BCCMA: Targeting Gut-Microbiome in Veterans Deployment Related Gastrointestinal and Liver Diseases; CMA1- The Role of GWI Gut Microbiome in Susceptibility to Diarrheal Diseases

BCCMA：针对退伍军人部署相关胃肠道和肝脏疾病中的肠道微生物组；

• 批准号: 10485710
• 负责人: Pradeep K Dudeja
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 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/10485710
• 关键词: Address; Animal Model; Apical; Award; Bicarbonates; Biological Response Modifier Therapy; Butyrates; Chemicals; Chlorides; Chronic stress; Citrobacter rodentium; Clostridium difficile; Collaborations; Colon; Data; Development; Diarrhea; Disease; E-Cadherin; Electrolytes; Event; Exhibits; Exposure to; Fluids and Secretions; Functional disorder; Funding; Gastroenterology; Gastrointestinal Diseases; Gulf War; Healthcare; Human; Incidence; Infection; Inflammation; Inflammatory Bowel Diseases; Intestinal Absorption; Intestines; Ions; Journals; Knockout Mice; Knowledge; Link; Liver diseases; Metagenomics; Microbe; Modality; Modeling; Morbidity - disease rate; Mus; Neutrophil Infiltration; Outcome; Pathogenesis; Persian Gulf Syndrome; Phenotype; Play; Post-Traumatic Stress Disorders; Predisposition; Probiotics; Proteins; Publishing; Research; Research Personnel; Risk; Role; SLC26A3 gene; Source; Structure; Symptoms; Technology; Therapeutic; Time; Transgenic Mice; Veterans; War; absorption; beneficial microorganism; care burden; diarrheal disease; dysbiosis; efficacy evaluation; enteropathogenic Escherichia coli; fecal transplantation; gut dysbiosis; gut inflammation; gut microbiome; human subject; humanized mouse; imaging system; in vivo Model; in vivo optical imaging; intestinal barrier; meetings; microbial; microbiome; microbiome alteration; mouse model; novel; novel strategies; novel therapeutics; occludin; overexpression; pathogen; sodium-hydrogen exchanger 3; transcriptome sequencing; translational impact; treatment strategy

This revised BLRD and CSRD Collaborative Merit Award (BCCMA) application is being submitted as part of a group of 5-linked CMAs from nationwide VA investigators in gastrointestinal (GI) and liver diseases, who formed a national steering committee after participating in a successful field-based meeting in San Diego in May 2019 (funded by VAORD). The roadmap developed at this meeting was published in the journal “Gastroenterology” (PMC7249241). This cluster of CMAs is aimed at in depth understanding of the emerging role of gut microbiome in the pathophysiology of Veterans deployment related GI and liver diseases including the Gulf War Illness (GWI), Post Traumatic Stress Disorder (PTSD) and Inflammatory Bowel Diseases (IBD), and to develop potential biotherapeutics to alleviate the disease symptoms. This specific proposal CMA1, is driven by the facts that while diarrheal disorders are highly prevalent in Veterans with GWI and are a major cause of high morbidity, the pathophysiology of GWI is not well-defined, and the treatment options are inadequate. Therefore, in view of the emerging role of the gut microbiome in GWI, there is a critical need to better understand the role of microbial dysbiosis and the mechanisms involved in higher incidence of diarrheal disorders and IBS in these Veterans. Recent studies have further highlighted the crucial role of gut microbiome in susceptibility to diarrheal pathogens. For example, gut microbiome has been shown to be the key determinant in susceptibility to infection and diarrhea by C. rodentium (CR, murine counterpart of the human enteropathogenic E. coli). Additionally, fecal microbial transplant (FMT) based treatment strategies for C. difficile infection further support the critical role of gut microbiome in diarrheal diseases. However, direct causal relationship of microbial dysbiosis observed in GWI Veterans and diarrheal illnesses remains uninvestigated. In this regard, in preliminary studies we established a humanized GWI mouse model where FMT from GWI Veterans in mice for 14 days almost recapitulated some features of the functional bowel disorders associated with GWI, including a) significant dysregulation in intestinal barrier integrity; and b) mild inflammation as assessed by neutrophil infiltration. Another novel and striking finding in the humanized GWI mice was a marked decrease in colonic expression of the key chloride transporter (DRA, Down Regulated in Adenoma). Of note, decreased DRA expression is a key event in infectious or IBD associated diarrhea and is also linked to compromised barrier integrity. Also, in preliminary studies, we observed that DRA KO mice were much more susceptible to CR infection. Based on these data, we hypothesize that “Dysbiosis in GWI Veterans is associated with compromised barrier integrity and decreased DRA expression which contributes to increased predisposition of veterans to pathogen infections and diarrhea. We propose to utilize state-of- the-art animal models e.g., the humanized and conventional GWI mice (exposure to gulf war chemicals), and approaches using apical-out enteroids/colonoids, inducible DRA overexpressing transgenic mice, and in vivo optical imaging system (IVIS) for in depth mechanistic understanding of the role of dysbiosis in GWI. We also propose to investigate the role of biotherapeutics e.g., FMT from healthy Veterans, probiotics, and a bacterial metabolite butyrate in alleviating gut dysbiosis, susceptibility to CR infection and gut barrier integrity. Two Specific Aims are proposed: 1). Determine the susceptibility of humanized (FMT) and conventional (chemical induced) GWI mice to C. rodentium induced diarrhea and elucidate the underlying mechanisms; 2). Develop effective strategies aimed at correcting dysbiosis and diarrheal phenotype in C. rodentium infected GWI mouse models. A successful outcome of the proposed studies is likely to increase our understanding of the role of GWI microbiome in susceptibility to diarrheal diseases, higher incidence of IBS (as repeated bouts of infectious diarrhea increase the risk of IBS) and has potential of developing novel biotherapeutics for alleviation of dysbiosis and associated GWI symptoms.

该修订后的BLRD和CSRD合作功绩奖（BCCMA）申请正在作为一部分 来自全国VA胃肠道（GI）和肝病的全国VA调查人员的5连锁CMA组，他们形成 2019年5月在圣地亚哥参加成功在圣地亚哥举行的基于现场的会议后，国家指导委员会 （由Vaord资助）。在本次会议上开发的路线图发表在《胃肠病学》杂志上 （PMC7249241）。该CMA集群的目的是深入了解肠道微生物组的新兴作用 在退伍军人部署相关的GI和肝病的病理生理中，包括海湾战争疾病（GWI）， 创伤后应激障碍（PTSD）和炎症性肠病（IBD），并发展潜力 生物治疗药可减轻疾病症状。该具体提议CMA1是由事实驱动的 腹泻疾病在GWI的退伍军人中非常普遍，是发病率高的主要原因，但 GWI的病理生理学并不明确，治疗方案不足。因此，在 肠道微生物组在GWI中的新兴作用的看法，迫切需要更好地了解 微生物营养不良的作用以及腹泻疾病和IBS较高事件所涉及的机制 在这些退伍军人中。最近的研究进一步强调了肠道微生物组在 对腹泻病原体的敏感性。例如，肠道微生物组已被证明是关键的确定器 为了感染感染和腹泻的易感性（Cr，人类的鼠类对应物 肠病大肠杆菌）。另外，基于粪便的艰难梭菌基于粪便微生物移植（FMT）治疗策略 感染进一步支持肠道微生物组在腹泻疾病中的关键作用。但是，直接的灾难性 在GWI退伍军人和腹泻病中观察到的微生物营养不良的关系仍未被评估。在 在这方面，在初步研究中，我们建立了一个人源化的GWI小鼠模型，其中GWI的FMT 小鼠的退伍军人几乎概括了与功能性肠道疾病相关的某些特征 GWI，包括a）肠屏障完整性的明显失调； b）轻度炎症 通过中性粒细胞浸润评估。人源化的GWI小鼠中的另一个小说和惊人的发现是一个标记 关键氯化物转运蛋白的结肠表达降低（DRA，在腺瘤中调节）。值得注意的是， DRA表达降低是感染或IBD相关腹泻的关键事件，也与 障碍的完整性受损。同样，在初步研究中，我们观察到DRA KO小鼠的次数更多 容易感染CR。基于这些数据，我们假设“ GWI退伍军人的营养不良是 与受损的屏障完整性和改善的DRA表达相关，这有助于 退伍军人对病原体感染和腹泻的倾向增加。我们建议利用最新 艺术动物模型，例如人源化和常规的GWI小鼠（暴露于海湾战争化学物质），以及 使用顶端的肠to/肠结构素，诱导的DRA过表达转基因小鼠和体内的方法 光学成像系统（IVI），以深入了解GWI中营养不良的作用。我们也是 研究生物治疗剂的作用，例如健康的退伍军人，益生菌和细菌的FMT 代谢产物丁酸酯缓解了肠道营养不良，对CR感染的敏感性和肠道屏障完整性。二 提出了具体目标：1）。确定人性化（FMT）和常规的敏感性 （化学诱导的）GWI小鼠至啮齿动物C.诱导的腹泻并阐明了基础 机制； 2）。制定旨在纠正营养不良和腹泻的有效策略 啮齿动物念珠菌感染的GWI小鼠模型中的表型。拟议研究的成功结果 可能会增加我们对GWI微生物组在腹泻疾病易感性中的作用的理解， IBS的发病率更高（随着感染性腹泻的反复发作会增加IBS的风险），并且具有潜力 开发新型的生物治疗药来减轻营养不良和相关的GWI符号。