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

• Published in: Cellular and molecular gastroenterology and hepatology Vol. 12; no. 3; pp. 943 - 981
• Main Authors: Garcia, Tânia Martins, van Roest, Manon, Vermeulen, Jacqueline L.M., Meisner, Sander, Smit, Wouter L., Silva, Joana, Koelink, Pim J., Koster, Jan, Faller, William J., Wildenberg, Manon E., van Elburg, Ruurd M., Muncan, Vanesa, Renes, Ingrid B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; Elsevier
• Subjects: Amoxicillin - administration & dosage; Amoxicillin - adverse effects; Animals; Animals, Newborn; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - adverse effects; Antibiotic Treatment; Disease Models, Animal; Enterocytes - cytology; Enterocytes - drug effects; Enterocytes - metabolism; Fetal Organoids; Gene Expression Profiling - methods; Gene Expression Regulation - drug effects; Gene Regulatory Networks - drug effects; Intestines - cytology; Intestines - drug effects; Intestines - metabolism; Metronidazole - administration & dosage; Metronidazole - adverse effects; Mice; Neonatal Intestine; Oligonucleotide Array Sequence Analysis; Original Research; Permeability - drug effects; Postnatal Care; Vacuoles - drug effects; Vacuoles - metabolism; Vancomycin - administration & dosage; Vancomycin - adverse effects; Neonatal Intestine; EpCAM; FCCP; P; FITC; SI; Antibiotic Treatment; PBS; AB; EEC; Arg2; IEC; qRT-PCR; GO; GSEA; 2-DG; NEC; Ass1; ECAR; GIP; ACS; Fetal Organoids; Sis; ATP; OCR
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2021.05.019

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