Sleep fragmentation induced dysbiosis as a driving force of organ damage and outcome in sepsis

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Summary: Sepsis remains a major global cause of critical illness and mortality, despite decades of research and incremental improvements in supportive care (Rudd et al., 2020; Singer et al., 2016). In parallel, sleep disruption is nearly universal in intensive care units, and emerging evidence suggests that sleep fragmentation and circadian dysregulation are not merely epiphenomena of critical illness but are biologically active determinants of immune function and clinical outcomes (Gibbs et al., 2012; Pisani et al., 2015; van der Poll et al., 2017). A converging body of work indicates that sleep and circadian signals are powerful regulators of gut microbial ecology, influencing community structure and microbial metabolite production (Thaiss et al., 2014; Liang et al., 2015; Levy et al., 2017). Because the gut microbiome and its metabolites are critical modulators of intestinal barrier integrity and systemic inflammation, sleep fragmentation-associated dysbiosis may represent an underexplored upstream driver of sepsis pathophysiology and organ injury (Klingensmith & Coopersmith, 2016; Dickson,2016; Byndloss & Bäumler, 2018). This proposal tests the central hypothesis that pre-existing or ICU-acquired sleep fragmentation exacerbates sepsis severity by inducing reproducible changes in gut microbiome composition and metabolite depletion, thereby amplifying barrier dysfunction and dysregulated immune activation. Specifically, we will dissect how sleep fragmentation reshapes microbial community features linked to sepsis phenotypes. We will correlate specific alterations—such as shifts in the Firmicutes/Bacteroidota ratio, Enterococcus expansion, depletion of short-chain fatty acids (e.g., butyrate, propionate), and disruption of tryptophan metabolism (Tannahill et al., 2013; Nobel et al., 2021)—with established sepsis severity scores (e.g., Sequential Organ Failure Assessment [SOFA] (Vincent et al., 1996) and APACHE II (Knaus et al., 1985)) and downstream markers of organ damage. The main objectives: WP.1 Gut microbiome dynamics and sleep fragmentation signatures in ICU septic patients. Sleep disruption is pervasive in intensive care and is frequently accompanied by circadian hormone dysregulation. Increasing evidence indicates that sleep and circadian signals can reshape gut microbial ecology and microbial metabolite availability, with plausible downstream consequences for barrier integrity and systemic immune tone. In sepsis, where organ injury trajectories are strongly influenced by the magnitude, timing, and resolution of inflammation, this sleep-circadianmicrobiome axis may represent a clinically relevant upstream modifier of disease severity. Yet, its translational significance remains insufficiently defined because many ICU microbiome studies lack structured control groups and do not integrate endocrine proxies of circadian disruption with rigorous clinical outcome phenotyping. Furthermore, ICUspecific exposures, including antibiotics, sedation, enteral feeding, vasopressors, and altered motility, can rapidly reconfigure microbial communities, complicating causal inference and making it essential to distinguish microbiome features that track with sepsis pathophysiology from those reflecting critical illness or ICU stay more broadly (McDonald et al., 2016). This work package therefore aims to establish clinically anchored microbiome-metabolome signatures associated with sepsis severity and outcome. WP 3: Sleep fragmentation and neutrophil-dependent cytotoxicity during sepsis. Sepsis pathogenesis is shaped not only by pathogen burden or inflammatory magnitude, but by the balance between effective antimicrobial defense and collateral tissue injury. Neutrophils sit at the center of this trade-off. They eliminate microbes through cytotoxic effector programs that are largely ROS-dependent, including phagocytosis, degranulation, and neutrophil extracellular trap formation (NETs) (Teng et al. 2017, Hampton, Kettle, and Winterbourn 1998, Babior 1984). However, when neutrophil activation is prolonged or poorly resolved, excessive ROS release, proteolytic degranulation, and inappropriate tissue infiltration can drive pathological inflammation and organ damage (Adrover et al., 2019). Sleep restriction has been associated with low-grade inflammation and increased circulating leukocytes, suggesting that sleep disruption can shift baseline innate immune setpoints (Lasselin et al., 2014). In parallel, circadian biology has been shown to exert strong regulatory effects on tissue susceptibility and immune function, with disruption of circadian regulators producing systemic consequences across myocardial function, vascular integrity, and thrombo-inflammatory pathways (Scheiermann et al., 2013; Durgan and Young, 2010, Man, Li and Xia, 2021, Nakazato et al., 2017).