BCCMA: Targeting Gut Microbiome in Gastrointestinal and Liver Diseases in US Veterans; CMA4: At the Crossroads of the Gut Microbiome, Cirrhosis, and PTSD

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 enroll 320 Veterans (80 each with PTSD+cirrhosis, PTSD alone, cirrhosis alone, and controls) from Richmond and Los Angeles VAMCs. Stool metagenomics and microbial function (stool SCFA/bile acids), and

systemic inflammatory cytokines will be linked with quality of life. PTSD and cirrhosis severity will be matched. Aim 2: Determine which microbial taxa mediate development of intestinal barrier change, altered bile acids, and brain inflammation using human to germ-free mouse transplants, and evaluate their impact

on resilience from stress. Aim 2.1: Define the impact of colonization of GF mice with stools from Veterans with PTSD+cirrhosis compared to PTSD alone, cirrhosis alone, and controls on gut and neuroinflammation, and changes in intestinal barrier with resultant changes in behavior using a validated mouse model of PTSD.

Aim 2.2: Define the role of this differential colonization in mediating resilience towards PTSD-related stress. The study team is experienced in cirrhosis, microbiome analysis, PTSD and gnotobiotic studies. This proposal will form a platform to investigate microbially-based treatments in Veterans with cirrhosis and PTSD.