Early growth restriction disrupts mice intestinal clock and homeostasis without being prevented by lactoferrin

Léa Chantal Tran; Lucie Marousez; Edwina Micours; Laure Dubernat; Jean-Pascal Meneboo; Martin Figeac; Céline Ribière; Cécile Bonhomme; Frédéric Gottrand; Jean Lesage; Delphine Ley

doi:10.1038/s41390-025-04466-3

Early growth restriction disrupts mice intestinal clock and homeostasis without being prevented by lactoferrin

Pediatr Res. 2025 Nov 11. doi: 10.1038/s41390-025-04466-3. Online ahead of print.

Authors

Léa Chantal Tran^#^{1

2}, Lucie Marousez^#³, Edwina Micours³, Laure Dubernat³, Jean-Pascal Meneboo⁴, Martin Figeac⁴, Céline Ribière⁵, Cécile Bonhomme⁶, Frédéric Gottrand^{3

7}, Jean Lesage³, Delphine Ley^{3

7}

Affiliations

¹ Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France. lea.tran@chu-lille.fr.
² Univ. Lille, CHU Lille, Division of Gastroenterology Hepatology and Nutrition, Department of Paediatrics, Jeanne de Flandre Children's Hospital, Lille, France. lea.tran@chu-lille.fr.
³ Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, Lille, France.
⁴ Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Plateforme de génomique fonctionnelle et Structurale, US 41-UAR 2014-PLBS, Lille, France.
⁵ Vaiomer, 516 Rue Pierre et Marie Curie, Labège, France.
⁶ Lactalis Nutrition Santé, Torce, France.
⁷ Univ. Lille, CHU Lille, Division of Gastroenterology Hepatology and Nutrition, Department of Paediatrics, Jeanne de Flandre Children's Hospital, Lille, France.

^# Contributed equally.

PMID: 41219462
DOI: 10.1038/s41390-025-04466-3

Abstract

Background: Preterm infants and growth-restricted newborns are highly susceptible to intestinal inflammation and sepsis. We studied the effects of oral supplementation with bovine lactoferrin (bLf) during lactation in postnatal growth-restricted (PNGR) mice on intestinal development and susceptibility to colitis at weaning.

Methods: Growth restriction was induced in FVB/NRj mice from large litters from postnatal day (PN) 4 to 21. bLf (300 mg/kg/d) was administered from PN8 to PN21. Intestinal function was evaluated at PN21 by morphology, RNA sequencing, microbiota composition, and cecal short chain fatty acid levels. At PN22, acute colitis was induced by 3% dextran sulfate sodium (DSS). Colitis severity was assessed at PN29 histologically and RT-qPCR.

Results: PNGR altered the expression of genes related to circadian rhythm in intestines but did not increase susceptibility to DSS-induced acute colitis post weaning. PNGR-induced growth retardation and intestinal immaturity were not improved by bLf supplementation. bLf supplementation affected the microbiota composition in control, but not PNGR pups, and slightly reduced the inflammatory effects of colitis in PNGR.

Conclusion: PNGR alters intestinal development by affecting the intestinal transcriptome during lactation. bLf supplementation does not prevent growth restriction effects on gut health but could modulate gut microbiota in control pups during this period.

Impact: Postnatal growth restriction induces changes in the intestinal transcriptome with a disruption of clock-related gene expression. Postnatal growth restriction alters intestinal microbiota composition but does not amplify the response to an inflammatory-induced acute colitis after weaning. Bovine lactoferrin supplementation does not improve an induced growth restriction and its altered intestinal barrier structure. Bovine lactoferrin supplementation may induce positive intestinal microbial changes especially in control mice during lactation.