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)会导致终末器官损害，如肝脏 肝硬变。肝硬变和创伤后应激障碍都会单独导致肠道生态失调和脑功能障碍。我们已经展示了 退伍军人肝硬变患者认知功能障碍与大便高危、胆汁酸改变有关 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，退伍军人合并创伤后应激障碍肝硬化患者的肠道-肝脏-脑轴的改变需要进一步的研究 调查。这是协作优点应用程序(CMA)的一部分，标题为 退伍军人部署与胃肠道和肝脏疾病相关的疾病“。这些建议的重点是 退伍军人中的创伤后应激障碍和海湾战争疾病对肝硬变、炎症性肠病和腹泻疾病的影响。 我们公布的数据显示，患有创伤后应激障碍肝硬变的退伍军人有更大的认知障碍，微生物 与无创伤后应激障碍的肝硬变患者相比，患者的微生态失调和血清脂多糖结合蛋白(LBP)水平降低。我们的 初步数据显示：a)患有创伤后应激障碍肝硬变的退伍军人比 仅有肝硬变；2)与PTSD肝硬变相比，合成SCFA基因丰度较低的元基因组学 和，3)PTSD肝硬变患者转移到无菌(GF)小鼠的微生物区系显示较低 与肝硬变、创伤后应激障碍和对照组相比，微生物多样性和更高的肠道和皮质炎症。 目前治疗创伤后应激障碍的药物疗效相对较差。鉴于肝脏在人体内的核心作用 代谢药物和潜在肝性脑病(HE)的发展，神经活性物质的使用 治疗肝硬变的药物是具有挑战性的。微生物调节可能是安全治疗肠源性肺炎的重要步骤 炎症可导致患有创伤后应激障碍肝硬变的退伍军人的脑功能障碍。我们已经表演了三场 退伍军人肝硬变患者粪便微生物区系移植(FMT)1期随机试验。这些试验 表现出安全性、较好的认知性、较低的血清LBP和全身炎症环境，以及较高的 大便/血浆SCFA。然而，在我们将这些应用于患有创伤后应激障碍肝硬变的退伍军人之前，我们需要 确定微生物变化的作用。这项提议是朝着这一总体目标迈出的第一步。 我们的总体假设是：肠道微生物改变导致肠道屏障损伤增加。 与退伍军人合并创伤后应激障碍和肝硬变相比，退伍军人认知功能障碍更严重 那些仅有创伤后应激障碍或肝硬变的患者，由于协同炎症过程“。这是由于增加了 与微生物转化的胆汁酸和单链脂肪酸相关的炎症和肠道屏障改变。这 假设将通过以下两个目标进行检验： 目标1：确定肠道微生物群落组成和功能与健康之间的联系 退伍军人合并创伤后应激障碍肝硬变患者的相关生活质量与单纯的肝硬变和单纯创伤后应激障碍的比较。 我们将招募320名退伍军人(80名患有创伤后应激障碍肝硬变，单独患有创伤后应激障碍，单独患有肝硬变，以及对照组)。 里士满和洛杉矶的VAMC。粪便元基因组学和微生物功能(粪便SCFA/胆汁酸)，以及 全身炎症细胞因子将与生活质量联系在一起。创伤后应激障碍和肝硬变的严重程度将匹配。 目的2：确定哪些微生物类群介导了肠道屏障改变、胆汁改变的发展 酸，以及使用人到无菌小鼠移植的脑部炎症，并评估其影响 从压力中恢复的能力。目标2.1：确定退伍军人粪便对GF小鼠定居的影响 PTSD肝硬化组与单纯PTSD组、单纯肝硬化组以及肠道和神经炎症对照组相比， 以及使用经验证的创伤后应激障碍小鼠模型，肠道屏障的变化以及由此导致的行为变化。 目标2.2：确定这种不同的定植在调节对创伤后应激相关应激的恢复力中的作用。 研究团队在肝硬变、微生物组分析、创伤后应激障碍和生理学研究方面经验丰富。这项建议 将形成一个平台，研究患有肝硬变和创伤后应激障碍的退伍军人的微生物治疗。

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.