BCCMA: Targeting Gut-Microbiome in Veterans Deployment Related Gastrointestinal and Liver Diseases: Dysbiosis, PTSD, and Epithelial and Immune Biology in Inflammatory Bowel Disease in Veterans

BCCMA：针对退伍军人部署相关胃肠道和肝脏疾病的肠道微生物组：退伍军人炎症性肠病中的生态失调、创伤后应激障碍以及上皮和免疫生物学

• 批准号: 10586940
• 负责人: Keith T. Wilson
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586940
• 关键词: Address; Attenuated; Award; Biological; Biological Assay; Biology; Cells; Cellular biology; Chronic stress; Clinical; Clinical Management; Clinical Research; Colitis; Collaborations; Colon; Crohn' s disease; Data; Diagnosis; Disease; Early Diagnosis; Epithelium; Feces; Functional disorder; Gastroenterologist; Gastrointestinal Diseases; Gene Expression; Genes; Germ-Free; Grant; Human; Immune; Immune System Diseases; Immunofluorescence Immunologic; Incidence; Inflammatory Bowel Diseases; Inflammatory Response; Intervention; Intestines; Knowledge; Link; Liver diseases; Messenger RNA; Metagenomics; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Organoids; Outcome; Pathogenesis; Patients; Persian Gulf Syndrome; Physicians; Post-Traumatic Stress Disorders; Predisposition; Prevalence; Prevention; Proteins; Psychological Stress; Recording of previous events; Research; Research Infrastructure; Role; Sampling; Scientist; Services; Source; Spermidine; Structure; Techniques; Technology; Testing; Tissues; Ulcerative Colitis; Veterans; Work; bench to bedside; clinical infrastructure; diarrheal disease; dysbiosis; experience; gastrointestinal epithelium; gut bacteria; gut inflammation; gut microbiome; gut-brain axis; human disease; human microbiota; humanized mouse; improved; in vivo Model; inflammatory marker; intestinal epithelium; metabolomics; microbiome; microbiome alteration; microbiota; military service; mouse model; novel; novel therapeutics; programs; response; stool sample; synergism; systemic autoimmunity; systemic inflammatory response; translational goal; translational impact

This Merit Review Project is part of a Collaborative Merit Review Award (CMA), in response to an RFA seeking collaborative projects related to military service exposures and post-traumatic stress disorder (PTSD). Here in CMA2 we focus on the gut microbiome, PTSD, and host features specific to inflammatory bowel disease (IBD) in Veterans. Our overall CMA has 5 projects based on the concept that while emerging evidence supports the importance of the gut microbiome in human diseases, there are no systematic studies focusing on the role of the gut microbiome in deployment-related GI and liver diseases in Veterans. Our overall CMA application, based on the Roadmap developed by our group, proposes to address this knowledge gap. The questions to be addressed include the novel role of the gut microbiome and chronic stress in mechanisms underlying the higher incidence of diarrheal diseases, IBD, and liver diseases in Veterans. A highly collaborative group of high-impact translational projects (3 CSRD & 2 BLRD) will address: CMA1- the role of Gulf War Illness (GWI) and PTSD gut microbiome in susceptibility to diarrheal diseases; CMA2 (this project)- the role of PTSD in increased incidence of IBD/gut inflammation; CMA3- the role of PTSD microbiome in gut-barrier structure and function; CMA4- the role of PTSD and microbiome in liver disease; and CMA5- functional metagenomics in GWl-related gut dysfunctions. The CMA approach is critical as the PIs will collaborate on shared sources of: a) gut microbiome from Veterans; b) metagenomics, metabolomics, and gene expression data; and c) state of the art mouse models and organoid technologies. This CMA2 proposal considers the following concepts. IBD is increasing in the USA and in the VA, and causes morbidity in VA patients. Psychological stress, especially PTSD has been implicated in IBD. PTSD is linked to systemic inflammation and autoimmunity, but specific effects on the gut are unknown. An altered microbiome (dysbiosis) is strongly associated with IBD. Deployment related PTSD in Veterans may be related to dysbiosis, which has been linked to an altered gut-brain axis. More work is needed to determine biological links between PTSD and IBD, which we will study in VA patients. The PI is a gastroenterologist at the VATVHS, and he and his VA GI colleagues can obtain clinical samples for this project, based on our VINCI analysis of the high number of IBD patients at the VATVHS who also have PTSD. Our hypothesis is that PTSD predisposes to and exacerbates IBD in Veterans due to a dysbiotic microbiome, and gut epithelial and immune dysfunction. The Specific Aims are: 1) To test the hypothesis that the dysbiotic gut microbiome in PTSD contributes to IBD pathogenesis in Veterans. We will study the gut microbiome and its function in stool samples and colon tissues. This will be related to deployment history and PTSD assessments. We will utilize: A) metagenomics; and B) metabolomics. The translational goal is to develop strategies to manipulate the microbiome to attenuate PTSD and IBD. 2) To test the hypothesis that PTSD dysregulates intestinal epithelial and immune cell biology and contributes to IBD pathogenesis. We will quantify markers of inflammation established in our Lab at the level of A) mRNA by qPCR; and B) protein, using standard and multiplex immunofluorescence, and Luminex assays. We will conduct C) metabolomics and spermidine studies, based on data from our Lab. The Translational goal is to develop new strategies for diagnosis, prevention, and treatment of IBD in Veterans. 3) To test the hypothesis that human organoids and human microbiota-associated (HMA) mice can be used to validate the causal role of specific microbiome constituents and cellular dysfunction in PTSD and IBD in Veterans. We will use: A) patient-derived organoids from control and IBD patients ± PTSD to establish microbiome constituents and metabolites causing inflammatory responses; and B) germ-free mice humanized with VA patient microbiota studied in colitis models. The Translational goal is to develop a bench to bedside pipeline to guide clinical management of IBD ± PTSD. Together, these studies are expected to improve understanding of IBD and the interaction with PTSD in Veterans and yield new interventions for VA patients.

该优秀评审项目是协作优秀评审奖（CMA）的一部分，以响应RFA寻求 与兵役暴露和创伤后应激障碍（PTSD）有关的合作项目。这里 CMA 2我们专注于肠道微生物组，PTSD和炎症性肠病（IBD）特有的宿主特征 在退伍军人。我们的总体CMA有5个项目，基于这样的概念，即虽然新兴证据支持 虽然肠道微生物组在人类疾病中的重要性，但目前还没有系统的研究关注肠道微生物组在人类疾病中的作用。 退伍军人部署相关胃肠道和肝脏疾病中的肠道微生物组。我们的整体CMA应用程序，基于 我们小组制定的路线图建议解决这一知识差距。需要解决的问题 包括肠道微生物组和慢性应激在高发病率机制中的新作用， 退伍军人中的肠炎、IBD和肝病。一个高度合作的高影响力小组 翻译项目（3 CSRD和2 BLRD）将解决：CMA 1-海湾战争疾病（GWI）和PTSD肠道的作用 微生物组对牙周病易感性; CMA 2（本项目）-PTSD在发病率增加中的作用 IBD/肠道炎症; CMA 3-PTSD微生物组在肠道屏障结构和功能中的作用; CMA 4- PTSD和微生物组在肝脏疾病中的作用;以及GWl相关肠道中的CMA 5功能宏基因组学 功能障碍CMA方法至关重要，因为PI将在以下共享来源上进行合作：a）肠道微生物组 来自退伍军人; B）宏基因组学、代谢组学和基因表达数据;和c）现有技术小鼠模型 和类器官技术。CMA 2提案考虑了以下概念。IBD在美国正在增加 在VA中，并且引起VA患者的发病率。心理压力，尤其是创伤后应激障碍 在IBD。PTSD与全身炎症和自身免疫有关，但对肠道的具体影响尚不清楚。 微生物组的改变（生态失调）与IBD密切相关。退伍军人中部署相关的PTSD可能 与生态失调有关，而生态失调与肠脑轴的改变有关。需要更多的工作来确定 PTSD和IBD之间的生物学联系，我们将在VA患者中进行研究。PI是一名胃肠病学家， VATVHS，他和他的VA GI同事可以根据我们的芬奇获得该项目的临床样本 VATVHS中大量IBD患者同时患有PTSD的分析。我们的假设是创伤后应激障碍 由于微生物群失调，易患和加重退伍军人IBD，肠道上皮和 免疫功能紊乱具体目的是：1）检验以下假设： 创伤后应激障碍（PTSD）与退伍军人IBD发病机制有关。我们将研究肠道微生物组及其在粪便中的功能 样品和结肠组织。这将与部署历史和PTSD评估有关。我们将利用：A） 宏基因组学;和B）代谢组学。翻译的目标是开发策略来操纵 减少PTSD和IBD。2)为了验证创伤后应激障碍导致肠上皮细胞失调的假设， 和免疫细胞生物学，并有助于IBD发病机制。我们将量化炎症的标志物 在我们的实验室中，使用标准和多重PCR，在A）mRNA水平和B）蛋白水平上建立 免疫荧光和Luminex测定。我们将进行C）代谢组学和亚精胺研究，基于 来自我们实验室的数据转化的目标是发展新的诊断、预防和治疗策略 IBD在退伍军人3)为了检验人类类器官和人类微生物相关（HMA）的假设， 小鼠可用于验证特定微生物组成分和细胞功能障碍在PTSD中的因果作用 退伍军人中的IBD我们将使用：用途：A）来自对照和IBD患者± PTSD的患者来源的类器官，以建立 引起炎症反应的微生物组成分和代谢物;和B）人源化的无菌小鼠 在结肠炎模型中研究VA患者微生物群。翻译的目标是开发一个长椅到床边 指导IBD ± PTSD的临床管理。总之，这些研究有望改善 了解IBD和退伍军人与PTSD的相互作用，并为VA患者提供新的干预措施。