitigating such risk.