51 2 Organoids as a model to study intestinal and liver dysfunction in severe malnutrition β-oxidation capacity resulting in reduced hepatic fat deposition30. In general, contrasting effects of fenofibrate on triglyceride have been described. For instance, in healthy mice fenofibrate reduced levels of triglycerides in serum but increased triglycerides in the liver65. Also in HEPG2 cells, fenofibrate increased the levels of tryglicerides65. The positive effect on peroxisomal protein levels, however, offers therapeutic potential44. Fenofibrate is usually well-tolerated during treatment of dyslipidemia, but side effects such as rhabdomyolysis are a risk in severely malnourished children66. Further investigation is required into the mechanisms of action, into the later effects of malnutrition on the mitochondria, and into the possibilities of PPAR-α-modulating dietary components (e.g. polysaturated fatty acids, flavonoids) in improving hepatic function in severe malnutrition67,68. In starved intestinal organoids, rapamycin treatment preserved mitochondria and peroxisomes. This coincided with higher levels of the tight junction protein claudin-3 than in starved, untreated organoids, suggesting better maintained barrier function. Accumulating data suggests a key role for mitochondria in maintaining the intestinal barrier26, but for peroxisomes this is less known. Improved mitochondrial health may be attributed to stimulated mitochondrial biogenesis, as PGC1-α protein levels were increased in rapamycin-administered starved organoids. In addition, rapamycin could improve mitochondrial homeostasis via clearance of dysfunctional mitochondria through autophagy activation69, thereby contributing to the potentially improved barrier function. The potential positive impact of rapamycin on the intestinal barrier has therapeutic implications for severely malnourished children, because it could have potential to prevent bacterial translocation-induced clinical deterioration and death56–58. A limitation of this study is that no human organoids were included. The choice for mouse organoids enabled us to make a direct comparison between organoids and mouse liver or intestine, particularly concerning the mitochondrial and peroxisomal phenotype. This comparison could not be made with human tissue, since invasive samples in malnourished children are scarce. A next step should be the translation to human organoids. CONCLUSIONS The results of this study support the notion that hepatic and intestinal organoid models can be used to further investigate underlying mechanisms of organ
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