The Gut as a Target to Improve Outcomes in Sepsis

在美国，脓毒症是危重病人死亡的主要原因，而脓毒症对 医疗保险受益人每年超过620亿美元。除抗生素外，脓毒症的治疗是非特异性的， 而且，一旦抗生素和支持疗法失败，就没有批准的治疗方法可用。患有疾病的患者 癌症患脓毒症的可能性几乎是普通人群的十倍，癌症代表着 败血症患者中最常见的并存。此外，癌症是与癌症相关的共同发病率 脓毒症的死亡风险最高，死亡率的增加在年轻成人患者中不成比例地出现。 长期以来，肠道一直被描述为多器官功能障碍综合征的动力。所有主要元素 在脓毒症中，肠道完整性的改变，伴随着上皮的失调(通透性，细胞凋亡，增殖， 迁移)、微生物群和粘膜免疫系统。此外，免疫力和肠道完整性都是 与以前的健康/败血症宿主相比，癌症/脓毒症宿主受到的影响不成比例。本节目 旨在了解脓毒症肠道完整性失调的潜在机制。第一种方法将是 检查上皮、粘膜免疫系统和微生物组内发生的事情，以阐明 脓毒症引起的肠道改变的机制在单独的隔离过程中。下一步 将检查肠道的三个主要组件之间的串扰，因为每个元素都直接 相互影响，导致所有方面的进一步变化。最后一种方法将是检查直觉如何引导 到肠外对远处器官的影响，其中肠源性变化导致亚细胞、细胞和器官 功能障碍，导致发病率和死亡率恶化。此外，该项目还试图了解为什么 通过检查获得性免疫系统和获得性免疫系统的差异，癌症和脓毒症的结果是不同的 和胆量的完整性。“一刀切”治疗先天异质性综合症可能是一个关键原因。 为什么在降低败血症的临床死亡率方面没有取得更多进展，以及 了解慢性共病如何导致床边不同结果的机制是 向脓毒症患者的精准医学迈进。该计划将使用人体样本(肠道、血液和 粪便)在可行时与临床数据和结果配对。然后将探讨机械性问题。 使用床边到长凳的范例，通过检查人体样本获得的见解将被 当实验不能在患者身上进行时，使用各种体内和体外技术进行评估。 由于肠道在引发和传播危重疾病方面起着重要作用，而合并症则起着重要作用 在败血症患者预后恶化中的关键作用，了解肠道完整性 在一种疾病中，脓毒症尤其是患有癌症的宿主的调节失调会对公共卫生产生重大影响 这很常见，代价非常高，而且非常致命。

Sepsis is the leading cause of death among critically ill patients in the United States, and costs of sepsis for Medicare beneficiaries exceed $62 billion annually. Outside of antibiotics, treatment for sepsis is non-specific, and there are no approved therapeutics available once antibiotics and supportive therapy fail. Patients with cancer are nearly ten times more likely to develop sepsis than the general population, and cancer represents the most common co-morbidity in septic patients. Moreover, cancer is the co-morbidity associated with the highest risk of death in sepsis, and the increased mortality is seen disproportionately in younger adult patients. The gut has long been characterized as the motor of multiple organ dysfunction syndrome. All major elements of gut integrity are altered in sepsis, with dysregulation in the epithelium (permeability, apoptosis, proliferation, migration), the microbiome and the mucosal immune system. Further, both immunity and gut integrity are disproportionately impacted in cancer/sepsis hosts compared to previously healthy/sepsis hosts. This program seeks to understand mechanisms underlying dysregulated gut integrity in sepsis. The first approach will be to examine what happens within the epithelium, the mucosal immune system and the microbiome, to elucidate mechanisms of sepsis-induced intestinal alterations within individual processes in isolation. The next approach will be to examine crosstalk between the three broad components of the gut since each element directly impacts each other, leading to further alterations in all. The final approach will be to examine how the gut leads to extra-intestinal effects on distant organs, where gut-derived changes lead to subcellular, cellular and organ dysfunction, resulting in worsened morbidity and mortality. Additionally, the program seeks to understand why outcomes are different in cancer/sepsis, by examining differences seen in both the adaptive immune system and gut integrity. A “one size fits all” approach to an inherently heterogeneous syndrome is likely a key reason why more progress has not been made in decreasing mortality from sepsis clinically, and the goal of understanding mechanisms of how a chronic co-morbidity leads to different outcomes at the bedside is to move towards precision medicine in septic patients. The program will use human samples (gut, blood and stool) paired when feasible with clinical data and outcomes. Mechanistic questions will then be approached using a bedside to bench paradigm whereby insights obtained examining human samples will then be evaluated using a variety of in vivo and in vitro techniques when experiments cannot be performed in patients. Since the gut plays a major role in both initiating and propagating critical illness and co-morbidities play a crucial role in worsening outcomes in septic patients, understanding mechanisms through which gut integrity is dysregulated in sepsis especially in hosts with cancer has significant public health implications in a disease that is common, very costly, and highly lethal.