Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning

Tânia Martins Garcia; Manon van Roest; Jacqueline L M Vermeulen; Sander Meisner; Wouter L Smit; Joana Silva; Pim J Koelink; Jan Koster; William J Faller; Manon E Wildenberg; Ruurd M van Elburg; Vanesa Muncan; Ingrid B Renes

doi:10.1016/j.jcmgh.2021.05.019

Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning

Tânia Martins Garcia
, Manon van Roest
, Jacqueline L M Vermeulen
, Sander Meisner
, Wouter L Smit
, Joana Silva
, Pim J Koelink
, Jan Koster
, William J Faller
, Manon E Wildenberg
, Ruurd M van Elburg
, Vanesa Muncan^*
, Ingrid B Renes

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

31 Citations (Scopus)

Abstract

Background & Aims
The use of antibiotics (ABs) is a common practice during the first months of life. ABs can perturb the intestinal microbiota, indirectly influencing the intestinal epithelial cells (IECs), but can also directly affect IECs independent of the microbiota. Previous studies have focused mostly on the impact of AB treatment during adulthood. However, the difference between the adult and neonatal intestine warrants careful investigation of AB effects in early life.

Methods
Neonatal mice were treated with a combination of amoxicillin, vancomycin, and metronidazole from postnatal day 10 to 20. Intestinal permeability and whole-intestine gene and protein expression were analyzed. IECs were sorted by a fluorescence-activated cell sorter and their genome-wide gene expression was analyzed. Mouse fetal intestinal organoids were treated with the same AB combination and their gene and protein expression and metabolic capacity were determined.

Results
We found that in vivo treatment of neonatal mice led to decreased intestinal permeability and a reduced number of specialized vacuolated cells, characteristic of the neonatal period and necessary for absorption of milk macromolecules. In addition, the expression of genes typically present in the neonatal intestinal epithelium was lower, whereas the adult gene expression signature was higher. Moreover, we found altered epithelial defense and transepithelial-sensing capacity. In vitro treatment of intestinal fetal organoids with AB showed that part of the consequences observed in vivo is a result of the direct action of the ABs on IECs. Lastly, ABs reduced the metabolic capacity of intestinal fetal organoids.

Conclusions
Our results show that early life AB treatment induces direct and indirect effects on IECs, influencing their maturation and functioning.

Original language	English
Pages (from-to)	943-981
Number of pages	39
Journal	Cellular and Molecular Gastroenterology and Hepatology
Volume	12
Issue number	3
Early online date	6 Jun 2021
DOIs	https://doi.org/10.1016/j.jcmgh.2021.05.019
Publication status	Published - 30 Jul 2021

Bibliographical note

Keywords

Amoxicillin/administration & dosage
Animals
Animals, Newborn
Anti-Bacterial Agents/administration & dosage
Disease Models, Animal
Enterocytes/cytology
Gene Expression Profiling/methods
Gene Expression Regulation/drug effects
Gene Regulatory Networks/drug effects
Intestines/cytology
Metronidazole/administration & dosage
Mice
Oligonucleotide Array Sequence Analysis
Permeability/drug effects
Postnatal Care
Vacuoles/drug effects
Vancomycin/administration & dosage

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Garcia, T. M., van Roest, M., Vermeulen, J. L. M., Meisner, S., Smit, W. L., Silva, J., Koelink, P. J., Koster, J., Faller, W. J., Wildenberg, M. E., van Elburg, R. M., Muncan, V., & Renes, I. B. (2021). Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning. Cellular and Molecular Gastroenterology and Hepatology, 12(3), 943-981. https://doi.org/10.1016/j.jcmgh.2021.05.019

@article{19dc9b5924f44117bb2fb0169d717a70,

title = "Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning",

abstract = "Background \& Aims The use of antibiotics (ABs) is a common practice during the first months of life. ABs can perturb the intestinal microbiota, indirectly influencing the intestinal epithelial cells (IECs), but can also directly affect IECs independent of the microbiota. Previous studies have focused mostly on the impact of AB treatment during adulthood. However, the difference between the adult and neonatal intestine warrants careful investigation of AB effects in early life. Methods Neonatal mice were treated with a combination of amoxicillin, vancomycin, and metronidazole from postnatal day 10 to 20. Intestinal permeability and whole-intestine gene and protein expression were analyzed. IECs were sorted by a fluorescence-activated cell sorter and their genome-wide gene expression was analyzed. Mouse fetal intestinal organoids were treated with the same AB combination and their gene and protein expression and metabolic capacity were determined. Results We found that in vivo treatment of neonatal mice led to decreased intestinal permeability and a reduced number of specialized vacuolated cells, characteristic of the neonatal period and necessary for absorption of milk macromolecules. In addition, the expression of genes typically present in the neonatal intestinal epithelium was lower, whereas the adult gene expression signature was higher. Moreover, we found altered epithelial defense and transepithelial-sensing capacity. In vitro treatment of intestinal fetal organoids with AB showed that part of the consequences observed in vivo is a result of the direct action of the ABs on IECs. Lastly, ABs reduced the metabolic capacity of intestinal fetal organoids. Conclusions Our results show that early life AB treatment induces direct and indirect effects on IECs, influencing their maturation and functioning.",

keywords = "Amoxicillin/administration \& dosage, Animals, Animals, Newborn, Anti-Bacterial Agents/administration \& dosage, Disease Models, Animal, Enterocytes/cytology, Gene Expression Profiling/methods, Gene Expression Regulation/drug effects, Gene Regulatory Networks/drug effects, Intestines/cytology, Metronidazole/administration \& dosage, Mice, Oligonucleotide Array Sequence Analysis, Permeability/drug effects, Postnatal Care, Vacuoles/drug effects, Vancomycin/administration \& dosage",

author = "Garcia, \{T{\^a}nia Martins\} and \{van Roest\}, Manon and Vermeulen, \{Jacqueline L M\} and Sander Meisner and Smit, \{Wouter L\} and Joana Silva and Koelink, \{Pim J\} and Jan Koster and Faller, \{William J\} and Wildenberg, \{Manon E\} and \{van Elburg\}, \{Ruurd M\} and Vanesa Muncan and Renes, \{Ingrid B\}",

year = "2021",

month = jul,

day = "30",

doi = "10.1016/j.jcmgh.2021.05.019",

language = "English",

volume = "12",

pages = "943--981",

journal = "Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier Inc.",

number = "3",

}

Garcia, TM, van Roest, M, Vermeulen, JLM, Meisner, S, Smit, WL, Silva, J, Koelink, PJ, Koster, J, Faller, WJ, Wildenberg, ME, van Elburg, RM, Muncan, V & Renes, IB 2021, 'Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning', Cellular and Molecular Gastroenterology and Hepatology, vol. 12, no. 3, pp. 943-981. https://doi.org/10.1016/j.jcmgh.2021.05.019

Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning. / Garcia, Tânia Martins; van Roest, Manon; Vermeulen, Jacqueline L M et al.
In: Cellular and Molecular Gastroenterology and Hepatology, Vol. 12, No. 3, 30.07.2021, p. 943-981.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning

AU - Garcia, Tânia Martins

AU - van Roest, Manon

AU - Vermeulen, Jacqueline L M

AU - Meisner, Sander

AU - Smit, Wouter L

AU - Silva, Joana

AU - Koelink, Pim J

AU - Koster, Jan

AU - Faller, William J

AU - Wildenberg, Manon E

AU - van Elburg, Ruurd M

AU - Muncan, Vanesa

AU - Renes, Ingrid B

PY - 2021/7/30

Y1 - 2021/7/30

N2 - Background & Aims The use of antibiotics (ABs) is a common practice during the first months of life. ABs can perturb the intestinal microbiota, indirectly influencing the intestinal epithelial cells (IECs), but can also directly affect IECs independent of the microbiota. Previous studies have focused mostly on the impact of AB treatment during adulthood. However, the difference between the adult and neonatal intestine warrants careful investigation of AB effects in early life. Methods Neonatal mice were treated with a combination of amoxicillin, vancomycin, and metronidazole from postnatal day 10 to 20. Intestinal permeability and whole-intestine gene and protein expression were analyzed. IECs were sorted by a fluorescence-activated cell sorter and their genome-wide gene expression was analyzed. Mouse fetal intestinal organoids were treated with the same AB combination and their gene and protein expression and metabolic capacity were determined. Results We found that in vivo treatment of neonatal mice led to decreased intestinal permeability and a reduced number of specialized vacuolated cells, characteristic of the neonatal period and necessary for absorption of milk macromolecules. In addition, the expression of genes typically present in the neonatal intestinal epithelium was lower, whereas the adult gene expression signature was higher. Moreover, we found altered epithelial defense and transepithelial-sensing capacity. In vitro treatment of intestinal fetal organoids with AB showed that part of the consequences observed in vivo is a result of the direct action of the ABs on IECs. Lastly, ABs reduced the metabolic capacity of intestinal fetal organoids. Conclusions Our results show that early life AB treatment induces direct and indirect effects on IECs, influencing their maturation and functioning.

AB - Background & Aims The use of antibiotics (ABs) is a common practice during the first months of life. ABs can perturb the intestinal microbiota, indirectly influencing the intestinal epithelial cells (IECs), but can also directly affect IECs independent of the microbiota. Previous studies have focused mostly on the impact of AB treatment during adulthood. However, the difference between the adult and neonatal intestine warrants careful investigation of AB effects in early life. Methods Neonatal mice were treated with a combination of amoxicillin, vancomycin, and metronidazole from postnatal day 10 to 20. Intestinal permeability and whole-intestine gene and protein expression were analyzed. IECs were sorted by a fluorescence-activated cell sorter and their genome-wide gene expression was analyzed. Mouse fetal intestinal organoids were treated with the same AB combination and their gene and protein expression and metabolic capacity were determined. Results We found that in vivo treatment of neonatal mice led to decreased intestinal permeability and a reduced number of specialized vacuolated cells, characteristic of the neonatal period and necessary for absorption of milk macromolecules. In addition, the expression of genes typically present in the neonatal intestinal epithelium was lower, whereas the adult gene expression signature was higher. Moreover, we found altered epithelial defense and transepithelial-sensing capacity. In vitro treatment of intestinal fetal organoids with AB showed that part of the consequences observed in vivo is a result of the direct action of the ABs on IECs. Lastly, ABs reduced the metabolic capacity of intestinal fetal organoids. Conclusions Our results show that early life AB treatment induces direct and indirect effects on IECs, influencing their maturation and functioning.

KW - Amoxicillin/administration & dosage

KW - Animals

KW - Animals, Newborn

KW - Anti-Bacterial Agents/administration & dosage

KW - Disease Models, Animal

KW - Enterocytes/cytology

KW - Gene Expression Profiling/methods

KW - Gene Expression Regulation/drug effects

KW - Gene Regulatory Networks/drug effects

KW - Intestines/cytology

KW - Metronidazole/administration & dosage

KW - Mice

KW - Oligonucleotide Array Sequence Analysis

KW - Permeability/drug effects

KW - Postnatal Care

KW - Vacuoles/drug effects

KW - Vancomycin/administration & dosage

U2 - 10.1016/j.jcmgh.2021.05.019

DO - 10.1016/j.jcmgh.2021.05.019

M3 - Article (Academic Journal)

C2 - 34102314

SN - 2352-345X

VL - 12

SP - 943

EP - 981

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

IS - 3

ER -