Microbiome in TB treatment response and disease resolution

结核病的治疗是由两个因素决定的：联合化疗的要求和 延长疗程。对于抗生素敏感型疾病，最短的疗程 95%的受试者接受2个月的INH/RIF/PZA/ETH治疗，然后是4个月的 INH/RIF(2HRZE/4HR)。然而，大量的临床试验证据表明，大多数 经过治疗的受试者治愈的时间较短，但我们缺乏临床或实验室。 可以识别这些候选缩短治疗的生物标记物。使用的抗菌剂 治疗结核病，包括对药物敏感和耐药的药物，主要是分枝杆菌特异性的和 直到最近，它们对肠道微生物群的影响还不清楚。在第一个颁奖期内，这三个人- I TBRU率先对结核病感染中的肠道微生物群进行了分析，从而推动了 肠道微生物群是结核病易感性和反应中一个未被探索的辅助因素的想法 去接受治疗。我们发现，在对患有结核病的人类受试者的横断面和纵向研究中， HRZE疗法对肠道微生物群组成有快速但持久的影响： 梭状芽孢杆菌枯竭了，其他分类单元相对保存下来。梭状芽胞杆菌至关重要 与宿主免疫系统相互作用的微生物群的组成部分，通过产生 多种化学介体，包括短链脂肪酸和其他代谢物。 因此，我们还发现，使用在 在之前的获奖期，结核病的解决可以被模拟为 病原菌(Mtb)灭菌及抗分枝杆菌诱导微生物群的免疫效应 微扰。我们压倒一切的假设是微生物群组成的个体差异 和功能，无论是预处理或在治疗期间由抗分枝杆菌药物诱导的，都是 与不同的病原体清除率、解决率相关并可预测 活动性肺结核的炎性标志物，最终治疗成功(早期绝育和 没有复发)。我们提出的研究将把这一概念扩展到1)验证微生物组 派生的结核病治疗成功的生物标志物；2)开发预测计算模型， 整合微生物组、转录组和微生物学数据以预测治疗成功；3)产量 微生物群驱动的免疫调节与结核病相互作用的机械论洞察。 加上这个特快堆的其他项目和核心，这个项目将推进我们的 对少菌型结核病控制的认识。

Treatment of TB is defined by two factors: the requirement for combination chemotherapy and extended duration of therapy. For antibiotic sensitive disease, the shortest duration of therapy that will cure >95% of treated subjects is 2 months of INH/RIF/PZA/ETH, followed by 4 months of INH/RIF (2HRZE/4HR). However, abundant clinical trial evidence indicates that the majority of treated subjects are cured with shorter durations of treatment, yet we lack any clinical or laboratory biomarkers that can identify these candidates for treatment shortening. The antimicrobials used to treat TB, both drug-sensitive and drug-resistant, are predominantly mycobacterial-specific and until recently, their effects on the gut microbiome were unknown. In the first award period, this Tri- I TBRU pioneered the analysis of the intestinal microbiome in TB infection and thereby advanced the idea that the intestinal microbiome is an unexplored cofactor in TB susceptibility and response to therapy. We found, in both cross sectional and longitudinal studies of human subjects with TB, that HRZE therapy has rapid, but long-lasting, effects on intestinal microbiome composition: Clostridiales are depleted, with relative preservation of other taxons. Clostridiales are critical components of the microbiota that interact with the host immune system through production of diverse chemical mediators including short chain fatty acids as well as other metabolites. Accordingly, we have also found, using new statistical modeling techniques developed during the prior award period, that the resolution of TB disease can be modeled as a combined effect of pathogen (Mtb) sterilization and the immune effects of antimycobacterial-induced microbiome perturbation. Our overriding hypothesis is that individual differences in microbiome composition and function, either pretreatment or induced by antimycobacterials during treatment, are associated with, and predictive of, different rates of pathogen clearance, resolution of inflammatory markers of active TB, and ultimately treatment success (both early sterilization and lack of relapse). We propose studies that will expand this concept to 1) validate microbiome derived biomarkers of TB treatment success; 2) develop predictive computational models that integrate microbiome, transcriptomic, and microbiologic data to predict treatment success; 3) yield mechanistic insight into the interaction of microbiome driven immunomodulation and TB disease. Coupled with the other projects and cores of this TBRU, this project will advance our understanding of the control of paucibacillary TB.