ABSTRACT
Hospitalized children with severe malnutrition face high mortality rates and often suffer from hepatic and intestinal dysfunction, with negative impacts on their survival. New treatments cannot be developed without
understanding the underlying pathophysiology. We have established and characterized translational organoid
models of severe malnutrition of the liver and the intestine. In these models, amino acid starvation recapitulates
the expected organ-specific functional changes (e.g., hepatic steatosis, barrier dysfunction) accompanied by
reduced mitochondrial and peroxisomal proteins, and altered intestinal tight junction proteins. Resupplementation of amino acids or pharmacological interventions with rapamycin or fenofibrate lead to partial recovery. Restoration of protein levels aligned with signs of improved peroxisomal function in both organoids, and increased mitochondrial proteins and tight junction protein claudin-3 in intestinal organoids. We
present two organoid models as novel tools to gain mechanistic insights and to act as a testing platform for
potential treatments for intestinal and hepatic dysfunction in severe malnutrition.
