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.

对于退伍军人来说，创伤后应激障碍 (PTSD) 可导致肝脏等终末器官损伤 我们已经证明，肝硬化和创伤后应激障碍会独立导致肠道菌群失调和大脑功能障碍。 患有肝硬化的退伍军人的认知功能障碍与高粪便病原体、胆汁酸的改变有关 和短链脂肪酸（SCFA），以及与认知和患者相关的促炎环境 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。 这是题为“针对肠道微生物组”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”。 创伤后应激障碍（PTSD）和海湾战争病对退伍军人的肝硬化、炎症性肠病和腹泻病的影响。 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、微生物 与无 PTSD 的肝硬化相比，菌群失调和血清脂多糖结合蛋白（LBP）。 初步数据显示 a) 与患有 PTSD+肝硬化的退伍军人相比，其肝硬化相关结果更差 2) 与单纯肝硬化相比，PTSD+肝硬化中合成 SCFA 的基因丰度较低 肝硬化；3) 来自 PTSD+肝硬化患者的微生物群转移到无菌 (GF) 小鼠中表现出较低 与肝硬化、创伤后应激障碍（PTSD）和对照组相比，微生物多样性以及更高的肠道和皮质炎症。 鉴于肝脏在创伤后应激障碍中的核心作用，目前治疗创伤后应激障碍的药物取得的成功相对有限。 代谢药物和肝性脑病 (HE) 发展的潜力、神经活性药物的使用 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道来源的一个重要步骤。 炎症可能导致患有创伤后应激障碍（PTSD）+肝硬化的退伍军人出现脑功能障碍，我们已经进行了三项研究。 对患有肝硬化的退伍军人进行粪便微生物移植 (FMT) 的 1 期随机试验。 证明安全性、更好的认知、更低的血清 LBP 和全身炎症环境以及更高的 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该提案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加剧 与患有 PTSD 和肝硬化的退伍军人相比，认知功能障碍更严重 那些患有创伤后应激障碍（PTSD）或肝硬化的人，由于协同炎症过程而导致”。 与微生物转化的胆汁酸和 SCFA 相关的炎症和肠道屏障变化。 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 与单纯肝硬化和单纯 PTSD 相比，患有 PTSD+肝硬化的退伍军人的生活质量相关。 我们将招募 320 名退伍军人（每人 80 名患有 PTSD+肝硬化、仅有 PTSD、仅有肝硬化和对照组） 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），以及 全身炎症细胞因子将与生活质量相关，并且肝硬化的严重程度也将与之相匹配。 目标 2：确定哪些微生物类群介导肠道屏障变化、胆汁改变的发展 使用人类到无菌小鼠移植物来研究酸和脑炎症，并评估其影响 目标 2.1：确定退伍军人粪便定植 GF 小鼠的影响。 与单纯 PTSD、单纯肝硬化相比，PTSD+肝硬化，并控制肠道和神经炎症， 使用经过验证的 PTSD 小鼠模型，肠道屏障发生变化，从而导致行为变化。 目标 2.2：定义这种差异定植在调节 PTSD 相关压力恢复力方面的作用。 该研究团队在肝硬化、微生物组分析、创伤后应激障碍（PTSD）和生殖研究方面经验丰富。 将形成一个平台，研究针对患有肝硬化和创伤后应激障碍的退伍军人的基于微生物的治疗。