Longitudinal microbiome-host interactions and clinical outcomes in drug-resistant tuberculosis patients

耐药结核病患者的纵向微生物组-宿主相互作用和临床结果

• 批准号: 10672997
• 负责人: Charissa Camille Naidoo
• 金额: $ 8.93万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672997
• 关键词: 16S ribosomal RNA sequencing; Acetates; Adolescent; Adult; Affect; African; Aftercare; Anaerobic Bacteria; Antibiotic Therapy; Antibiotics; Antitubercular Antibiotics; Butyrates; Cause of Death; Clinical; Clinical Trials; Collaborations; Combined Antibiotics; Computing Methodologies; Data; Dedications; Dietary Supplementation; Dose; Drug Kinetics; Drug resistance in tuberculosis; Enterobacter; Enterobacteriaceae; Epidemic; Ethambutol; Etiology; Feces; Foundations; Funding; Future; HIV; Health; Health Benefit; Hospitals; Human Microbiome; Immune; Inflammatory; Injections; Intervention; Klebsiella; Knowledge; Leukocytes; Levaquin; Life; Linezolid; Mass Chromatography; Mass Fragmentography; Mass Spectrum Analysis; Measures; Mediator; Mentors; Mentorship; Metabolic; Metadata; Monitor; Multidrug-Resistant Tuberculosis; Mus; New York; Oral; Outcome; Pantoea; Parents; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Production; Propionates; Prospective, cohort study; Province; Pulmonary Tuberculosis; Pyrazinamide; Regimen; Research; Research Priority; Research Support; Resistance; Rifampicin resistance; Rifampin; Sampling; Scientist; South Africa; South African; Sputum; Structure; Testing; Treatment outcome; Tuberculosis; Uncertainty; Universities; Volatile Fatty Acids; Withholding Treatment; Work; absorption; career; career development; cohort; combinatorial; commensal microbes; design; diagnostic tool; drug-sensitive; experimental study; global health emergency; gut microbiota; host microbiome; human microbiota; immunoregulation; improved; isoniazid; longitudinal analysis; low and middle-income countries; medical schools; microbial; microbial community; microbial host; microbiome; microbiome research; microbiota; microbiota profiles; mortality; multidisciplinary; programs; resilience; response; risk prediction; treatment response; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY The human microbiome is an essential mediator of health and influences important metabolic functions through production of short chain fatty acids (SCFAs). These compounds have been shown to independently predict risk for developing tuberculosis (TB) – a leading cause of death in South Africa. Antibiotics may profoundly impact the microbiome yet the impact of treatment on the microbiome remains completely uncharacterized in patients with rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB; resistance to the two most effective TB drugs). In response to the RR/MDR-TB epidemic, the South African National Programme rolled-out an all- oral shorter course regimen (SCR) which is being investigated within the funded observational prospective cohort study (SHIFT-TB; PI: Dr Graeme Meintjes) that this proposal (NASCENT; PI: Dr Charissa Naidoo) will leverage. We hypothesize that the SCR, though comprising lifesaving antibiotics for TB, also contain others which could plausibly affect the commensal microbiota (≤540 broad-spectrum antibiotic doses given over 9 months). Using 16S rRNA gene sequencing, we will longitudinally characterize the sputum and stool microbiota in 260 RR/MDR- TB adults and adolescents (≥ 15 years) initiating the SCR at Nkqubela Hospital, Eastern Cape Province, South Africa, at five intervals before, during, and after treatment. We will correlate the microbiota with important clinical metadata measured in the parent study, including repeated pharmacokinetic (Pk) data and pre-defined clinical outcomes. This work will lay the foundation for future trials where the microbiome is monitored as a diagnostic tool for clinical outcomes or modulated (through dietary supplementation, host-directed therapies) to improve long-term health (i.e., post-TB lung sequalae). Specifically, Aim 1 will evaluate changes in the sputum and stool microbiota in patients receiving treatment for RR/MDR-TB. Aim 2 will, using targeted as chromatography-mass spectrometry in stool, longitudinally quantify microbially-produced SCFAs (butyrate, propionate, acetate) and correlate SCFAs with the microbiota in co- occurrence network analyses. Aim 3 will evaluate longitudinal associations between the microbiota and drug Pk (where we expect greater drug absorption to result in greater microbial shifts and loss of diversity), and whether distinct microbiomes reflect favorable vs. unfavorable outcomes. Together, the proposal will achieve the following: 1) promote an independently funded research career for the candidate at Stellenbosch University (through structured mentorship with scientific experts), 2) strengthen South African analytical capacity for microbiome research in a low-middle income country (LMIC) research priority (TB), 3) and enhance long term collaboration with leading US scientists.

项目摘要 人类微生物组是健康的重要介体，通过 短链脂肪酸（SCFA）的产生。这些化合物已被证明可以独立预测风险 用于发展结核病（TB） - 南非的主要死亡原因。抗生素可能会对 微生物组然而，治疗对微生物组的影响仍然完全没有特征 抗利福平耐药和多药耐药性结核病（RR/MDR-TB；对两种最有效的抗性 结核病药物）。为了回应RR/MDR-TB的流行，南非国家计划将 口服较短的课程方案（SCR），该方案正在资助的前瞻性队列中进行研究 研究（Shift-TB； PI：Graeme Meintjes博士），该提议（新生； PI：Charissa Naidoo博士）将利用。 我们假设SCR虽然完成了TB的救生抗生素，但也包含其他可能 合理地影响共生微生物群（≤540次在9个月内给予的广谱抗生素剂量）。使用 16S rRNA基因测序，我们将纵向表征260 RR/MDR-中的痰液和粪便菌群 结核病成年人和青少年（≥15岁）在南开普省Nkqubela医院启动SCR 非洲，在治疗之前，期间和之后以五个间隔。我们将将微生物群与重要的临床相关 在家长研究中测量的元数据，包括重复的药代动力学（PK）数据和预定义的临床 结果。这项工作将为以后的试验奠定基础，在该试验中，将微生物组作为诊断监测 用于临床结果或调制的工具（通过补充饮食，宿主指导的疗法）改善 长期健康（即结核病后肺序列）。 具体而言，AIM 1将评估接受治疗治疗的患者的痰液和粪便菌群的变化 RR/MDR-TB。 AIM 2将使用靶向作为色谱 - 质量光谱法的目标，纵向量化 微生物生产的SCFA（丁酸酯，丙酸，乙酸酯），并将SCFA与菌群中的SCFA相关联 AIM 3将评估微生物群和药物PK之间的纵向关联 （我们期望有更多的药物滥用会导致更大的微生物转变和多样性的丧失），以及是否是否 不同的微生物组反映了有利的和不利的结果。 该提案将共同实现以下方面：1）促进独立资助的研究职业 Stellenbosch大学的候选人（通过与科学专家的结构化心态），2）加强南方 低中型收入国家（LMIC）研究优先级（TB）的微生物组研究的非洲分析能力， 3）并增强与领先的美国科学家的长期合作。