Understanding pathology of sepsis-induced physical disability for future precision medicine.

摘要 脓毒症是一种威胁生命的器官功能障碍，由宿主对感染的反应失调引起。由于 脓毒症后急性存活率提高，许多患者发展为慢性危重病(CCI)，定义为 因器官功能障碍未解决而长期住院。CCI经常表现为持久的 炎症、免疫抑制和分解代谢综合征(PICS)。患有PICS的脓毒症幸存者 长期结果变数很大，特别是表现为萎缩的肌肉无力， 延缓康复，并导致身体残疾。尽管我们已经证明败血症会导致生理 残疾，这需要干预来预防它，大多数运动训练和营养临床试验 在防止功能衰退方面效果不佳。到目前为止，试验的一个主要缺陷是“一刀切”。 干预方法，忽略患者群体中的任何异质性(年龄、性别和种族/民族)。至 发展精准医学(或干预措施)，我们需要更好地了解年龄、性别、 和种族/民族，以及免疫活跃的外周器官到败血症引起的身体残疾。部分 这种精确的方法包括肠道微生物组。肠道微生物群独一无二地影响宿主的免疫状态， 依赖于生物变量，并与骨骼肌等终末器官功能相互作用和控制。 已知肠道微生物群失调在脓毒症的整体病理中起作用，并可能是PICS的驱动因素。 以及败血症引起的急性和长期肌肉丧失/无力和身体残疾。首席调查员 (PI)已经证明，年龄越大，临床轨迹越差，长期肌力越差 和身体功能结果，并显示老年人的PICS有更大的像差 生物标记物与年轻个体相比。PI还显示出持续的肠道微生物群失调。 在临床前动物败血症模型中，脓毒症患者和肠道微生物群在年龄和性别之间存在差异。 根据目前的发现，这一应用程序的首要目标是描述年龄、性别、 种族/民族和肠道微生物群在导致脓毒症所致肌肉丧失/无力的PICS发展中的作用 和身体残疾。PI实验室未来5年的研究计划的目标是 (1)脓毒症幸存者慢性肌肉丧失/无力和身体残疾；(2)PICS的作用 (3)性别、年龄、种族/民族对PICS和体格发育的影响。 以及(4)肠道微生物群对PICS和身体残疾的异质性的独特贡献。 表征慢性脓毒症引起的肌肉丧失/无力和身体残疾的异质性和 创建有身体残疾风险的患者档案将是将精准医学应用于 防止身体残疾。根据这项研究的发现，未来的干预措施可以定制为 在适当的时间、类型和形式的运动训练和/或肠道功能方面- 加强治疗，以预防不断扩大的慢性病败血症幸存者的身体残疾。

ABSTRACT Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Due to improved acute survival following sepsis, many patients develop chronic critical illness (CCI), defined as prolonged hospitalization with unresolved organ dysfunction. CCI frequently manifests as a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Sepsis survivors suffering from PICS have highly variable poor long-term outcomes, especially regarding muscle weakness, which manifests as atrophy, delays recovery, and leads to physical disability. Although we have demonstrated that sepsis leads to physical disability, which warrants interventions to prevent it, the majority of exercise training and nutritional clinical trials have been ineffective to prevent functional decline. A key deficiency of trials to date has been a “one size fits all” approach to intervention, ignoring any heterogeneity in patient populations (age, sex, and race/ethnicity). To develop precision medicine (or interventions), we need a better understanding of the contribution of age, sex, and race/ethnicity, and immunologically active peripheral organs to sepsis-induced physical disability. Part of this precision approach includes the gut microbiome. The gut microbiome uniquely affects host immune status, depends on biological variables, and interacts with and controls end-organ function such as skeletal muscle. Gut-microbiome dysbiosis is known to play a role in the overall pathology of sepsis and may be a driver of PICS and sepsis-induced acute and long-term muscle loss/weakness and physical disability. The Principal Investigator (PI) has demonstrated that older age is associated with worse clinical trajectories, long-term muscle-strength and physical-function outcomes, and has revealed that older adults have greater aberrations of the PICS biomarkers compared to younger individuals. The PI has also shown persistent gut-microbiome dysbiosis in sepsis patients and that gut microbiome differs between ages and sexes in a preclinical animal sepsis model. Given the current findings, the overarching goal for this application is to characterize the role of age, sex, race/ethnicity, and gut microbiome in the development of PICS leading to sepsis-induced muscle loss/weakness and physical disability. The goal of the PI laboratory’s research program over the next 5 years is to characterize (1) sepsis-induced chronic muscle loss/weakness and physical disability in sepsis survivors; (2) the role of PICS pathophysiology; (3) the effects of sex, age, and race/ethnicity on PICS and the development of physical disability; and (4) the unique contribution of the gut microbiome to heterogeneity of PICS and physical disability. Characterizing the heterogeneity of chronic sepsis-induced muscle loss/weakness and physical disability and creating patient profiles at risk of developing physical disability will be the key to applying precision medicine to prevent physical disability. Based on the findings of this study, future interventions can be customized to particular patients in terms of appropriate timing, type, and modality of exercise training and/or gut-function- enhancing treatments to prevent physical disability in an expanding population of chronically ill sepsis survivors.