Your browser doesn't support javascript.
loading
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.
Afiliación
  • Ling C; 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.
  • Versloot CJ; 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.
  • Arvidsson Kvissberg ME; 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.
  • Hu G; 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.
  • Swain N; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • Horcas-Nieto JM; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Miraglia E; 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.
  • Thind MK; 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.
  • Farooqui A; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • Gerding A; 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.
  • van Eunen K; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Koster MH; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Kloosterhuis NJ; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Chi L; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • ChenMi Y; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • Langelaar-Makkinje M; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Bourdon C; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • Swann J; 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.
  • Smit M; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • de Bruin A; Department of Biomolecular Health Sciences, Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • Youssef SA; 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.
  • Feenstra M; Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
  • van Dijk TH; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Thedieck K; 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 Resea
  • Jonker JW; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
  • Kim PK; Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: pkim@sickkids.ca.
  • Bakker BM; Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address: b.m.bakker01@umcg.nl.
  • Bandsma RHJ; 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 Disease
EBioMedicine ; 96: 104809, 2023 Oct.
Article en En | MEDLINE | ID: mdl-37738832
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.

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.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: EBioMedicine Año: 2023 Tipo del documento: Article País de afiliación: Canadá
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: EBioMedicine Año: 2023 Tipo del documento: Article País de afiliación: Canadá