The central role of mitochondrial health in malnutrition induced enterohepatic dysfunction

Childhood malnutrition is a global burden that contributes to a large proportion of mortality of children under the age of five. Malnutrition is caused by a combination of inadequate nutrient intake, malabsorption of nutrients and increased energy needs, most often due to infections. This thesis is comprised of clinical studies and pre-clinical studies that aim to better understand the metabolic changes seen in severe malnutrition. It consists of an introduction to malnutrition that covers the prevalence and management of severe malnutrition, followed by an introduction on human metabolism and the metabolic changes seen in severe malnutrition with a focus on liver metabolism. It also discusses the different animal models of severe malnutrition that have been reported. There are two clinical chapters that investigate carbohydrate malabsorption in severely malnourished children and a metabolic profiling study in ill children that are severely malnourished. The last three experimental chapters are pre-clinical studies investigating mechanisms underlying hepatic and intestinal pathology of malnutrition using a low-protein diet induced mouse model for malnutrition. This thesis further validated a malnutrition murine model using a low protein diet. Using this model, we were able to show improving beta-oxidation by both clearing dysfunctional mitochondria and increasing mitochondrial and peroxisomal amount improved liver and intestinal function. Metabolome analysis also indicated mitochondrial dysfunction in ill children with severe malnutrition. Together, this thesis highlights the importance of mitochondrial health in the underlying pathophysiology of severe malnutrition and that this may be a future area of intervention in this vulnerable patient population.