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EBioMedicine, Volume 96, October 2023, 104809 | https://doi.org/10.1016/j.ebiom.2023.104809 Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.

Catriona Ling ^a,b,o, Christian J. Versloot ^a,c,o, Matilda E. Arvidsson Kvissberg ^a,c, Guanlan Hu^a,b, Nathan Swain ^a, José M. Horcas-Nieto ^c, Emily Miraglia ^a,d,e, Mehakpreet K. Thind ^a,b, Amber Farooqui ^a, Albert Gerding ^c,f, Karen van Eunen ^c, Mirjam H. Koster ^c, Niels J. Kloosterhuis ^c, Lijun Chi ^a, YueYing ChenMi ^a, Miriam Langelaar-Makkinje ^c, Celine Bourdon ^a, Jonathan Swann ^g,h, Marieke Smit ^c, Alain de Bruin ⁱ, Sameh A. Youssef ^i,j, Marjon Feenstra ^a, Theo H. van Dijk ^c, Kathrin Thedieck ^c,k,l, Johan W. Jonker^c, Peter K. Kim ^d,e, Barbara M. Bakker ^c, Robert H.J. Bandsma ^a,b,c,m

^aTranslational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada

^bDepartment of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

^cDepartment of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands

^dDepartment of Biochemistry, University of Toronto, Toronto, ON, Canada

^eCell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada

^fDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, the Netherlands

^gFaculty of Medicine, School of Human Development and Health, University of Southampton, United Kingdom

^hDepartment of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom

ⁱDepartment of Biomolecular Health Sciences, Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands

^jJanssen Pharmaceutica Research and Development, 2340, Beerse, Belgium

^kInstitute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria

^lFreiburg Materials Research Center (FMF), University Freiburg, Freiburg, Germany

^mDivision of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada

Corresponding authors: Peter K. Kim, Barbara M. Bakker, Robert H.J. Bandsma

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 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.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-13)
연구진국외 연구진
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