Sleep fragmentation induced dysbiosis as a driving force of organ damage and outcome in sepsis
Supervisor Name
Montaser Haddad
Supervisor Email
montaser.haddad@ppu.edu
University
Palestine Polytechnic University
Research field
Medical Sciences
Bio
Dr. Montaser Haddad holds a Bachelor’s degree in Medical Laboratory Science from Jordan University of Science and Technology, where he graduated as the top-ranking student in his cohort. This outstanding achievement earned him a scholarship to pursue a Master’s degree in Hematology and Blood Banking at the same university, where he again graduated with the highest distinction. During his Master’s studies, Dr. Haddad gained international exposure through several prestigious fellowships in Germany, further broadening his academic and research horizons. Dr. Haddad continued his academic journey with a joint Ph.D. in Immunology and Hematopoietic Stem Cells at Weizmann Institute of Science. His groundbreaking research earned him multiple publications and awards at international conferences, reflecting the significant impact of his work in the field. With extensive teaching experience at various universities in Palestine and Jordan, Dr. Haddad joined Palestine Polytechnic University (PPU) in 2022. As an educator, he is passionate about inspiring students and fostering their curiosity in advanced medical sciences, particularly in immunology and stem cell research. Dr. Haddad’s research interests focus on immunology, hematopoietic stem cells mobilization from bone marrow to the circulation.
Description
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. 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 (Showler et al., 2023; 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). 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-associated organ injury (Klingensmith & Coopersmith, 2016; Dickson, 2016; Levy et al., 2017). 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 (Byndloss & Bäumler, 2018; Takahashi 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. To establish mechanistic causality, we will integrate (i) a clinical observational arm in ICU sepsis patients with microbiome-metabolome profiling and detailed clinical phenotyping, (ii) a murine model of sleep fragmentation using orexin/hypocretin-deficient mice (Hcrt-KO), developed by Chemelli et al. (1999), to test whether sleep fragmentation increases sepsis mortality and organ damage, and (iii) a rescue strategy using exogenous orexin administration as a potential intervention to reverse sleep fragmentation-linked immune-metabolic dysregulation. Finally, to bridge microbial changes to host injury mechanisms, we will quantify immune activation states and inflammation-resolving mediators, with a focus on neutrophil-driven cytotoxicity pathways. Together, these aims seek to define a tractable neuro-immune-microbiome axis linking sleep disruption to gut dysbiosis and sepsis outcomes.
