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 人体微生物组是健康的重要介质，并通过以下方式影响重要的代谢功能： 生产短链脂肪酸（SCFA）。这些化合物已被证明可以独立预测风险 结核病（TB）是南非的主要死因。抗生素可能会严重影响 然而，治疗对微生物组的影响在患者中仍然完全不确定 耐利福平和耐多药结核病（RR/MDR-TB;对两种最有效的 结核病药物）。为了应对RR/MDR-TB流行，南非国家方案推出了一项全面的 口服短程方案（SCR），正在资助的观察性前瞻性队列中进行研究 研究（SHIFT-TB; PI：Graeme Meintjes博士），该提案（NASCENT; PI：Charissa Naidoo博士）将利用。 我们假设，SCR虽然包含挽救生命的结核病抗生素，但也包含其他可能的抗生素。 可能影响肠道微生物群（9个月内给予≤540次广谱抗生素剂量）。使用 16 S rRNA基因测序，我们将纵向描述260例RR/MDR患者的痰和粪便微生物群。 在南东开普省Nkqubela医院启动SCR的结核病成人和青少年（≥ 15岁） 非洲，在治疗前，治疗期间和治疗后的五个间隔。我们将微生物与重要的临床 母研究中测量的元数据，包括重复药代动力学（Pk）数据和预定义的临床 结果。这项工作将为未来将微生物组作为诊断手段进行监测的试验奠定基础 用于临床结局或调节（通过膳食补充剂，宿主导向疗法）以改善 长期健康（即，肺结核后遗症）。 具体而言，目标1将评估接受以下治疗的患者的痰和粪便微生物群的变化： RR/MDR-TB。目的2将，使用靶向作为色谱-质谱法在粪便中，纵向定量 微生物产生的SCFAs（丁酸盐、丙酸盐、乙酸盐），并将SCFAs与共同培养的微生物群相关联。 发生网络分析目标3将评估微生物群和药物Pk之间的纵向关联 （我们预计更大的药物吸收会导致更大的微生物转移和多样性丧失），以及是否 不同的微生物组反映了有利与不利的结果。 总之，该提案将实现以下目标：1）促进独立资助的研究事业， 斯泰伦博斯大学的候选人（通过与科学专家的结构化指导），2）加强南 非洲中低收入国家微生物组研究的分析能力（LMIC）研究优先事项（TB）， 3)并加强与美国领先科学家的长期合作。