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.

这份修订后的BLRD和CSRD协作功勋奖(BCCMA)申请将作为 由来自全国退伍军人管理局胃肠道(GI)和肝病研究人员的5名关联CMA组成的小组，他们组成了 在参加了2019年5月在圣地亚哥成功举行的实地会议后成立的国家指导委员会 (VAORD提供资金)。此次会议制定的路线图发表在《胃肠病学》杂志上。 (PMC7249241)。这一组CMA旨在深入了解肠道微生物组的新角色 在退伍军人部署相关胃肠道疾病和包括海湾战争病(GWI)在内的肝脏疾病的病理生理学中， 创伤后应激障碍(PTSD)和炎症性肠病(IBD)，并开发潜力 用生物疗法来缓解疾病症状。这一具体的提案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，但也是高发病率的主要原因， GWI的病理生理机制尚未明确，治疗方案也不够完善。因此，在 鉴于肠道微生物组在GWI中的新角色，迫切需要更好地了解 微生物失调的作用及其在腹泻性疾病和肠易激综合征发病中的作用 在这些老兵身上。最近的研究进一步强调了肠道微生物群在 对腹泻病原体的敏感性。例如，肠道微生物群已被证明是关键的决定因素 对轮状芽胞杆菌(CR，人类的小鼠对应物)感染和腹泻的易感性 致肠性大肠杆菌)。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群在腹泻疾病中的关键作用。然而，直接因果关系 在退伍军人中观察到的微生物失调与腹泻疾病的关系仍未得到调查。在……里面 在这方面，在初步研究中，我们建立了人源化的GWI小鼠模型，其中FMT来自GWI 退伍军人在小鼠身上进行了14天的实验，几乎概括了与功能性肠病相关的一些特征。 GWI，包括a)严重的肠道屏障完整性失调；b)轻度炎症，如 通过中性粒细胞渗入进行评估。在人源化的GWI小鼠中，另一个新颖而引人注目的发现是一个明显的 关键的氯离子转运蛋白(DRA，在腺瘤中下调)在结肠的表达减少。值得注意的是， DRA表达降低是感染性或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小鼠比 易受CR感染。基于这些数据，我们假设“第一次世界大战退伍军人的生物失调是 与屏障完整性受损和DRA表达减少相关，这有助于 退伍军人对病原体感染和腹泻的易感性增加。我们建议使用状态- 最先进的动物模型，例如人源化和传统的GWI小鼠(暴露于海湾战争化学品)，以及 使用根尖外肠样/结肠样细胞、可诱导的DRA过表达转基因小鼠和体内的方法 光学成像系统(IVIS)，用于深入了解生物失调在GWI中的作用。我们也 建议研究生物疗法的作用，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生物失调、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)。人源化(FMT)和常规 (化学诱导)GWI小鼠对轮状芽胞杆菌所致腹泻及其机制的研究 机制；2)。制定有效的策略，以纠正生态失调和腹泻 轮状念珠菌感染GWI小鼠模型的表型。拟议研究的成功结果 可能会增加我们对GWI微生物群在腹泻疾病易感性中的作用的理解， IBS的发病率较高(因为反复发作的感染性腹泻增加了IBS的风险)，并具有潜在的 开发新的生物疗法，以缓解生物失调和相关的GWI症状。