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DC Field | Value | Language |
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dc.contributor.advisor | Fox-Robichaud, Alison | - |
dc.contributor.author | Eng, Mikaela | - |
dc.date.accessioned | 2024-08-26T15:02:14Z | - |
dc.date.available | 2024-08-26T15:02:14Z | - |
dc.date.issued | 2024 | - |
dc.identifier.uri | http://hdl.handle.net/11375/30082 | - |
dc.description.abstract | Introduction: Sepsis, a severe and often fatal condition, is influenced by obesity, with some studies suggesting an "obesity paradox" where obesity enhances survival. However, outcomes in murine models of sepsis and obesity show variability. This PhD thesis investigates the role of obesity in sepsis using a murine model of diet-induced obesity (DIO). Additionally, it explores how the gut-lung axis and short-chain fatty acids (SCFAs) influence macrophage function in the context of sepsis and obesity. Aims: This thesis aims to (1) systematically review the literature DIO and sepsis in murine models, (2) describe the impact of sepsis and obesity using a DIO fecal-induced peritonitis (FIP) model, and (3) provide a mechanistic understanding of how sepsis, obesity, and season affect organ function, focusing on circadian clock genes and subsequent dysbiosis impacting macrophage function. Results: The scoping review identified a lack of standardization and high variability in outcomes and methodologies in murine models of obesity and sepsis, complicating translational relevance. In our DIO FIP model, findings revealed no "obesity paradox," with obese mice showing decreased survival. Using a single predefined dose in DIO FIP models is optimal for observing the impact of obesity on sepsis outcomes, minimizing confounding effects. Increased mortality in septic mice during fall was influenced by infradian cycles, with BMAL1 downregulation in fall and obese mice suggesting a link between circadian rhythms and sepsis outcomes. Reduced SCFA levels in fall and high-fat diet mice impaired macrophage function, affecting inflammation resolution. SCFAs play a crucial role in modulating macrophage polarization and inflammation resolution in sepsis and obesity. Conclusion: This study highlights the importance of seasonality, metabolic alterations from dysbiosis, and their collective impact on immune responses in sepsis. Addressing these factors can improve the translational relevance of obesity and sepsis research, enhancing the utility of animal models in clinical applications. | en_US |
dc.language.iso | en | en_US |
dc.subject | Sepsis | en_US |
dc.subject | obesity | en_US |
dc.subject | macrophages | en_US |
dc.subject | mouse models | en_US |
dc.title | THE COMPLEX INTERACTION BETWEEN SEPSIS, IMMUNITY, AND THE MICROBIOME IN A MURINE MODEL OF OBESITY | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Dissertation | en_US |
dc.description.degree | Doctor of Philosophy (Medical Science) | en_US |
dc.description.layabstract | Sepsis, a severe and deadly condition, is influenced by obesity. Some research suggests that obesity might improve survival in sepsis, but animal study results are inconsistent. This thesis explores obesity's role in sepsis using a mouse model of diet-induced obesity (DIO). Aims: This thesis aims to review the literature on DIO and sepsis in mice, develop a standardized mouse model of sepsis and obesity, and understand how sepsis, obesity, and season affect organ and immune function Results: Our review identified a lack of standardization in murine studies, complicating translational relevance. Our DIO sepsis model, obese mice showed decreased survival. Increased fall mortality was linked to downregulation of the BMAL1 gene, suggesting circadian rhythms impact sepsis outcomes. Reduced SCFA levels impaired macrophage function, crucial for resolving inflammation. Conclusion: This study shows how seasonal changes, gut health, and metabolism affect immune responses in sepsis, improving the relevance of obesity and sepsis research. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Eng_Mikaela_K_finalsubmission2024August_PhD.pdf | 5.42 MB | Adobe PDF | View/Open |
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