Effects of TB and TB treatment on the pediatric intestinal microbiome

结核病和结核病治疗对儿童肠道微生物组的影响

• 批准号: 10042944
• 负责人: Tania A Thomas
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042944
• 关键词: 5 year old; Adult; Affect; Aftercare; Age; Attention; Bioinformatics; Child; Childhood; Clinical Data; Cohort Studies; Communicable Diseases; Complex; DNA; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Enrollment; Ethambutol; Evaluation; Future; Gender; Goals; Growth; Health; Human; Human Microbiome; Immune; Immune signaling; Immune system; Immunity; Immunocompetence; Infection; Inflammation; Innate Immune Response; Intestines; Investigation; Knowledge; Life; Literature; Long-Term Effects; Lung; Lung diseases; Measurable; Metabolism; Methods; Microbiology; Mucosal Immunity; Mus; Mycobacterium tuberculosis; Organism; Participant; Pathogenesis; Pathway interactions; Play; Population; Predisposition; Pyrazinamide; Regulation; Research; Rifampin; Risk; Risk Factors; Role; Rural; Severity of illness; Site; Tanzania; Testing; Time; Treatment outcome; Tuberculosis; United States National Institutes of Health; Universities; Virginia; absorption; aerosolized; age effect; age related; aged; antimicrobial; commensal bacteria; dysbiosis; gut microbiome; gut microbiota; gut-lung axis; high risk; improved; infancy; insight; isoniazid; metagenomic sequencing; microbial; microbiome; microbiota; microorganism; nutrient metabolism; nutrition; pathogen; recruit; resilience; response; stool sample; treatment comparison; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT While nearly one quarter of the world’s population is latently infected with Mycobacterium tuberculosis, only a small fraction develops active TB. In 2017, 10 million people developed TB, including 1 million children. Risk factors for progression to active TB after aerosolized exposure are, in large part, related to age and immunologic competency. However, improved methods are needed to identify people at highest risk of developing active TB. There is a growing appreciation that the microbiome—comprised of the trillions of organisms that live within the human—plays essential roles in the regulation of host metabolism and immunity. Immune pathways include the ability of commensal organisms to outcompete invasive pathogens and the ability of certain flora to stimulate innate immune responses, subsequently influencing adaptive responses that promote mucosal immunity. While the majority of the microbiome is found in the human intestines, additional important flora reside within various other compartments, most relevant of which includes the lungs; there is an emerging appreciation for the cross-talk between these two compartments, termed the gut-lung axis. Regarding TB, little is understood about ways in which the microbiome may impact risk of progression to active TB or disease outcomes. Although it is well known that the use of antimicrobials leads to a disruption in the intestinal flora, the impacts of first-line TB treatment with rifampin, isoniazid, pyrazinamide and ethambutol on the microbiome are understudied. The recommended course of TB treatment is lengthy—at least six months; therefore, there is a concern that this period of continuous antimicrobial exposure can have long-term effects on the microbiome. In this application, we propose to evaluate the intestinal microbiota from pediatric participants who were recruited in a cohort study of children from rural Tanzania undergoing evaluation for TB disease; we will use stool samples collected at three time points over six months, including a timepoint prior to any TB treatment initiation. We hypothesize that prior to TB treatment initiation, “cases” with TB will demonstrate perturbations in the intestinal microbiome that are distinguishable from “control” children without TB. Additionally, serial assessments of the intestinal microbiome will demonstrate how TB treatment is associated with alterations in microbiologic membership and functional potential compared to “control” children who did not need or receive TB treatment. We will test our hypotheses via the following aims: 1) evaluate the intestinal microbiome among children with TB disease compared children who have been ruled out from having TB disease, and 2) determine the longitudinal impacts of TB treatment on the composition, diversity, and resilience of the intestinal microbiome among children on TB treatment compared to controls. DNA extraction from stool samples and metagenomic sequencing will be conducted at our long-term collaborative research sites in Tanzania, and bioinformatic analyses will be led by the University of Virginia. Successful completion of these aims will highlight ways in which the intestinal microbiome affects TB pathogenesis.

项目摘要/摘要 虽然世界上将近四分之一的人口受到结核分枝杆菌感染，但只有一个 小部分会发展为主动结核。 2017年，1000万人患有结核病，其中包括100万儿童。风险 在雾化暴露后进展到活动性结核病的因素在很大程度上与年龄和免疫学有关 能力。但是，需要改进的方法来识别患有主动结核病风险的最高风险的人。 人们越来越多地赞赏微生物组 - 与数万亿的生物相结合 在人类中 - 扮演宿主代谢和免疫力的调节中的重要作用。免疫途径 包括共生生物胜过侵入性病原体的能力以及某些菌群的能力 刺激先天免疫调查，随后影响促进粘膜的适应性反应 免疫。尽管大多数微生物组都在人类肠道中发现，但其他重要的植物群休息 在其他各种隔间中，其中最相关的包括肺；有一个新兴的赞赏 对于这两个隔室之间的串扰，称为肠道轴。关于结核病，几乎没有理解 关于微生物组可能影响活跃结核病或疾病结果的风险的方式。虽然 众所周知，使用抗菌药会导致肠道菌群的破坏，这是一线的影响 在微生物组上，用利福平，异烟肼，吡嗪酰胺和乙酰丁醇治疗结核病。这 建议的结核病治疗过程很长，至少在六个月内；因此，有人担心 连续的抗菌暴露期间可能会对微生物组产生长期影响。 在此应用中，我们建议评估来自小儿参与者的肠道菌群 在对结核病疾病评估的一项对坦桑尼亚粗糙的儿童的队列研究中招募；我们将使用 六个月内在三个时间点收集的粪便样品，包括任何结核病之前的时间点 引发。我们假设在结核病治疗计划之前，“案例”与结核病有关 与没有结核病的“控制”儿童可以区分的肠道微生物组。另外，系列 肠道微生物组的评估将证明结核病治疗与改变 与不需要或接受的“对照”儿童相比，微生物的成员资格和功能潜力 结核病治疗。我们将通过以下目的测试我们的假设：1）评估肠道微生物组 结核病儿童比较了被排除在结核病疾病中的儿童，2）确定 结核病处理对肠道微生物组组成，多样性和弹性的纵向影响 与对照组相比，在结核病治疗的儿童中。从粪便样品和宏基因组中提取DNA 测序将在我们在坦桑尼亚的长期合作研究网站和生物信息学上进行 分析将由弗吉尼亚大学领导。这些目标的成功完成将突出显示的方式 肠道微生物组影响结核病发病机理。