The Gut as a Target to Improve Outcomes in Sepsis

肠道作为改善脓毒症预后的目标

• 批准号: 10552403
• 负责人: Craig M Coopersmith
• 金额: $ 53.21万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552403
• 关键词: Adaptive Immune System; Antibiotic Therapy; Antibiotics; Apoptosis; Blood; Cause of Death; Chronic; Clinical; Clinical Data; Critical Illness; Disease; Distant; Elements; Epithelium; Feces; Functional disorder; General Population; Goals; Human; Immunity; In Vitro; Individual; Intestines; Malignant Neoplasms; Medicare; Morbidity - disease rate; Motor; Mucosal Immune System; Multiple Organ Failure; Organ; Outcome; Patients; Permeability; Play; Process; Proliferating; Public Health; Role; Sampling; Sepsis; Supportive care; Syndrome; Techniques; Therapeutic; United States; bench to bedside; beneficiary; comorbidity; cost; experimental study; high risk; improved outcome; in vivo; insight; microbiome; migration; mortality; mortality risk; precision medicine; programs; septic patients; therapeutic target; young adult

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.

败血症是美国重症患者中死亡的主要原因，败血症的成本 医疗保险受益人每年超过620亿美元。在抗生素之外，败血症的治疗是非特异性的， 一旦抗生素和支持疗法失败，就没有批准的疗法。患者 癌症发展败血症的可能性几乎是普通人群的十倍，癌症代表 化粪池患者最常见的合并症。此外，癌症是与 年轻的成年患者的败血症死亡风险最高，死亡率的增加不成比例。 肠道长期以来一直被描述为多器官功能障碍综合征的电动机。所有主要要素 脓毒症的肠道完整性改变了，上皮的失调（渗透率，凋亡，增殖， 迁移），微生物组和粘膜免疫系统。此外，免疫和肠道完整性都是 与以前健康/败血症宿主相比，在癌症/败血症宿主中的影响不成比例。这个程序 试图理解败血症中肠道不良完整性的基础机制。第一种方法是 检查上皮，粘膜免疫系统和微生物组中发生的情况，以阐明 败血症引起的单个过程中败血症诱导的肠道改变的机制。下一个方法 将检查肠道的三个宽部分之间的串扰，因为每个元素都直接 相互影响，导致所有人的进一步改变。最后的方法是检查肠道如何领导 肠外对远处器官的影响，肠道衍生的变化导致亚细胞，细胞和器官 功能障碍，导致发病率恶化和死亡率。此外，该计划试图了解为什么 癌症/败血症的结果是不同的，通过检查差异，请参见两种自适应免疫系统 和肠道完整性。一种固有异质综合征的“一个尺寸适合所有人”的方法可能是关键原因 为什么在临床上降低败血症的死亡率以及目标的目的 了解慢性合并症如何导致床边不同结果的机制是 在化粪池患者中迈向精确医学。该程序将使用人类样品（肠道，血液和 粪便）与临床数据和结果可行时配对。然后将解决机理问题 利用床头到板凳范式，从而获得检查人类样本的见解将是 当无法在患者中进行实验时，使用各种体内和体外技术进行评估。 由于肠道在发起和传播重症疾病和合并症中都起着重要作用 在化脓性患者的担心结果中的关键作用，了解肠道完整性的机制 败血症中尤其是癌症宿主的失调，对疾病具有重大的公共卫生影响 这很常见，非常昂贵且高度致命。