Among Veterans, post- traumatic stress disorder (PTSD) can result in end-organ damage such as liver cirrhosis. Both cirrhosis and PTSD independently lead to gut dysbiosis and brain dysfunction. We have shown that cognitive dysfunction in Veterans with cirrhosis is linked with high stool pathobionts, alteration of bile acids and short-chain fatty acids (SCFA), and a pro-inflammatory milieu that were linked to cognition and patient- reported outcomes. However, alterations in gut-liver-brain axis in Veterans with PTSD+Cirrhosis require further investigation. This is part of a Collaborative Merit Application (CMA) entitled “Targeting Gut-Microbiome in Veterans Deployment related Gastrointestinal and Liver diseases”. These proposals focus on the impact of PTSD and Gulf War Illness on cirrhosis, inflammatory bowel disease and diarrheal diseases in Veterans. Our published data shows that Veterans with PTSD+cirrhosis have greater cognitive impairment, microbial dysbiosis and serum lipopolysaccharide-binding protein (LBP) compared to cirrhosis without PTSD. Our preliminary data show a) Veterans with PTSD+cirrhosis have worse cirrhosis-related outcomes versus cirrhosis alone; 2) metagenomics with lower abundance of genes synthesizing SCFA in PTSD+cirrhosis versus cirrhosis; and, 3) microbiota from PTSD+cirrhosis patients transferred to germ-free (GF) mice show lower microbial diversity and higher intestinal and cortical inflammation versus cirrhosis, PTSD, and controls. The current medications for PTSD have relatively modest success. Given the central role of the liver in metabolizing medications and potential for hepatic encephalopathy (HE) development, the use of neuroactive medications in cirrhosis is challenging. Microbial modulation may be a major step to safely treat the gut-derived inflammation that can result in brain dysfunction in Veterans with PTSD+cirrhosis. We have performed three phase 1 randomized trials of fecal microbiota transplant (FMT) in Veterans with cirrhosis. These trials demonstrate safety, better cognition, lower serum LBP and systemic inflammatory milieu, and higher stool/plasma SCFA. However, before we apply these to Veterans living with PTSD+cirrhosis, we need to determine the role of microbial changes. This proposal is a first step towards this overarching goal. Our overall hypothesis is: “Gut microbial alterations lead to increased impairment of intestinal barrier and greater cognitive dysfunction in Veterans with concomitant PTSD and cirrhosis, compared to those with PTSD or cirrhosis alone, due to synergistic inflammatory processes”. This is due to increased inflammation and intestinal barrier changes associated with microbially transformed bile acid and SCFAs. This hypothesis will be tested with the following two aims: Aim 1: Determine the linkage between gut microbial community composition and function with health- related quality of life in Veterans with PTSD+cirrhosis compared to cirrhosis alone and PTSD alone. We will ...