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

在退伍军人中，创伤后应激障碍（PTSD）可导致终末器官损伤，如肝脏 肝硬化肝硬化和创伤后应激障碍都独立地导致肠道生态失调和脑功能障碍。我们已经表明 患有肝硬化的退伍军人的认知功能障碍与高粪便致病菌，胆汁酸的改变 和短链脂肪酸（SCFA），以及与认知和患者相关的促炎环境。 报告结果。然而，患有PTSD+肝硬化的退伍军人的肠-肝-脑轴的改变需要进一步研究。 调查这是一个名为"靶向肠道微生物组"的合作优异申请（CMA）的一部分。 退伍军人部署相关的胃肠道和肝脏疾病"。这些建议的重点是 创伤后应激障碍和海湾战争疾病对退伍军人肝硬化，炎症性肠病和消化道疾病。 我们发表的数据显示，患有PTSD+肝硬化的退伍军人有更大的认知障碍， 与无创伤后应激障碍的肝硬化相比，我们 初步数据显示：a）患有PTSD+肝硬化的退伍军人与 2）PTSD+肝硬化与单纯肝硬化中合成SCFA的基因丰度较低的宏基因组学， 3）来自转移至无菌（GF）小鼠的PTSD+肝硬化患者的微生物群显示出较低的 微生物多样性和较高的肠道和皮质炎症与肝硬化，创伤后应激障碍和控制。 目前治疗创伤后应激障碍的药物效果相对有限。考虑到肝脏在 代谢药物和肝性脑病（HE）发展的可能性，使用神经活性药物 肝硬化的药物治疗具有挑战性。微生物调节可能是安全治疗肠源性 炎症可导致患有PTSD+肝硬化的退伍军人的脑功能障碍。我们表演了三个 在患有肝硬化的退伍军人中进行粪便微生物群移植（FMT）的I期随机试验。这些试验 证明安全性，更好的认知，更低的血清LBP和全身炎症环境， 粪便/血浆SCFA。然而，在我们将这些应用于患有PTSD+肝硬化的退伍军人之前，我们需要 确定微生物变化的作用。这项建议是实现这一总体目标的第一步。 我们的总体假设是："肠道微生物的改变导致肠道屏障受损增加 与对照组相比，伴有PTSD和肝硬化的退伍军人的认知功能障碍更大。 那些患有PTSD或肝硬化的人，由于协同炎症过程"。这是因为， 与微生物转化的胆汁酸和SCFA相关的炎症和肠屏障变化。这 将通过以下两个目标来检验假设： 目的1：确定肠道微生物群落组成和功能与健康之间的联系- 与单纯肝硬化和单纯PTSD相比，PTSD+肝硬化退伍军人的相关生活质量。 我们将招募320名退伍军人（各80名患有PTSD+肝硬化，单独的PTSD，单独的肝硬化和对照）， 里士满和洛杉矶的吸血鬼。粪便宏基因组学和微生物功能（粪便SCFA/胆汁酸），以及 全身炎性细胞因子将与生活质量相关。PTSD和肝硬化严重程度将匹配。 目的2：确定哪些微生物分类群介导了肠屏障变化的发展， 酸和脑炎症使用人类无菌小鼠移植，并评估其影响 关于压力的恢复力。目的2.1：确定退伍军人粪便对GF小鼠定植的影响 与单独的PTSD、单独的肝硬化以及肠道和神经炎症的对照相比， 以及肠屏障的变化，从而导致行为的变化。 目的2.2：定义这种差异定植在介导对PTSD相关压力的恢复力中的作用。 该研究团队在肝硬化，微生物组分析，创伤后应激障碍和gnotobiotic研究方面经验丰富。这项建议 将形成一个平台，以调查基于微生物的治疗退伍军人肝硬化和创伤后应激障碍。

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.