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

项目总结 人体微生物群是健康的重要媒介，通过以下途径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 发展结核病(TB)--南非的主要死亡原因。抗生素可能会对 然而，治疗对患者微生物群的影响仍然完全不确定。 对利福平耐药和多药耐药结核病(RR/MDR-TB；对这两种耐药最有效 结核病药物)。为应对RR/耐多药结核病疫情，南非国家方案推出了一项全面-- 口服较短疗程方案(SCR)，这是在受资助的观察性前瞻性队列中进行的研究 研究(Shift-TB；PI：Graeme Meintjes博士)，这项提议(初生；PI：Charissa Naidoo博士)将发挥作用。 我们推测，SCR虽然包含治疗结核病的救命抗生素，但也包含其他可能 似乎会影响共生微生物区系(≤540广谱抗生素剂量超过9个月)。vbl.使用 16S rRNA基因测序，我们将纵向表征260 RR/MDR中的痰和粪便微生物群。 结核病成人和青少年(≥15岁)在南部东开普省恩库贝拉医院启动SCR 非洲，在治疗前、治疗中和治疗后间隔五次。我们将把微生物区系与重要的临床联系起来 在母研究中测量的元数据，包括重复药代动力学(PK)数据和预先定义的临床数据 结果。这项工作将为未来的试验奠定基础，在这些试验中，微生物组被监测为诊断 临床结果的工具或调整(通过饮食补充、宿主指导的治疗)以改善 长期健康(即结核病后肺部后遗症)。 具体地说，AIM 1将评估接受治疗的患者的痰和粪便微生物区系的变化。 耐多药结核病。AIM 2将使用靶向作为大便中色谱质谱联用纵向定量 微生物产生的单链脂肪酸(丁酸盐、丙酸、乙酸酯)，并将单链脂肪酸与微生物区系相关联 产状网络分析。目标3将评估微生物区系和药物PK之间的纵向联系 (我们预计更多的药物吸收将导致更多的微生物转移和多样性的丧失)，以及 不同的微生物群反映了有利与不利的结果。 总的来说，该提案将实现以下目标：1)促进独立资助的研究事业 StellenBosch大学的候选人(通过与科学专家的结构化指导)，2)加强南方 非洲对中低收入国家微生物组研究的分析能力研究优先事项(TB)， 3)加强与美国顶尖科学家的长期合作。

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.