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