Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 33, Room 1W10A, 33 North Drive, MSC 3202, Bethesda, MD, 20892-3202, USA.
Present Address: Center for Innovation in Global Health Technologies, Northwestern University, Evanston, IL, USA.
Microbiome. 2017 Jul 7;5(1):71. doi: 10.1186/s40168-017-0286-2.
Effective treatment of Mycobacterium tuberculosis (Mtb) infection requires at least 6 months of daily therapy with multiple orally administered antibiotics. Although this drug regimen is administered annually to millions worldwide, the impact of such intensive antimicrobial treatment on the host microbiome has never been formally investigated. Here, we characterized the longitudinal outcome of conventional isoniazid-rifampin-pyrazinamide (HRZ) TB drug administration on the diversity and composition of the intestinal microbiota in Mtb-infected mice by means of 16S rRNA sequencing. We also investigated the effects of each of the individual antibiotics alone and in different combinations.
While inducing only a transient decrease in microbial diversity, HRZ treatment triggered a marked, immediate and reproducible alteration in community structure that persisted for the entire course of therapy and for at least 3 months following its cessation. Members of order Clostridiales were among the taxa that decreased in relative frequencies during treatment and family Porphyromonadaceae significantly increased post treatment. Experiments comparing monotherapy and different combination therapies identified rifampin as the major driver of the observed alterations induced by the HRZ cocktail but also revealed unexpected effects of isoniazid and pyrazinamide in certain drug pairings.
This report provides the first detailed analysis of the longitudinal changes in the intestinal microbiota due to anti-tuberculosis therapy. Importantly, many of the affected taxa have been previously shown in other systems to be associated with modifications in immunologic function. Together, our findings reveal that the antibiotics used in conventional TB treatment induce a distinct and long lasting dysbiosis. In addition, they establish a murine model for studying the potential impact of this dysbiosis on host resistance and physiology.
有效治疗结核分枝杆菌（Mtb）感染需要至少 6 个月的每日治疗，采用多种口服抗生素。尽管这种药物方案每年在全球范围内为数百万患者使用，但这种密集的抗菌治疗对宿主微生物组的影响从未被正式研究过。在这里，我们通过 16S rRNA 测序来描述常规异烟肼-利福平-吡嗪酰胺（HRZ）抗结核药物治疗对感染 Mtb 的小鼠肠道微生物多样性和组成的纵向结果。我们还研究了每种抗生素单独使用以及不同组合使用的影响。
虽然 HRZ 治疗仅导致微生物多样性短暂下降，但它引发了明显的、立即的和可重复的群落结构改变，这种改变持续整个治疗过程，并在治疗结束后至少 3 个月持续存在。在治疗过程中相对频率降低的类群中包括梭菌目（Clostridiales）的成员，而治疗后卟啉单胞菌科（Porphyromonadaceae）显著增加。比较单药治疗和不同联合治疗的实验表明，利福平是 HRZ 鸡尾酒引起的观察到的改变的主要驱动因素，但也揭示了异烟肼和吡嗪酰胺在某些药物组合中的意外作用。
本报告首次详细分析了抗结核治疗导致的肠道微生物群的纵向变化。重要的是，许多受影响的分类群在其他系统中已经显示与免疫功能的改变有关。总之，我们的研究结果表明，常规结核病治疗中使用的抗生素会导致明显且持久的菌群失调。此外，它们建立了一个用于研究这种菌群失调对宿主抵抗力和生理学潜在影响的小鼠模型。
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