Tuberculosis (TB) claims more human lives than any other infectious organism. The lethal synergy between TB-HIV infection and the rapid emergence of drug resistant strains has created a global public health threat that requires urgent attention. Mycobacterium tuberculosis, the causative agent of TB is an exquisitely well-adapted human pathogen, displaying the ability to promptly remodel metabolism when encountering stressful environments during pathogenesis. A careful study of the mechanisms that enable this adaptation will enhance the understanding of key aspects related to the microbiology of TB disease. However, these efforts require microbiological model systems that mimic host conditions in the laboratory. Herein, we describe several in vitro model systems that generate non-replicating and differentially culturable mycobacteria. The changes that occur in the metabolism of M. tuberculosis in some of these models and how these relate to those reported for human TB disease are discussed. We describe mechanisms that tubercle bacteria use to resuscitate from these non-replicating conditions, together with phenotypic heterogeneity in terms of culturabiliy of M. tuberculosis in sputum. Transcriptional changes in M. tuberculosis that allow for adaptation of the organism to the lung environment are also summarized. Finally, given the emerging importance of the microbiome in various infectious diseases, we provide a description of how the lung and gut microbiome affect susceptibility to TB infection and response to treatment. Consideration of these collective aspects will enhance the understanding of basic metabolism, physiology, drug tolerance and persistence in M. tuberculosis to enable development of new therapeutic interventions.

结核病（TB）比其他任何传染性生物都夺走更多的生命。TB-HIV感染与耐药菌株的迅速出现之间的致命协同作用已经造成了全球公共卫生威胁，需要紧急关注。结核分枝杆菌，结核病的病原体是一种非常适合人类的病原体，在发病过程中遇到压力大的环境时，具有迅速重塑新陈代谢的能力。对实现这种适应性的机制进行仔细研究，将增进对与结核病微生物学有关的关键方面的理解。然而，这些努力需要模仿实验室中宿主条件的微生物模型系统。在这里，我们描述了几个体外模型系统，它们会生成非复制性和可差异培养的分枝杆菌。结核分枝杆菌代谢中发生的变化讨论了其中一些模型，以及这些模型与报告的人类结核病模型之间的关系。我们描述了结核细菌用于从这些非复制条件中复苏的机制，以及根据痰中结核分枝杆菌的培养表型异质性。还总结了结核分枝杆菌的转录变化，使微生物适应肺部环境。最后，考虑到微生物组在各种传染病中的重要性，我们提供了关于肺部和肠道微生物组如何影响结核病感染易感性和对治疗反应的描述。考虑这些共同方面将增进对基本代谢，生理学，药物耐受性和持久性的理解。结核分枝杆菌能够开发新的治疗措施。