Host-microbe interactions: Harnessing co-evolution to treat disease

摘要 治疗疾病的新视角。我们的治病方法之间有一种脱节 以及我们对保持健康的机制的理解；这种情况需要改变。过去的五十年 生物学研究在理解疾病发病机制方面做得很好，因为它减少了 生物体对其组成部分的了解，以了解这些部分如何功能障碍的复杂细节 会导致疾病。然而，这种方法的一个重要限制是，生理不存在于 与世隔绝；当一个系统功能失调时，整个身体都会受到影响。第二个问题是 使这一方法复杂化的是，目前治疗疾病的方法主要包括阻断病原体 而不是诱导维持健康的途径。原因有两个：1) 科学家研究的是疾病，而不是健康，因此不了解促进健康的机制； 2)通常认为，阻断致病反应将使患者恢复健康 国家，这不一定是正确的。因此，与其问我们应该如何治疗疾病，不如问 应该问的是，“健康是如何维持的？” 要理解并最终操纵发生在 在我们的生理学中，提出了一种新的方法来应用。此方法基于 认识到身体和其驻留的微生物区系已经共同进化为依赖于 以维持适当的生理功能。这项提议的总体假设是 健康是一个活跃的过程，包括由微生物协调的生理机制的诱导。 通过了解我们身体编码的生理机制以及微生物如何协调这些 维持健康的过程，通过凌驾于 可能会出现生理性衰退，使患者在感染的情况下仍能保持健康。此应用程序 提出了一种研究疾病的新范式，其中完整的动物模型、进化原理和宿主- 微生物的相互作用被用来定义管理健康的属性和基本原则。这项工作 将建立一个新的概念框架和方法，在其中 机械地理解健康意味着什么，以及如何将其应用于治疗疾病。

Abstract A new perspective for treating disease. There is a disconnect between our methods for treating diseases and our understanding of the mechanisms that keep us healthy; this needs to change. The past fifty years of biological research have done an excellent job of understanding disease pathogenesis by reducing the organism to its component parts, in order to understand the intricate details of how dysfunction of these parts leads to disease. A significant limitation to this approach, however, is that physiologies do not exist in isolation; when one system becomes dysfunctional, the whole body is affected. A second issue that complicates this approach is that current methods for treating disease primarily involve blocking pathogenic responses rather than inducing pathways that work to maintain health. The reason for this is two-fold: 1) scientists study disease, not health, and therefore do not understand the mechanisms that promote health; and 2) It is commonly assumed that blocking a pathogenic response will bring the patient back to a healthy state, which is not necessarily true. Therefore, rather than asking how we should treat disease, the question that should be asked is, “How is health maintained?” To understand and ultimately manipulate the complex multi-directional interactions that occur between all of our physiologies, a novel approach is proposed in this application. This approach is based on understanding that the body and its resident microbiota have co-evolved to rely on communication between all physiologies in order to maintain proper physiological function. The overall hypothesis of this proposal is that health is an active process that includes the induction of physiological mechanisms coordinated by microbes. By understanding the physiological mechanisms our bodies encode and how microbes coordinate these processes to maintain health, treatments that work to extend health-span and lifespan by overriding physiological decline can be developed, enabling patients to stay healthy despite infection. This application proposes a new paradigm for studying disease, where whole animal models, evolutionary principles and host- microbe interactions are used to define the properties and fundamental principles governing health. The work resulting from this application will establish a new conceptual framework and approaches in which to mechanistically understand what it means to be healthy and how this can be applied to treat diseases.