Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition
- PMID: 37738832
- PMCID: PMC10520344
- DOI: 10.1016/j.ebiom.2023.104809
Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition
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.
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of interests All authors declare no conflicts interests.
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References
-
- United Nations Children’s Fund. World Health Organization. World Bank Group Levels and trends in child malnutrition: key findings of the 2020 edition of the joint child malnutrition estimates. https://www.who.int/publications-detail/jme-2020-edition Available from:
-
- Grenov B., Lanyero B., Nabukeera-Barungi N., et al. Diarrhea, dehydration, and the associated mortality in children with complicated severe acute malnutrition: a prospective cohort study in Uganda. J Pediatr. 2019;210:26–33. - PubMed
-
- Nabukeera-Barungi N., Grenov B., Lanyero B., et al. Predictors of mortality among hospitalized children with severe acute malnutrition: a prospective study from Uganda. Pediatr Res. 2018;84(1):92–98. - PubMed
-
- Boaz R.T., Joseph A.J., Kang G., Bose A. Vol. 50. Indian pediatrics; India: 2013. Intestinal permeability in normally nourished and malnourished children with and without diarrhea; pp. 152–153. - PubMed
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