Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutritionResearch in context
Catriona Ling,
Christian J. Versloot,
Matilda E. Arvidsson Kvissberg,
Guanlan Hu,
Nathan Swain,
José M. Horcas-Nieto,
Emily Miraglia,
Mehakpreet K. Thind,
Amber Farooqui,
Albert Gerding,
Karen van Eunen,
Mirjam H. Koster,
Niels J. Kloosterhuis,
Lijun Chi,
YueYing ChenMi,
Miriam Langelaar-Makkinje,
Celine Bourdon,
Jonathan Swann,
Marieke Smit,
Alain de Bruin,
Sameh A. Youssef,
Marjon Feenstra,
Theo H. van Dijk,
Kathrin Thedieck,
Johan W. Jonker,
Peter K. Kim,
Barbara M. Bakker,
Robert H.J. Bandsma
Affiliations
Catriona Ling
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Christian J. Versloot
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Matilda E. Arvidsson Kvissberg
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Guanlan Hu
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Nathan Swain
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
José M. Horcas-Nieto
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Emily Miraglia
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada
Mehakpreet K. Thind
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Amber Farooqui
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
Albert Gerding
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, the Netherlands
Karen van Eunen
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Mirjam H. Koster
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Niels J. Kloosterhuis
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Lijun Chi
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
YueYing ChenMi
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
Miriam Langelaar-Makkinje
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Celine Bourdon
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
Jonathan Swann
Faculty of Medicine, School of Human Development and Health, University of Southampton, United Kingdom; Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom
Marieke Smit
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Alain de Bruin
Department of Biomolecular Health Sciences, Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
Sameh A. Youssef
Department of Biomolecular Health Sciences, Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands; Janssen Pharmaceutica Research and Development, 2340, Beerse, Belgium
Marjon Feenstra
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada
Theo H. van Dijk
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Kathrin Thedieck
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands; Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria; Freiburg Materials Research Center (FMF), University Freiburg, Freiburg, Germany
Johan W. Jonker
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands
Peter K. Kim
Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada; Corresponding author. Cell Biology Program, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
Barbara M. Bakker
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands; Corresponding author. Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, the Netherlands.
Robert H.J. Bandsma
Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada; Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands; Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada; Corresponding author. Division of Gastroenterology, Hepatology and Nutrition, Translational Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
Summary: 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. 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.
