Immune dysregulation is a key feature of severe and complex obesity, and has been directly linked to the development of many obesity-related co-morbidities, including type 2 diabetes mellitus (T2DM) and cancer. Obesity is also strongly associated with increased risk of adverse outcomes following infection, as most-evident from the COVID-19 pandemic. Again, immune dysregulation has been shown to both drive excessive inflammation and defective host protection in the setting of obesity. The exact mechanisms/factors that drive obesity-related immune dysregulation have not been fully elucidated. Obesity is linked with systemic alterations in metabolism and nutrient availability, one such nutrient is iron. Iron is a an essential micronutrient critical for many physiological and metabolic processes including mitochondrial fitness. We have strong supporting data which identifies iron deficiency as a potential driver of defective immunity. In the proposed project, we aim to investigate the iron requirements of several important effector populations (including CD8+ T cells, NK cells and MAIT cells). We will investigate the mitochondrial fitness and functionality of these immune population in cohorts of people with obesity (PWO) who are either iron replete or iron deficient. Finally, we will establish if iron supplementation in PWO who are iron deficient can restore effector immunity. Our project will address a major gap in our understanding of how obesity affects the immune system. Furthermore, it has potential to improve patient outcomes by boosting immunity in this at risk group via an accessible nutritional intervention. Finally, our research team is uniquely placed to have our research outputs translated into clinical policy and practice.
