Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.
Ling, Catriona; Versloot, Christian J; Arvidsson Kvissberg, Matilda E; Hu, Guanlan; Swain, Nathan; Horcas-Nieto, José M; Miraglia, Emily; Thind, Mehakpreet K; Farooqui, Amber; Gerding, Albert; van Eunen, Karen; Koster, Mirjam H; Kloosterhuis, Niels J; Chi, Lijun; ChenMi, YueYing; Langelaar-Makkinje, Miriam; Bourdon, Celine; Swann, Jonathan; Smit, Marieke; de Bruin, Alain; Youssef, Sameh A; Feenstra, Marjon; van Dijk, Theo H; Thedieck, Kathrin; Jonker, Johan W; Kim, Peter K; Bakker, Barbara M; Bandsma, Robert H J
(2023) EBioMedicine, volume 96
(Article)
Abstract
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
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the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health. METHODS: SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD +-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. INTERPRETATION: Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials. FUNDING: This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.
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Keywords: Malnutrition, Enteropathy, SIRT1, Mitochondria, Autophagy
ISSN: 2352-3964
Publisher: Elsevier BV
Note: Funding Information: This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen.CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49). CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children. CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (156307). BMB and JHN have received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296. Funding Information: CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49) . CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children . CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research ( 156307 ). BMB and JHN have received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296 . Publisher Copyright: © 2023 The Authors
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