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 BruinSameh A Youssef, Marjon Feenstra, Theo H van Dijk, Kathrin Thedieck, Johan W Jonker, Peter K Kim, Barbara M Bakker, Robert H J Bandsma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number104809
Number of pages21
JournalEBioMedicine
Volume96
Early online date20 Sept 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • Malnutrition
  • Enteropathy
  • SIRT1
  • Mitochondria
  • Autophagy

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