Year: 2025
Type: dissertation
Abstract: Severe malnutrition is associated with life-threatening complications, such as intestinal and systemic disease that underlies morbidity and mortality in children under five. Immune dysregulations, especially of innate immunity, and metabolic disturbances underlie these adverse outcomes. Other than general impairments in innate immune functions that are associated with poor prognosis, little is known about the mechanism for these impairments in malnutrition that could be specifically targeted for therapy. In this thesis, I first present three novel preclinical models of intestinal infection and inflammation, using oral administration of dextran sodium sulfate (DSS), Citrobacter rodentium, or Salmonella typhimurium in mice fed a low-protein diet (LPD) for 2-weeks, that can be explored further to understand the aetiology of intestinal diseases. Sytemic disease responses in these mice were studied upon lipopolysaccharide (LPS)-challenge. LPD-fed mice were more susceptible to the different insults compared to mice fed a regular diet as evidenced by increased clinical severity scores, systemic bacterial spread, and mortality. I used the LPS-challenged protein restriction mouse model to further investigate the impact of protein malnutrition and acute inflammation on neutrophil biology, the first responders of innate immunity that remain understudied in malnutrition. Oxidative phosphorylation-driven mitochondrial ATP production, as determined through the real-time extracellular flux analysis, was disturbed in the LPD neutrophils. Additionally, the gene expression of transcription factors (TFs) for neutrophil differentiation, and their downstream targets (granule proteins) were reduced, and an accumulation of immature neutrophils, uncovered through flow cytometry, marked the bone marrow cellular composition in LPD-fed mice. These immature neutrophils also accumulated in the lungs of the LPD mice and had a reduced capacity for antimicrobial responses such as NADPH-oxidase mediated ROS production. Nicotinamide, a form of Vitamin B3, supplementation in LPD-fed mice was able to restore mitochondrial ATP production and gene expression of these TFs, as well shift the bone marrow cellular composition towards the CPD-state. Overall, this study provides a novel understanding of neutrophil responses in malnutrition and inflammation. I also highlight a novel therapeutic strategy that can be explored further in children with malnutrition to improve immune function and clinical outcomes.
Source: TSpace (University of Toronto)
Author: Thind, Mehakpreet Kaur
Institution: University of Toronto
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7167299631