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.

修订后的 BLRD 和 CSRD 合作优异奖 (BCCMA) 申请是作为 由来自全国 VA 胃肠道 (GI) 和肝脏疾病研究人员的 5 个连锁 CMA 组成的小组 2019 年 5 月参加在圣地亚哥成功举办的实地会议后成立国家指导委员会 （由 VORD 资助）。本次会议制定的路线图发表在《胃肠病学》杂志上 （PMC7249241）。该 CMA 集群旨在深入了解肠道微生物组的新兴作用 退伍军人部署相关的胃肠道和肝脏疾病的病理生理学，包括海湾战争病（​​GWI）， 创伤后应激障碍（PTSD）和炎症性肠病（IBD），并开发潜力 生物疗法可减轻疾病症状。这一具体提案 CMA1 是由以下事实驱动的： 虽然腹泻疾病在患有 GWI 的退伍军人中非常普遍，并且是高发病率的主要原因， GWI 的病理生理学尚未明确，治疗方案也不充分。因此，在 鉴于肠道微生物组在 GWI 中的新兴作用，迫切需要更好地了解 微生物失调的作用以及腹泻病和肠易激综合症高发病率的机制 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 对腹泻病原体的易感性。例如，肠道微生物组已被证明是关键的决定因素 对啮齿类梭菌（CR，人类的鼠类对应物）的感染和腹泻的易感性 肠致病性大肠杆菌）。此外，基于粪便微生物移植（FMT）的艰难梭菌治疗策略 感染进一步支持肠道微生物组在腹泻疾病中的关键作用。然而，直接因果关系 在 GWI 退伍军人中观察到的微生物失调与腹泻疾病之间的关系尚未得到研究。在 为此，在初步研究中，我们建立了人源化 GWI 小鼠模型，其中来自 GWI 的 FMT 退伍军人在小鼠身上进行了 14 天的实验，几乎重现了相关功能性肠道疾病的一些特征 GWI，包括 a) 肠道屏障完整性显着失调； b) 轻度炎症如 通过中性粒细胞浸润进行评估。人源化 GWI 小鼠的另一个新颖且惊人的发现是 关键氯离子转运蛋白的结肠表达减少（DRA，腺瘤中下调）。值得注意的是， DRA 表达减少是感染性或 IBD 相关性腹泻的关键事件，也与 屏障完整性受损。此外，在初步研究中，我们观察到 DRA KO 小鼠的表现要好得多。 易受 CR 感染。根据这些数据，我们假设“GWI 退伍军人的生态失调是 与屏障完整性受损和 DRA 表达减少有关，这有助于 退伍军人更容易感染病原体和腹泻。我们建议利用state-of- 最先进的动物模型，例如人源化和传统 GWI 小鼠（暴露于海湾战争化学品），以及 使用顶端出肠样/结肠样、诱导型 DRA 过表达转基因小鼠和体内方法 光学成像系统 (IVIS)，用于深入了解 GWI 中生态失调的作用。我们也 提议研究生物治疗药物的作用，例如来自健康退伍军人的 FMT、益生菌和细菌 代谢物丁酸盐可缓解肠道菌群失调、CR 感染易感性和肠道屏障完整性。二 提出的具体目标： 1)。确定人源化 (FMT) 和常规的敏感性 （化学诱导）GWI 小鼠对 C. rodentium 诱导的腹泻并阐明其根本原因 机制； 2）。制定旨在纠正生态失调和腹泻的有效策略 啮齿类柠檬酸杆菌感染的 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了解， IBS 的发病率较高（因为反复发作的感染性腹泻会增加 IBS 的风险），并且有可能 开发新型生物治疗药物以缓解生态失调和相关的 GWI 症状。