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.

项目概要/摘要 虽然世界上近四分之一的人口潜伏感染结核分枝杆菌，但只有 一小部分人患有活动性结核病 2017 年，有 1000 万人患有结核病，其中包括 100 万儿童。 雾化暴露后进展为活动性结核病的因素在很大程度上与年龄和免疫学有关 然而，需要改进方法来识别罹患活动性结核病的最高风险人群。 人们越来越认识到微生物组是由数万亿个生物体组成的 在人体内部——在调节宿主代谢和免疫途径中发挥重要作用。 包括共生生物战胜入侵病原体的能力以及某些菌群的能力 刺激先天免疫反应，随后影响适应性反应，从而促进粘膜 虽然大多数微生物组存在于人类肠道中，但还存在其他重要的菌群。 在其他各个部位，其中最相关的是肺部； 关于结核病，人们对这两个区室之间的相互作用（称为肠-肺轴）知之甚少。 关于微生物组可能影响活动性结核病进展风险或疾病结果的方式。 众所周知，抗菌药物的使用会导致肠道菌群破坏，一线药物的影响 使用利福平、异烟肼、吡嗪酰胺和乙胺丁醇治疗结核病对微生物群的影响尚待研究。 推荐的结核病治疗疗程较长——至少六个月；因此，人们担心这 持续接触抗菌药物会对微生物组产生长期影响。 在此应用中，我们建议评估儿科参与者的肠道微生物群，这些参与者 我们将使用来自坦桑尼亚农村儿童的队列研究来进行结核病评估； 在六个月内的三个时间点收集粪便样本，包括任何结核病治疗之前的时间点 我们认为，在开始结核病治疗之前，结核病“病例”将表现出紊乱。 肠道微生物组与未患结核病的“对照”儿童不同。 对肠道微生物组的评估将证明结核病治疗与肠道菌群改变之间的关系 与不需要或不需要接受的“对照”儿童相比，微生物成员和功能潜力 我们将通过以下目标来检验我们的假设：1）评估肠道微生物群 将患有结核病的儿童与已排除患有结核病的儿童进行比较，并且 2) 确定 结核病治疗对肠道微生物组的组成、多样性和恢复力的纵向影响 接受结核病治疗的儿童与对照组的粪便样本 DNA 提取和宏基因组比较。 测序将在我们位于坦桑尼亚的长期合作研究基地进行，生物信息学 分析将由弗吉尼亚大学领导，成功完成这些目标将突出显示实现这些目标的方法。 肠道微生物群影响结核病的发病机制。