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

摘要 脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍。由于 脓毒症后急性存活率的改善，许多患者发展为慢性危重病（CCI），定义为 住院时间延长，器官功能障碍未解决。CCI经常表现为持续的 炎症、免疫抑制和卡他综合征（PICS）。患有PICS的脓毒症幸存者 高度可变的不良长期结局，特别是关于肌肉无力，表现为萎缩， 延迟康复，并导致身体残疾。虽然我们已经证明败血症会导致身体 残疾，这需要干预措施，以防止它，大多数运动训练和营养临床试验 无法有效防止功能衰退。迄今为止，审判的一个关键缺陷是“一刀切”。 干预方法，忽略患者人群的任何异质性（年龄、性别和人种/种族）。到 发展精准医学（或干预措施），我们需要更好地了解年龄，性别， 以及免疫活性外周器官对脓毒症诱导的身体残疾的影响。的一部分 这种精确的方法包括肠道微生物组。肠道微生物组独特地影响宿主免疫状态， 依赖于生物变量，并与终末器官功能如骨骼肌相互作用和控制。 已知肠道微生物组生态失调在脓毒症的整体病理学中发挥作用，并且可能是PICS的驱动因素 以及脓毒症引起的急性和长期肌肉损失/虚弱和身体残疾。主要研究者 (PI)已经证明，老年与更差的临床轨迹，长期的肌肉力量， 和身体功能的结果，并揭示了老年人有更大的畸变的PICS 与年轻人相比。PI还显示出持续的肠道微生物组生态失调， 在临床前脓毒症动物模型中，年龄和性别之间的肠道微生物组不同。 鉴于目前的研究结果，该应用程序的首要目标是描述年龄，性别， 人种/种族和肠道微生物组在PICS发展中导致脓毒症诱导的肌肉损失/无力 和身体残疾。PI实验室在未来5年的研究计划的目标是表征 (1)脓毒症诱导的慢性肌肉损失/虚弱和脓毒症幸存者的身体残疾;（2）PICS的作用 病理生理学;（3）性别，年龄和种族/民族对PICS和身体发育的影响。 残疾;（4）肠道微生物组对PICS和身体残疾异质性的独特贡献。 描述慢性脓毒症引起的肌肉损失/无力和身体残疾的异质性， 创建有身体残疾风险的患者档案将是应用精准医学的关键， 防止身体残疾。根据这项研究的结果，未来的干预措施可以定制， 在适当的时间、类型和运动训练方式和/或肠道功能方面， 加强治疗，以防止不断扩大的慢性病败血症幸存者群体的身体残疾。

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.