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;
基本信息
- 批准号:10475994
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAlcohol abuseAwardBehaviorBile AcidsBrainChronic stressCirrhosisCognitionCollaborationsDataDevelopmentDiseaseEncephalitisEnrollmentFatty AcidsFecesFunctional disorderGastrointestinal DiseasesGenesGerm-FreeGnotobioticGoalsHepatic EncephalopathyHumanImpaired cognitionImpairmentIncidenceInflammationInflammatoryInflammatory Bowel DiseasesIntestinesInvestigationKnowledgeLeadLinkLiverLiver CirrhosisLiver diseasesLos AngelesMediatingMetagenomicsMicrobeModalityModelingMusOrganOutcomePatient Outcomes AssessmentsPatient TransferPersian Gulf SyndromePharmaceutical PreparationsPhasePlasmaPost-Traumatic Stress DisordersPredispositionProcessPublishingQuality of lifeResearchRoleSafetySerumSeveritiesSiteSourceStressStructureSubstance abuse problemSymptomsTechnologyTestingTransplantationVeteransVolatile Fatty Acidsaddictionbrain dysfunctioncytokinediarrheal diseasedysbiosisexperiencefecal transplantationgut dysbiosisgut inflammationgut microbesgut microbiomegut microbiotahealth related quality of lifehumanized mousein vivo Modelinflammatory milieuintestinal barrierlipopolysaccharide-binding proteinmicrobialmicrobial based therapymicrobiomemicrobiome analysismicrobiotamilitary veteranmouse modelneuroinflammationnovelnovel therapeuticspathobiontrandomized trialresiliencestress resiliencesuccesssystemic inflammatory responsetargeted treatmenttranscriptome sequencingtranslational impact
项目摘要
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.
在退伍军人中,创伤后应激障碍(PTSD)会导致终末器官损害,如肝脏
肝硬变。肝硬变和创伤后应激障碍都会单独导致肠道生态失调和脑功能障碍。我们已经展示了
退伍军人肝硬变患者认知功能障碍与大便高危、胆汁酸改变有关
和短链脂肪酸(SCFA),以及与认知和患者相关的促炎环境-
报告结果。然而,患有创伤后应激障碍+肝硬变的退伍军人的肠道-肝脏-脑轴的改变需要进一步的研究
调查。这是协作优点应用程序(CMA)的一部分,标题为
退伍军人部署与胃肠道和肝脏疾病相关的疾病“。这些建议的重点是
退伍军人中的创伤后应激障碍和海湾战争疾病对肝硬变、炎症性肠病和腹泻疾病的影响。
我们公布的数据显示,患有创伤后应激障碍+肝硬变的退伍军人有更大的认知障碍,微生物
与无创伤后应激障碍的肝硬变患者相比,患者的微生态失调和血清脂多糖结合蛋白(LBP)水平降低。我们的
初步数据显示:a)患有创伤后应激障碍+肝硬变的退伍军人比
仅有肝硬变;2)创伤后应激障碍+肝硬变患者合成SCFA基因丰度较低的元基因组学
和,3)PTSD+肝硬变患者转移到无菌(GF)小鼠的微生物区系显示较低
与肝硬变、创伤后应激障碍和对照组相比,微生物多样性和更高的肠道和皮质炎症。
目前治疗创伤后应激障碍的药物疗效相对较差。鉴于肝脏在人体内的核心作用
代谢药物和潜在肝性脑病(HE)的发展,神经活性物质的使用
治疗肝硬变的药物是具有挑战性的。微生物调节可能是安全治疗肠源性肺炎的重要步骤
炎症可导致患有创伤后应激障碍+肝硬变的退伍军人的脑功能障碍。我们已经表演了三场
退伍军人肝硬变患者粪便微生物区系移植(FMT)1期随机试验。这些试验
表现出安全性、较好的认知性、较低的血清LBP和全身炎症环境,以及较高的
大便/血浆SCFA。然而,在我们将这些应用于患有创伤后应激障碍和肝硬变的退伍军人之前,我们需要
确定微生物变化的作用。这项提议是朝着这一总体目标迈出的第一步。
我们的总体假设是:肠道微生物改变导致肠道屏障损伤增加。
与退伍军人合并创伤后应激障碍和肝硬变相比,退伍军人认知功能障碍更严重
那些仅有创伤后应激障碍或肝硬变的患者,由于协同炎症过程“。这是由于增加了
与微生物转化的胆汁酸和单链脂肪酸相关的炎症和肠道屏障改变。这
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
退伍军人合并创伤后应激障碍合并肝硬变的相关生活质量与仅有肝硬变和仅有创伤后应激障碍的比较。
我们将招募320名退伍军人(80名患有创伤后应激障碍合并肝硬变、单独患有创伤后应激障碍、单独患有肝硬变和对照组)。
里士满和洛杉矶的VAMC。粪便元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联系在一起。创伤后应激障碍和肝硬变的严重程度将匹配。
目的2:确定哪些微生物类群介导了肠道屏障改变、胆汁改变的发展
酸,以及使用人到无菌小鼠移植的脑部炎症,并评估其影响
从压力中恢复的能力。目标2.1:确定退伍军人粪便对GF小鼠定居的影响
PTSD+肝硬化组与单纯PTSD组、单纯肝硬化组以及肠道和神经炎症对照组相比,
以及使用经验证的创伤后应激障碍小鼠模型,肠道屏障的变化以及由此导致的行为变化。
目标2.2:确定这种不同的定植在调节对创伤后应激相关应激的恢复力中的作用。
研究团队在肝硬变、微生物组分析、创伤后应激障碍和生理学研究方面经验丰富。这项建议
将形成一个平台,研究患有肝硬变和创伤后应激障碍的退伍军人的微生物治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jasmohan S Bajaj其他文献
WED-383 - Serum ammonia levels do not correlate with overt hepatic encephalopathy severity and time to resolution in hospitalized patients with cirrhosis
- DOI:
10.1016/s0168-8278(23)00853-x - 发表时间:
2023-06-01 - 期刊:
- 影响因子:
- 作者:
Jasmohan S Bajaj;Nikolaos T. Pyrsopoulos;Robert Rahimi;Zeev Heimanson;Christopher Allen;Robert Israel;Don Rockey - 通讯作者:
Don Rockey
THU494 - Serum metabolites on admission associate with the development of nosocomial infections in inpatients with cirrhosis
THU494 - 入院时的血清代谢物与肝硬化住院患者医院感染的发生发展相关
- DOI:
10.1016/s0168-8278(22)01041-8 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jasmohan S Bajaj;Jacqueline O’Leary;Puneeta Tandon;Guadalupe Garcia-Tsao;Patrick S. Kamath;Paul J. Thuluvath;Ram Subramanian;Hugo E. Vargas;Sara McGeorge;Andrew Fagan;Florence Wong;Jennifer Lai;Leroy Thacker;Rajender Reddy - 通讯作者:
Rajender Reddy
THU023 - Active alcohol misuse is linked with lower short-chain fatty acid producing microbiota in a matched study of 450 patients with cirrhosis
THU023 - 在一项针对 450 例肝硬化患者的配对研究中,积极的酒精滥用与短链脂肪酸产生微生物群减少有关
- DOI:
10.1016/s0168-8278(22)00643-2 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jasmohan S Bajaj;Amirhossein Shamsaddini;Masoumeh Sikaroodi;Brian Davis;Puneet Puri;Michael Fuchs;Andrew Fagan;Sara McGeorge;Patrick Gillevet - 通讯作者:
Patrick Gillevet
FRI-546 - Nosocomial infections in cirrhosis are unpredictable and vary based on region of the world: CLEARED study
- DOI:
10.1016/s0168-8278(23)00733-x - 发表时间:
2023-06-01 - 期刊:
- 影响因子:
- 作者:
Jasmohan S Bajaj;Florence Wong;Qing Xie;Patrick S. Kamath;Mark Topazian;Shiv Kumar Sarin;Shiva Kumar;Sebastián Marciano;Fiona Tudehope;Robert Gibson;Adam Doyle;Stephen Riordan;Alberto Queiroz Farias;Nabiha Faisal;Puneeta Tandon;Marie Jeanne Lohoues;Carlos Benitez;Yongchao Xian;Chuanwu Zhu;Minghua Su - 通讯作者:
Minghua Su
SAT496 - SBP vs. non-SBP bacterial infections at admission have comparable outcomes in a multi-center cohort of inpatients with cirrhosis
在一项多中心肝硬化住院患者队列中,入院时 SAT496 - SBP 与非 SBP 细菌感染的结局相当
- DOI:
10.1016/s0168-8278(22)02066-9 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jacqueline O’Leary;K.Rajende Reddy;Puneeta Tandon;Patrick S. Kamath;Guadalupe Garcia-Tsao;Flornce Wong;Jennifer C Lai;Ram Subramanian;Paul J. Thuluvath;Benedict Maliakkal;Hugo E. Vargas;Scott Biggins;Leroy Thacker;Jasmohan S Bajaj - 通讯作者:
Jasmohan S Bajaj
Jasmohan S Bajaj的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jasmohan S Bajaj', 18)}}的其他基金
Fecal microbiota transplant for Alcohol-Associated Cirrhosis
粪便微生物群移植治疗酒精相关性肝硬化
- 批准号:
10703378 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Fecal microbiota transplant for Alcohol-Associated Cirrhosis
粪便微生物群移植治疗酒精相关性肝硬化
- 批准号:
10444624 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Gut Microbiota in the Modulation of Outcomes after Liver Transplant
肠道微生物群对肝移植后结果的调节
- 批准号:
10231248 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Gut Microbiota in the Modulation of Outcomes after Liver Transplant
肠道微生物群对肝移植后结果的调节
- 批准号:
10054215 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Health IT generated PROs to Improve Outcomes in Cirrhosis
健康 IT 生成 PRO 来改善肝硬化的治疗结果
- 批准号:
10374779 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Modulation of Gut-Brain Axis Using Fecal Microbiome Transplant Capsules in Cirrhosis
使用粪便微生物移植胶囊调节肝硬化的肠脑轴
- 批准号:
9335590 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Bile Acids and Gut Microbiome in the Pathogenesis of Inflammation in Cirrhosis
胆汁酸和肠道微生物组在肝硬化炎症发病机制中的作用
- 批准号:
8994662 - 财政年份:2015
- 资助金额:
-- - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Studentship














{{item.name}}会员




