Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition

作者：Catriona Ling, Christian J. Versloot, Matilda E. Arvidsson Kvissberg, Guanlan Hu, Nathan Swain, José M. Horcas‐Nieto, Emily Miraglia, Mehakpreet Kaur Thind, Amber Farooqui, Albert Gerding, Karen van Eunen, Mirjam H. Koster, Niels Kloosterhuis, Lijun Chi, YueYing ChenMi, Miriam Langelaar‐Makkinje, Céline Bourdon, Jonathan Richard Swann, Marieke Smit, Alain de Bruin, Sameh A. Youssef, Marjon E. Feenstra, Theo H. van Dijk, Kathrin Thedieck, Johan W. Jonker, Peter Kijun Kim, Barbara M. Bakker, Robert Bandsma · 发表于：EBioMedicine · 年份：2023 · DOI：10.1016/j.ebiom.2023.104809 · 被引用次数：41 · 研究领域：Sirtuins and Resveratrol in Medicine、Autophagy in Disease and Therapy、Nutrition and Health in Aging

BACKGROUND: The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health. METHODS: -precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities. FINDINGS: LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction...