35 2 Organoids as a model to study intestinal and liver dysfunction in severe malnutrition INTRODUCTION The recent discovery of organoids has opened exciting possibilities for studying diseases, modelling cell development and applying them as therapeutic tools1–4. Their three dimensional and proliferative nature grants them the ability to maintain many of their organ functions, which makes them a physiologically relevant system to study diseases5. Organoids have been used to understand organ-specific metabolism6,7 and to investigate the effect of nutrients on organ homeostasis8. Here, we present two organoid models as tools to study the impact of severe macronutrient deficiency on organ function, the role of organelle homeostasis, and study the effects of putative therapeutic compounds. Nutritional deficiencies compromise organ function and disrupt cellular metabolism9. Children with severe malnutrition present with the most severe form of macronutrient deficiency. In developing countries, low protein diets are common, as staple foods are often high in carbohydrates and relatively low in protein (e.g. maize). This together with low food diversity and high food insecurity is thought to contribute to the development of severe malnutrition10. Severely malnourished children face high mortality rates when admitted to hospital for treatment of acute, mostly infectious, illnesses (e.g. 23-46% in African hospitals)11–14. These children often show signs of hepatic dysfunction (e.g. hypoglycaemia, bile acid dysregulation) and intestinal dysfunction (e.g. diarrhoea, increased intestinal permeability), both of which have negative impacts on their survival15–18. Children with severe malnutrition are extremely vulnerable and simple re-feeding protocols do not produce acceptable levels of recovery, thus the development of co-therapies are urgently needed. Clinical studies have provided some insight into the pathophysiology of the functional impairments in severe malnutrition and suggest that disrupted cellular metabolism may play a key role. Data from severely malnourished children suggests that liver fat accumulation, i.e., hepatic steatosis, is caused by impaired lipid oxidation rather than impaired secretion of lipids19,20. In support, post-mortem electron microscopy images revealed hepatocytes to have dysmorphic mitochondria and a decreased number of peroxisomes, which are two of the main lipid-oxidation organelles21. Some studies have also reported mitochondrial morphological changes in the small intestine of severely malnourished children22–25, but their causal impact on intestinal dysfunction in severe malnutrition has not been demonstrated. Yet, a growing body of evidence suggests a pivotal role of mitochondria in maintaining intestinal homeostasis26–28. Further mechanistic insight is hindered by the need
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