The Gut as a Target to Improve Outcomes in Sepsis

脓毒症是美国危重患者死亡的主要原因， 医疗保险受益人每年超过620亿美元。除了抗生素，败血症的治疗是非特异性的， 一旦抗生素和支持性治疗失败，就没有批准的治疗方法可用。患者 癌症患者发生败血症的可能性是普通人群的近十倍， 脓毒症患者中最常见的合并症。此外，癌症是与癌症相关的共病。 败血症死亡风险最高，且死亡率增加在年轻成人患者中不成比例。 肠道长期以来被认为是多器官功能障碍综合征的动力。所有主要元素 肠完整性的改变，上皮细胞失调（通透性，凋亡，增殖， 迁移）、微生物组和粘膜免疫系统。此外，免疫力和肠道完整性都是 与先前健康/脓毒症宿主相比，在癌症/脓毒症宿主中不成比例地受到影响。这个程序 旨在了解脓毒症中肠道完整性失调的潜在机制。第一种方法是 检查上皮、粘膜免疫系统和微生物组内发生的情况，以阐明 脓毒症引起的肠道变化的机制在个别过程中孤立。下一个方法 将检查肠道的三个主要组成部分之间的串扰，因为每个元素直接 相互影响，导致所有的进一步变化。最后一种方法是检查肠道如何引导 肠外效应对远端器官，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，该计划旨在了解为什么 结果是不同的癌症/脓毒症，通过检查差异中看到的适应性免疫系统， 和内脏完整性一个“一刀切”的方法来解决一个固有的异质性综合征可能是一个关键原因 为什么临床上在降低脓毒症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旁不同结局的机制， 致力于败血症患者的精准医疗该计划将使用人类样本（肠道，血液和 粪便）与临床数据和结果配对。然后将探讨机械问题 使用从床边到工作台的范例，通过检查人体样本获得的见解， 当不能在患者中进行实验时，使用各种体内和体外技术进行评价。 由于肠道在引发和传播危重疾病方面起着重要作用， 在脓毒症患者的预后恶化中起着至关重要的作用，了解肠道完整性的机制， 败血症尤其是癌症宿主中的失调在疾病中具有重要的公共卫生意义， 这是很常见的，非常昂贵的，并且是致命的。

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.