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

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

doi:10.1016/j.ebiom.2023.104809

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

EBioMedicine. 2023 Oct:96:104809. doi: 10.1016/j.ebiom.2023.104809. Epub 2023 Sep 20.

Authors

Catriona Ling¹, Christian J Versloot², Matilda E Arvidsson Kvissberg², Guanlan Hu¹, Nathan Swain³, José M Horcas-Nieto⁴, Emily Miraglia⁵, Mehakpreet K Thind¹, Amber Farooqui³, Albert Gerding⁶, Karen van Eunen⁴, Mirjam H Koster⁴, Niels J Kloosterhuis⁴, Lijun Chi³, YueYing ChenMi³, Miriam Langelaar-Makkinje⁴, Celine Bourdon³, Jonathan Swann⁷, Marieke Smit⁴, Alain de Bruin⁸, Sameh A Youssef⁹, Marjon Feenstra³, Theo H van Dijk⁴, Kathrin Thedieck¹⁰, Johan W Jonker⁴, Peter K Kim¹¹, Barbara M Bakker¹², Robert H J Bandsma¹³

Affiliations

¹ 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.
² 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.
³ Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ Department of Biomolecular Health Sciences, Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
⁹ 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.
¹⁰ 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.
¹¹ Department of Biochemistry, University of Toronto, Toronto, ON, Canada; Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: [email protected].
¹² Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address: [email protected].
¹³ 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. Electronic address: [email protected].

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.

Keywords: Autophagy; Enteropathy; Malnutrition; Mitochondria; SIRT1.