Evidence of postnatal neglect-dependent resiliency in thymic, gut, and behavioral outcomes in a mouse model of early life stress

Jamie Y Choe; Michael Donkor; Yan Zhang; Isabelle K Gorham; Jessica L Bradshaw; Philip H Vann; Nathalie Sumien; Rebecca L Cunningham; Michael S Allen; Byron Quinn; Nicole R Phillips; Harlan P Jones

doi:10.1016/j.bbi.2025.06.036

Evidence of postnatal neglect-dependent resiliency in thymic, gut, and behavioral outcomes in a mouse model of early life stress

Brain Behav Immun. 2025 Jun 29:129:595-608. doi: 10.1016/j.bbi.2025.06.036. Online ahead of print.

Authors

Affiliations

¹ Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA; Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA.
² Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA.
³ Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁴ Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁵ Department of Biology, Langston University, Langston, OK, USA.
⁶ Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA; Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁷ Department of Microbiology, Immunology & Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA; Institute for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: Harlan.Jones@unthsc.edu.

PMID: 40592418
DOI: 10.1016/j.bbi.2025.06.036

Abstract

Background: Early life is an impressionable period often regarded as the window of opportunity. Environmental exposures, such as stress, in the early postnatal period can influence developmental trajectory and long-term health. The brain and immune systems continue to develop after birth and are shaped by postnatal exposures. While chronic traumatic stress is understood to adversely affect individuals by overwhelming coping abilities, there is evidence for stress exposure to be beneficial by promoting resilience. Early life stress (ELS) is a significant postnatal exposure, which encompasses childhood maltreatment and trauma. Neglect is the most common form of maltreatment in children and takes many forms, including physical and nutritional.

Methods: Here, we describe a novel mouse model of neglect-related ELS based on maternal separation with early weaning (MSEW) with a distinct early weaning (EW) stress group to study how an environment of neglect impacts the developing microbiome, thymocytes, and stress-related behavior. Neglect-related stress was emulated based on scheduled dam-pup separation (physical neglect) and a high carbohydrate early-wean diet (malnutrition). C57BL/6J mice were bred in-house and ELS pups were subjected to: (1) daily dam-pup separation on postnatal days (PD) 2-13 and/or (2) early weaning to a high carbohydrate diet on PD14-21.

Results: The present study focused on a defined early life window (PD0-21) and revealed that MSEW versus EW exposures generate distinguishable and distinct effects on behavior and thymic T cells, leading to phenotypes of stress resilience versus vulnerability. Although impacts of the two ELS groups were indistinguishable on lower gastrointestinal tract microbiome composition, the effects on ELS groups were significant compared to controls.

Conclusions: Our findings provide evidence for circumstances where prior stress can induce resilience and emphasizes the nuanced approach required for studies to begin parsing out toxic versus beneficial stress.

Keywords: Early life stress; Exposome; Psychoneuroimmunology; Resilience; Thymocytes.