Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis

Authors

Santosh K. Yadav, University of Nebraska Medical CenterFollow
Rizwan Ahmad, University of Nebraska Medical CenterFollow
Cassandra M. Moshfegh, University of Nebraska Medical Center
Jagadesan Sankarasubramanian, University of Nebraska Medical CenterFollow
Vineet A. Joshi, University of Nebraska Medical CenterFollow
Safwan K. Elkhatib, University of Nebraska Medical Center
Yashpal S. Chhonker, University of Nebraska Medical CenterFollow
Goeffrey A. Talmon, University of Nebraska Medical CenterFollow
Chittibabu Guda, University of Nebraska Medical CenterFollow
Adam Case, Texas A & M University - College Station
Amar B. Singh, University of Nebraska Medical CenterFollow

Document Type

Article

Journal Title

Biological Psychiatry Global Open Science

Publication Date

2023

Abstract

Background

Posttraumatic stress disorder (PTSD) is a mental health condition triggered by exposure to traumatic events in an individual’s life. Patients with PTSD are also at a higher risk for comorbidities. However, it is not well understood how PTSD affects human health and/or promotes the risk for comorbidities. Nevertheless, patients with PTSD harbor a proinflammatory milieu and dysbiotic gut microbiota. Gut barrier integrity helps to maintain normal gut homeostasis and its dysregulation promotes gut dysbiosis and inflammation.

Methods

We used a mouse model of repeated social defeat stress (RSDS), a preclinical model of PTSD. Behavioral studies, metagenomics analysis of the microbiome, gut permeability assay (on mouse colon, using an Ussing chamber), immunoblotting, and immunohistochemical analyses were performed. Polarized intestinal epithelial cells and 3-dimensional crypt cultures were used for mechanistic analysis.

Results

The RSDS mice harbor a heightened proinflammatory gut environment and microbiota dysbiosis. The RSDS mice further showed significant dysregulation of gut barrier functions, including transepithelial electrical resistance, mucin homeostasis, and antimicrobial responses. RSDS mice also showed a specific increase in intestinal expression of claudin-2, a tight junction protein, and epinephrine, a stress-induced neurotransmitter. Treating intestinal epithelial cells or 3-dimensional cultured crypts with norepinephrine or intestinal luminal contents (fecal contents) upregulated claudin-2 expression and inhibited transepithelial electrical resistance.

Conclusions

Traumatic stress induces dysregulation of gut barrier functions, which may underlie the observed gut microbiota changes and proinflammatory gut milieu, all of which may have an interdependent effect on the health and increased risk of comorbidities in patients with PTSD.

DOI Link

10.1016/j.bpsgos.2023.03.005

ISSN

2667-1743

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Yadav, Santosh K.; Ahmad, Rizwan; Moshfegh, Cassandra M.; Sankarasubramanian, Jagadesan; Joshi, Vineet A.; Elkhatib, Safwan K.; Chhonker, Yashpal S.; Talmon, Goeffrey A.; Guda, Chittibabu; Case, Adam; and Singh, Amar B., "Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis" (2023). Journal Articles: Cellular & Integrative Physiology. 47.
https://digitalcommons.unmc.edu/com_cell_articles/47