NYMC Student Theses and Dissertations

Date of Award

5-23-2024

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Basic Medical Sciences

First Advisor

Esther Sabban

Abstract

Exposure to traumatic stress is a major risk factor for the development of mood disorders in a subpopulation of individuals, while others remain resilient. Notably, women are twice as likely as men to develop affective disorders in the aftermath of trauma. The mechanisms and contributing factors that influence sex-related disparities in mood disorders and variations in resilience remain unclear. We hypothesized that sex-specific inter-individual differences in microbial composition, functionality, and metabolites would contribute to host resilience or susceptibility to stress-induced psychopathologies. In this study, we used single prolonged stress (SPS), an animal model of Post- Traumatic Stress Disorder (PTSD), to characterize pre-existing and trauma-induced differences in microbial, immunological, and molecular factors of stress-susceptible and stress-resilient male and female rats. Additionally, we investigated whether the microbial metabolite acetate could ameliorate SPS-triggered behavioral and molecular impairments. In aims 1 and 2 two cohorts of male and female Sprague-Dawley rats were randomly assigned to unstressed controls or groups exposed to SPS. Two weeks after SPS, all rats underwent a battery of behavioral tests. Based on their anxiety measures, the animals in the SPS group were further subdivided into resilient (SPS-R) and susceptible (SPS-S) subgroups. After the last behavioral test, the rats were euthanized, and different organs were collected. Additionally, stool samples were collected from each rat before and after SPS, and urine samples were collected before and 30 min into the immobilization step of SPS. Comparative analysis of fecal 16S sequencing before and after SPS exposure indicated significant sex-specific and group differences in gut microbial composition, functionality, and metabolites of the SPS-R and SPS-S subgroups. Additionally, alterations in the sympathoadrenal axis, blood-brain barrier permeability, and neuroinflammation were evident, especially in the SPS-S subgroups of each sex compared to their respective SPS-R subgroups. Across the study, alpha diversity remained consistently lower in males compared to females. Beta diversity revealed distinct separations between male and female susceptible groups before SPS, with this separation becoming evident in resilient groups following SPS. At the genus level, Lactobacillus, Lachnospiracaeae_Incertae_Sedis, and Barnesiella exhibited sex-specific alterations, displaying opposing abundances in the SPS-R and SPS-S subgroups for each sex. In line with the alterations observed in the gut microbiota, the levels of cecal short-chain fatty acids (SCFA) were also different, with SPS-S females having significantly higher levels of branchedchain SCFAs, whereas SPS-S males had lower levels of acetate compared to their respective SPSR subgroups. Lower levels of cecal acetate were also inversely and significantly correlated with anxiety index. To further examine the anxiolytic properties of acetate, in aim 3 a separate cohort of male rats was divided into unstressed controls or SPS-exposed groups and received continued oral supplementation of either 150 mM sodium acetate or 150 mM sodium chloride-matched water. Oral supplementation with acetate ameliorated SPS-induced physiological and behavioral impairments, induced epigenetic modifications, inhibited neuroinflammation, and increased serum β-hydroxybutyrate levels without affecting unstressed controls. Collectively, our results indicate, for the first time, preexisting and trauma-induced differences in the gut microbial composition, functionality, and metabolites of male and female rats that relate to their ability to cope with traumatic stress. Further characterization of these factors will be crucial for understanding susceptibility and fostering resilience, especially in females, who are more likely than males to develop mood disorders. Additionally, by demonstrating a causal relationship between oral acetate treatment and the mitigation of several SPS-induced behavioral impairments, our study highlights the preventive therapeutic potential of acetate supplementation in alleviating adverse responses to traumatic stress.

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