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)可导致终末器官损伤,如肝脏
肝硬化肝硬化和创伤后应激障碍都独立地导致肠道生态失调和脑功能障碍。我们已经表明
患有肝硬化的退伍军人的认知功能障碍与高粪便致病菌,胆汁酸的改变
和短链脂肪酸(SCFA),以及与认知和患者相关的促炎环境。
报告的结果。然而,患有PTSD+肝硬化的退伍军人的肠-肝-脑轴的改变需要进一步研究。
调查这是一个名为“靶向肠道微生物组”的合作优异申请(CMA)的一部分。
退伍军人部署相关的胃肠道和肝脏疾病”。这些建议的重点是
创伤后应激障碍和海湾战争疾病对退伍军人肝硬化,炎症性肠病和消化道疾病。
我们发表的数据显示,患有PTSD+肝硬化的退伍军人有更大的认知障碍,
与无创伤后应激障碍的肝硬化相比,我们
初步数据显示:a)患有PTSD+肝硬化的退伍军人与
2)PTSD+肝硬化与单纯肝硬化中合成SCFA的基因丰度较低的宏基因组学,
3)来自转移至无菌(GF)小鼠的PTSD+肝硬化患者的微生物群显示出较低的
微生物多样性和较高的肠道和皮质炎症与肝硬化,创伤后应激障碍和控制。
目前治疗创伤后应激障碍的药物效果相对有限。考虑到肝脏在
代谢药物和肝性脑病(HE)发展的可能性,使用神经活性药物
肝硬化的药物治疗具有挑战性。微生物调节可能是安全治疗肠源性
炎症可导致患有PTSD+肝硬化的退伍军人的脑功能障碍。我们表演了三个
在患有肝硬化的退伍军人中进行粪便微生物群移植(FMT)的I期随机试验。这些试验
证明安全性,更好的认知,更低的血清LBP和全身炎症环境,
粪便/血浆SCFA。然而,在我们将这些应用于患有PTSD+肝硬化的退伍军人之前,我们需要
确定微生物变化的作用。这项建议是实现这一总体目标的第一步。
我们的总体假设是:“肠道微生物的改变导致肠道屏障受损增加
与对照组相比,伴有PTSD和肝硬化的退伍军人的认知功能障碍更大。
那些患有PTSD或肝硬化的人,由于协同炎症过程”。这是因为,
与微生物转化的胆汁酸和SCFA相关的炎症和肠道屏障变化。这
将以下列两个目标检验假设:
目的1:确定肠道微生物群落组成和功能与健康之间的联系-
与单纯肝硬化和单纯PTSD相比,PTSD+肝硬化退伍军人的相关生活质量。
我们将招募320名退伍军人(各80名患有PTSD+肝硬化,单独的PTSD,单独的肝硬化和对照),
里士满和洛杉矶的吸血鬼。粪便宏基因组学和微生物功能(粪便SCFA/胆汁酸),以及
全身炎性细胞因子将与生活质量相关。PTSD和肝硬化严重程度将匹配。
目的2:确定哪些微生物分类群介导了肠屏障变化的发展,
酸和脑炎症使用人类无菌小鼠移植,并评估其影响
关于压力恢复力的研究目的2.1:确定退伍军人粪便对GF小鼠定植的影响
与单独的PTSD、单独的肝硬化以及肠道和神经炎症的对照相比,
以及肠屏障的变化,从而导致行为的变化。
目的2.2:定义这种差异定植在介导对PTSD相关压力的恢复力中的作用。
该研究团队在肝硬化,微生物组分析,创伤后应激障碍和gnotobiotic研究方面经验丰富。这项建议
将形成一个平台,以调查基于微生物的治疗退伍军人肝硬化和创伤后应激障碍。
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)
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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
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
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
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
THU156 - Fecal transplant-related reductions in Alcohol intake from human to mice are associated with alterations in the intestinal but not liver or prefrontal cortex transcriptome
THU156 - 从人类到小鼠的粪便移植相关酒精摄入量减少与肠道而非肝脏或前额叶皮质转录组的改变有关
- DOI:
10.1016/s0168-8278(22)00730-9 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jennifer Wolstenholme;Maren Smith;Ryan Balfour Sartor;Javier Maeso-Gonzalez;Derrick Zhao;Huiping Zhou;Jason Kang;Phillip Hylemon;Jasmohan S Bajaj - 通讯作者:
Jasmohan S Bajaj
Jasmohan S Bajaj的其他文献
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{{ 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:
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