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

BCCMA：针对美国退伍军人胃肠道和肝脏疾病中的肠道微生物组；

• 批准号: 10475994
• 负责人: Jasmohan S Bajaj
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475994
• 关键词: Address; Affect; Alcohol abuse; Award; Behavior; Bile Acids; Brain; Chronic stress; Cirrhosis; Cognition; Collaborations; Data; Development; Disease; Encephalitis; Enrollment; Fatty Acids; Feces; Functional disorder; Gastrointestinal Diseases; Genes; Germ-Free; Gnotobiotic; Goals; Hepatic Encephalopathy; Human; Impaired cognition; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Investigation; Knowledge; Lead; Link; Liver; Liver Cirrhosis; Liver diseases; Los Angeles; Mediating; Metagenomics; Microbe; Modality; Modeling; Mus; Organ; Outcome; Patient Outcomes Assessments; Patient Transfer; Persian Gulf Syndrome; Pharmaceutical Preparations; Phase; Plasma; Post-Traumatic Stress Disorders; Predisposition; Process; Publishing; Quality of life; Research; Role; Safety; Serum; Severities; Site; Source; Stress; Structure; Substance abuse problem; Symptoms; Technology; Testing; Transplantation; Veterans; Volatile Fatty Acids; addiction; brain dysfunction; cytokine; diarrheal disease; dysbiosis; experience; fecal transplantation; gut dysbiosis; gut inflammation; gut microbes; gut microbiome; gut microbiota; health related quality of life; humanized mouse; in vivo Model; inflammatory milieu; intestinal barrier; lipopolysaccharide-binding protein; microbial; microbial based therapy; microbiome; microbiome analysis; microbiota; military veteran; mouse model; neuroinflammation; novel; novel therapeutics; pathobiont; randomized trial; resilience; stress resilience; success; systemic inflammatory response; targeted treatment; transcriptome sequencing; translational impact

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.

在退伍军人中，创伤后应激障碍（PTSD）可能会导致末端损伤，例如肝脏 肝硬化。肝硬化和PTSD都独立导致肠道营养不良和脑功能障碍。我们已经显示了 肝硬化退伍军人的认知功能障碍与高凳子病原体有关，胆汁酸的改变 和短链脂肪酸（SCFA）以及与认知和患者有关的促炎环境 报告的结果。然而，具有PTSD+cirhosis的退伍军人的肠道脑轴改变需要进一步 投资。这是协作功绩申请（CMA）的一部分 退伍军人部署相关的胃肠道和肝病。 PTSD和海湾战争疾病对肝硬化，炎症性肠病和退伍军人的腹泻疾病。 我们已发表的数据表明，具有PTSD+肝硬化的退伍军人具有更大的认知障碍，微生物 与没有PTSD的肝硬化相比，营养不良和血清脂多糖结合蛋白（LBP）。我们的 初步数据显示a）具有PTSD+肝硬化的退伍军人的结果较差 仅肝硬化； 2）基因在PTSD+肝硬化中合成SCFA的基因较低的宏基因组学 肝硬化； 3）来自PTSD+肝硬化患者的微生物群，转移到无菌（GF）小鼠的患者显示较低 微生物多样性以及较高的肠道和皮质炎症与肝硬化，PTSD和对照。 当前的PTSD药物具有相对适度的成功。鉴于肝脏在 代谢药物和肝性脑病（HE）发育的潜力，神经活性的使用 肝硬化的药物具有挑战性。微生物调制可能是安全处理肠道衍生的主要步骤 炎症会导致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，粪便菌群移植（FMT）的1阶段随机试验。这些试验 证明安全性，更好的认知，较低的血清LBP和全身性炎症环境以及更高的 粪便/血浆SCFA。但是，在我们将这些应用于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。该提议是朝着这个总体目标迈出的第一步。 我们的总体假设是：“肠道微生物的改变导致肠壁障碍的增加 与伴随PTSD和Cirrhosis的退伍军人的认知功能障碍相比 由于协同炎症过程，仅患有PTSD或肝硬化的人。 与微生物转化的胆汁酸和SCFA相关的炎症和肠壁变化。这 假设将以以下两个目的进行检验： 目标1：确定肠道微生物群落组成与健康功能之间的联系 - 与单独的肝硬化和仅PTSD相比，具有PTSD+肝硬化的退伍军人的相关生活质量。 我们将从320名退伍军人（每位PTSD+Cirrhosis，PTSD，单独使用PTSD，单独使用PTSD和对照组）中注册 里士满和洛杉矶VAMC。粪便宏基因组学和微生物功能（粪便SCFA/胆汁酸），并且 系统性炎症细胞因子将与生活质量有关。 PTSD和肝硬化的严重程度将匹配。 目标2：确定肠屏障变化的微生物分类媒体开发，胆汁改变 使用人到无菌小鼠移植的酸和大脑感染，并评估其影响 关于压力的弹性。 AIM 2.1：定义与退伍军人的凳子的GF小鼠定殖的影响 与仅PTSD相比，仅PTSD+肝硬化，单独的肝硬化以及对肠道和神经炎症的对照， 并使用经过验证的PTSD小鼠模型的肠壁变化，导致行为变化。 AIM 2.2：定义这种差异定殖在介导与PTSD相关的压力的弹性中的作用。 研究小组在肝硬化，微生物组分析，PTSD和gnotobiotic研究方面经验丰富。这个建议 将形成一个平台，以研究肝硬化和PTSD的退伍军人中基于微生物的治疗。