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: 10797448
• 负责人: Craig M Coopersmith
• 金额: $ 3.06万
• 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/10797448
• 关键词: Adaptive Immune System; Antibiotic Therapy; Antibiotics; Apoptosis; Award; Blood; Cause of Death; Chronic; Clinical; Clinical Data; Critical Illness; Disease; Distant; Elements; Epithelium; Feces; Functional disorder; General Population; Goals; Grant; 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.

脓毒症是美国危重患者死亡的主要原因，脓毒症造成的费用为 医疗保险受益人每年超过 620 亿美元。除了抗生素之外，脓毒症的治疗是非特异性的， 一旦抗生素和支持疗法失败，就没有经过批准的治疗方法。患者患有 癌症患败血症的可能性是普通人群的近十倍，而癌症代表 脓毒症患者最常见的合并症。此外，癌症是与以下疾病相关的共病： 败血症的死亡风险最高，并且死亡率增加在年轻成年患者中不成比例地出现。 长期以来，肠道一直被认为是多器官功能障碍综合征的发动机。所有主要元素 败血症时肠道完整性发生改变，上皮细胞失调（通透性、细胞凋亡、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 与以前健康/脓毒症宿主相比，癌症/脓毒症宿主受到的影响不成比例。这个节目 试图了解脓毒症肠道完整性失调的机制。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 脓毒症引起的肠道改变在单独的单个过程中的机制。下一个方法 将检查肠道三大组成部分之间的串扰，因为每个元素都直接 相互影响，导致一切进一步改变。最后的方法是检查肠道如何引导 对远处器官的肠外影响，肠道来源的变化导致亚细胞、细胞和器官 功能障碍，导致发病率和死亡率恶化。此外，该计划还试图了解为什么 通过检查适应性免疫系统中发现的差异，癌症/败血症的结果是不同的 和肠道完整性。对固有异质综合征采取“一刀切”的方法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尚未取得更多进展，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疗迈进。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。然后将讨论机械问题 使用床边到工作台范式，通过检查人体样本获得的见解将被 当无法在患者身上进行实验时，使用各种体内和体外技术进行评估。 由于肠道在危重疾病的引发和传播中发挥着重要作用，而合并症则在危重疾病的引发和传播中发挥着重要作用。 了解肠道完整性的机制在脓毒症患者预后恶化中发挥着至关重要的作用 败血症的失调，尤其是患有癌症的宿主，对疾病具有重大的公共卫生影响 这很常见，成本很高，而且致命。