A persistent increase in gut permeability correlates with emotional dysregulation following maternal separation in male and female mice

Early life stress (ELS) can significantly influence vulnerability to the development of psychiatric disorders in adulthood. One of the most widely used preclinical models for investigating ELS is maternal separation with early weaning (MSEW), which mimics early-life neglect. The objective of this study was to evaluate the impact of ELS induced by MSEW on the emotional behaviour of male and female mice, as well as its relationship with intestinal permeability and neuroinflammatory markers in the hippocampus.

Our results show that MSEW leads to increased anxiety-like behaviours in the adulthood, particularly in females, and exacerbates depression-like behaviours and anhedonia in both sexes. Notably, increased intestinal permeability was observed, which correlated with higher anxiety and depression-like responses, suggesting that gut health plays a crucial role in emotional regulation. These alterations in intestinal permeability were long-lasting, indicating persistent effects on gut function following ELS.

Additionally, we observed that MSEW animals showed higher BDNF expression in the hippocampus, particularly in males. However, we did not find significant differences in the long-term survival of adult-born hippocampal cells, as measured by BrdU+ labeling. Furthermore, upon exposure to MSEW, both sexes showed increased NF-κB protein levels. However, only MSEW male mice exhibited changes in TNF-α and BDNF levels, suggesting a sex-specific regulatory mechanism in response to chronic stress.

The novel contribution of this study is its exploration of intestinal permeability as a mechanism linking ELS to emotional and behavioural dysregulation, particularly anxiety and depression. By showing a long-lasting increase in intestinal permeability and its correlation with mood disorders, our study extends the gut-brain axis hypothesis to ELS. Additionally, the inclusion of both male and female mice offers a more comprehensive understanding of the sex-specific effects of early stress, often overlooked in other studies. These findings suggest that intestinal permeability could serve as a biomarker for stress-related psychiatric conditions.

HIGHLIGHTS

• MSEW increases anxiety and depression-like behaviours, especially in females.

• Maternal separation leads to long-lasting gut permeability changes into adulthood.

• Increased gut permeability directly correlates with anxiety and anhedonia-like responses.

• Neuroinflammation via NF-kB may link gut permeability to mood disorders.

• Differential regulation of early-life stress is observed between males and females.