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

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)可导致末端器官损伤,如肝脏

项目成果

期刊论文数量(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
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

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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:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
  • 批准号:
    10487561
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
  • 批准号:
    10700058
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
  • 批准号:
    10308126
  • 财政年份:
    2021
  • 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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