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.

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 journal › Article › Academic › peer-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 language	English
Article number	104809
Number of pages	21
Journal	EBioMedicine
Volume	96
Early online date	20 Sept 2023
DOIs	https://doi.org/10.1016/j.ebiom.2023.104809
Publication status	Published - Oct 2023

Bibliographical note

Funding Information:
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.CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49). CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children. CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (156307). BMB and JHN have received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296.

Funding Information:
CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49) . CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children . CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research ( 156307 ). BMB and JHN have received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296 .

Publisher Copyright:
© 2023 The Authors

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.CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49). CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children. CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (156307). BMB and JHN have received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296. CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49) . CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children . CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research ( 156307 ). BMB and JHN have received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296 .

Funders	Funder number
Bill and Melinda Gates Foundation
Horizon 2020 Framework Programme
H2020 Marie Skłodowska-Curie Actions	81296
Stichting De Cock-Hadders	2018-49
Canadian Institutes of Health Research	156307
Boehringer Ingelheim Fonds
Universitair Medisch Centrum Groningen
Hospital for Sick Children
Horizon 2020
SickKids Research Institute

Keywords

Malnutrition
Enteropathy
SIRT1
Mitochondria
Autophagy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2023.104809Licence: CC BY

1-s2.0-S2352396423003754-mainFinal published version, 5.37 MBLicence: CC BY

Cite this

Ling, C., Versloot, C. J., Arvidsson Kvissberg, M. E., Hu, G., Swain, N., Horcas-Nieto, J. M., Miraglia, E., Thind, M. K., Farooqui, A., Gerding, A., van Eunen, K., Koster, M. H., Kloosterhuis, N. J., Chi, L., ChenMi, Y., Langelaar-Makkinje, M., Bourdon, C., Swann, J., Smit, M., ... Bandsma, R. H. J. (2023). Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition. EBioMedicine, 96, Article 104809. https://doi.org/10.1016/j.ebiom.2023.104809

@article{76893165ad6e446dadce79f530db4ced,

title = "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 = "Malnutrition, Enteropathy, SIRT1, Mitochondria, Autophagy",

author = "Catriona Ling and Versloot, {Christian J} and {Arvidsson Kvissberg}, {Matilda E} and Guanlan Hu and Nathan Swain and Horcas-Nieto, {Jos{\'e} M} and Emily Miraglia and Thind, {Mehakpreet K} and Amber Farooqui and Albert Gerding and {van Eunen}, Karen and Koster, {Mirjam H} and Kloosterhuis, {Niels J} and Lijun Chi and YueYing ChenMi and Miriam Langelaar-Makkinje and Celine Bourdon and Jonathan Swann and Marieke Smit and {de Bruin}, Alain and Youssef, {Sameh A} and Marjon Feenstra and {van Dijk}, {Theo H} and Kathrin Thedieck and Jonker, {Johan W} and Kim, {Peter K} and Bakker, {Barbara M} and Bandsma, {Robert H J}",

note = "Funding Information: 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.CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49). CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children. CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (156307). BMB and JHN have received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement No 81296. Funding Information: CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49) . CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children . CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research ( 156307 ). BMB and JHN have received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement No 81296 . Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

doi = "10.1016/j.ebiom.2023.104809",

language = "English",

volume = "96",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

Ling, C, Versloot, CJ, Arvidsson Kvissberg, ME, Hu, G, Swain, N, Horcas-Nieto, JM, Miraglia, E, Thind, MK, Farooqui, A, Gerding, A, van Eunen, K, Koster, MH, Kloosterhuis, NJ, Chi, L, ChenMi, Y, Langelaar-Makkinje, M, Bourdon, C, Swann, J, Smit, M, de Bruin, A, Youssef, SA, Feenstra, M, van Dijk, TH, Thedieck, K, Jonker, JW, Kim, PK, Bakker, BM & Bandsma, RHJ 2023, 'Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.', EBioMedicine, vol. 96, 104809. https://doi.org/10.1016/j.ebiom.2023.104809

TY - JOUR

T1 - Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.

AU - Ling, Catriona

AU - Versloot, Christian J

AU - Arvidsson Kvissberg, Matilda E

AU - Hu, Guanlan

AU - Swain, Nathan

AU - Horcas-Nieto, José M

AU - Miraglia, Emily

AU - Thind, Mehakpreet K

AU - Farooqui, Amber

AU - Gerding, Albert

AU - van Eunen, Karen

AU - Koster, Mirjam H

AU - Kloosterhuis, Niels J

AU - Chi, Lijun

AU - ChenMi, YueYing

AU - Langelaar-Makkinje, Miriam

AU - Bourdon, Celine

AU - Swann, Jonathan

AU - Smit, Marieke

AU - de Bruin, Alain

AU - Youssef, Sameh A

AU - Feenstra, Marjon

AU - van Dijk, Theo H

AU - Thedieck, Kathrin

AU - Jonker, Johan W

AU - Kim, Peter K

AU - Bakker, Barbara M

AU - Bandsma, Robert H J

N1 - Funding Information: 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.CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49). CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children. CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research (156307). BMB and JHN have received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296. Funding Information: CJV received an MD-PhD fellowship from the University Medical Center Groningen and financial support from Stichting De Cock-Hadders (2018-49) . CL received PhD funding through a Restracomp Scholarship from the Hospital for Sick Children . CL and JHN received funding from Boehringer Ingelheim Fonds travel grant. This research was supported by the Bill & Melinda Gates Foundation and the Canadian Institutes of Health Research ( 156307 ). BMB and JHN have received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 81296 . Publisher Copyright: © 2023 The Authors

PY - 2023/10

Y1 - 2023/10

N2 - 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.

AB - 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.

KW - Malnutrition

KW - Enteropathy

KW - SIRT1

KW - Mitochondria

KW - Autophagy

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U2 - 10.1016/j.ebiom.2023.104809

DO - 10.1016/j.ebiom.2023.104809

M3 - Article

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SN - 2352-3964

VL - 96

JO - EBioMedicine

JF - EBioMedicine

M1 - 104809

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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