Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome

海湾战争退伍军人的疾病：饮食和生活方式风险因素与肠道微生物组相互作用导致的慢性症状

• 批准号: 10293547
• 负责人: Donald M Kuhn
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293547
• 关键词: 16S ribosomal RNA sequencing; Animal Model; Behavior; Blood - brain barrier anatomy; Brain; Bromides; Characteristics; Chronic; Communication; Complex; Diet; Dietary Intervention; Disease; Elements; Equilibrium; Fermentation; Gulf War; Gulf War veteran; Health; High Fat Diet; Institute of Medicine (U.S.); Intervention; Mass Spectrum Analysis; Metabolism; Mus; Obesity; Outcome; Pathologic; Permethrin; Persian Gulf Syndrome; Production; Psychophysiologic Disorders; Public Health; Reporting; Risk Factors; Serum; Symptoms; Testing; Time; Volatile Fatty Acids; War; associated symptom; commensal bacteria; diagnostic criteria; dietary; dysbiosis; expectation; experimental study; fecal microbiota; gut bacteria; gut microbiome; gut-brain axis; high-fat/low-fiber diet; liquid chromatography mass spectrometry; metabolome; metabolomics; microbiome; microbiota; mouse model; new therapeutic target; next generation sequencing; persistent symptom; pyridostigmine; small molecule; western diet

Project Summary/Abstract Gulf War Veterans’ Illnesses (GWVI) presents as a complex constellation of diverse symptoms that have persisted in Gulf War Veterans more than 25 years after their deployment to the Gulf region. This set of symptoms is so broad, it baffles diagnostic criteria and as a result, consideration of GWVI as a bona fide illness has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by the VA) and “multisymptom illness”. The most recent report by the Institute of Medicine Committee on Gulf War and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes associated with this disorder. This august Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptom set associated with GWVI and as a result, “it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report). We agree that a single cause for all elements of GWVI is unlikely, it is possible that a single pathophysiological mechanism that could influence the diverse symptoms of GWVI, and explain their persistence, and that mechanism is a dysbiosis in the gut microbiome. The broad objectives of this project are to analyze the effects of Gulf War agents on the commensal bacteria in the gut and to determine if these interactions result in changes in the bacterial production of short chain fatty acids (SCFAs) and other bioactive small molecules produced by gut bacteria. These products of bacterial fermentation and metabolism exert numerous effects throughout the body to include the CNS. Mice will be treated with a validated mouse model of GWVI (pyridostigmine bromide plus permethrin) and the gut microbiome will be analyzed via 16S rRNA sequencing using the MiSeq platform. The effects of these same agents on SCFA production will be determined using liquid chromatography-mass spectrometry. CNS and GI disorders that are confirmed symptoms of GWVI will also be assessed. Thereafter, the effects of a high fat diet on the microbiome and SCFA production will be evaluated. Finally, a new treatment aim is proposed that will test dietary intervention and fecal microbiota transfer for their ability to restore balance in the GWVI-modified gut microbiome and to diminish the CNS and GI symptoms of this serious disorder. It is predicted that a high fat diet will magnify the effects of Gulf War agents on the microbiome and the metabolome and cause a time-dependent worsening of GWVI symptoms. Together, the application of next generation sequencing and cutting edge mass spectrometry will help fill gaps in our understanding of how Gulf War agents influence communication along the gut-brain axis. These studies may also reveal new therapeutic targets for GWVI by restoring balance in the gut microbiome through dietary and microbiota transfer interventions.

项目概要/摘要 海湾战争退伍军人疾病 (GWVI) 表现为一系列复杂的不同症状， 海湾战争退伍军人在部署到海湾地区后坚持了25年多。 症状如此广泛，以至于混淆了诊断标准，因此，将 GWVI 视为一种真正的疾病 慢慢地从否认其存在发展到使用“无法解释的疾病”等术语（由 VA）和“多症状疾病”。医学研究所委员会关于海湾战争的最新报告。 和健康 (2016) 的结论是，GWVI 不是一种心身疾病，现在有足够的证据表明 得出的结论是，被部署到海湾战争与健康结果之间存在因果关系 这个庄严的委员会指出，在阐明这一疾病方面进展甚微。 与 GWVI 相关的复杂症状组背后的病理机制，因此，“它 似乎没有单一机制可以解释海湾战争病中出现的多种症状，并且 战后这么多年，不太可能确定一个明确的致病因素”（报告第 3 页）。 我们一致认为，GWVI 所有因素的单一原因不太可能，单一的病理生理学因素可能是 可能影响 GWVI 多种症状并解释其持续存在的机制 机制是肠道微生物群失调。该项目的主要目标是分析其影响。 海湾战争特工对肠道共生细菌的影响，并确定这些相互作用是否会导致 细菌生产短链脂肪酸 (SCFA) 和其他生物活性小分子的变化 由肠道细菌产生的这些细菌发酵和代谢产物具有多种作用。 小鼠的全身（包括中枢神经系统）将接受经过验证的 GWVI 小鼠模型的治疗。 （溴吡斯的明加氯菊酯）和肠道微生物组将通过 16S rRNA 测序进行分析 使用 MiSeq 平台将确定这些相同试剂对 SCFA 生产的影响。 经液相色谱-质谱分析确认为 GWVI 症状的中枢神经系统和胃肠道疾病。 此后，还将评估高脂肪饮食对微生物组和 SCFA 产生的影响。 最后，提出了一个新的治疗目标，将测试饮食干预和粪便微生物群。 转移是因为它们能够恢复 GWVI 修饰的肠道微生物组的平衡并减少中枢神经系统和 据预测，高脂肪饮食将放大这种严重疾病的胃肠道症状。 微生物组和代谢组的药物，并导致 GWVI 症状随时间恶化。 下一代测序和尖端质谱技术的应用将有助于填补空白 这些研究帮助我们了解海湾战争特工如何影响肠脑轴的交流。 还可能通过饮食恢复肠道微生物组的平衡来揭示 GWVI 的新治疗靶点 和微生物群转移干预措施。