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. 2022 Mar 1:12:810815.
doi: 10.3389/fcimb.2022.810815. eCollection 2022.

Acute and Delayed Effects of Stress Eliciting Post-Traumatic Stress-Like Disorder Differentially Alters Fecal Microbiota Composition in a Male Mouse Model

Allison Hoke  1   2 , Nabarun Chakraborty  2 , Aarti Gautam  2 , Rasha Hammamieh  2 , Marti Jett  2
Affiliations

Acute and Delayed Effects of Stress Eliciting Post-Traumatic Stress-Like Disorder Differentially Alters Fecal Microbiota Composition in a Male Mouse Model

Allison Hoke et al. Front Cell Infect Microbiol. .

Abstract

The association between the shift in fecal resident microbiome and social conflicts with long-term consequences on psychological plasticity, such as the development of post-traumatic stress disorder (PTSD), is yet to be comprehended. We developed an aggressor-exposed (Agg-E) social stress (SS) mouse model to mimic warzone-like conflicts, where random life-threatening interactions took place between naïve intruder mice and aggressive resident mice. Gradually these Agg-E mice developed distinct characteristics simulating PTSD-like aspects, whereas the control mice not exposed to Agg-E SS demonstrated distinct phenotypes. To further investigate the role of Agg-E SS on the resident microbiome, 16S rRNA gene sequencing was assayed using fecal samples collected at pre-, during, and post-SS time points. A time agonist shift in the fecal microbial composition of Agg-E mice in contrast to its controls suggested a persistent impact of Agg-E SS on resident microbiota. At the taxonomic level, Agg-E SS caused a significant shift in the time-resolved ratios of Firmicutes and Bacteroidetes abundance. Furthermore, Agg-E SS caused diverging shifts in the relative abundances of Verrucomicrobia and Actinobacteria. An in silico estimation of genomic potential identified a potentially perturbed cluster of bioenergetic networks, which became increasingly enriched with time since the termination of Agg-E SS. Supported by a growing number of studies, our results indicated the roles of the microbiome in a wide range of phenotypes that could mimic the comorbidities of PTSD, which would be directly influenced by energy deficiency. Together, the present work suggested the fecal microbiome as a potential tool to manage long-term effects of social conflicts, including the management of PTSD.

Keywords: C57BL/6J; PTSD; microbiome; social defeat; stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overall Experimental Strategy. Agg-E SS C57BL/6J male mice were exposed to trained aggressor SJL mice for 6-hours/day in a “cage-within-cage” model. Fecal pellets were collected at Baseline, Day 6 and Day 10 during the Agg-E SS, and at Week 1 and Week 4 post-SS from Agg-E SS and control mice, and stored at -80°C. Ileum samples were collected at Week 4 post-SS. (Ctrl, control; Agg-E, aggressor-exposed; SS, social stress; light blue, daily 6-hour/day Agg-E SS; dark blue, control mice undergoing “cage-within-cage” 6-hour/day but no Agg-E SS; white, no “cage-within-cage” or Agg-E SS).
Figure 2
Figure 2
Beta diversity and abundance of phyla. (A) Beta diversity metric Weighted UniFrac Principal Coordinate Analysis (PCoA) plot of Control (○) and Agg-E SS (▪) samples. (2-way PERMANOVA: Stress p < 0.001, Time p < 0.05). (B) Percent abundance of phylum Verrucomicrobia. (2-way ANOVA: Time p = 0.06, Stress p < 0.001) (C) Percent abundance of phylum Actinobacteria. (2-way ANOVA: Stress p < 0.05). (D) Percent abundance of the summation of phyla Verrucomicrobia and Actinobacteria. (2-way ANOVA: Stress p < 0.05) (Agg-E SS, aggressor-exposed social stress mice, #p-value: 0.1<# < 0.05, *p-value < 0.05, **p-value < 0.01. white bars, control; dark gray bars, Agg-E SS). The whiskers represent the minimum and maximum values.
Figure 3
Figure 3
Significant taxonomy cladograms, Agg-E SS vs Control, normalized by baseline. Deseq2 analysis of taxonomic ASVs were fed into Linear discriminant analysis effect size (LEfSe) to generate cladograms to graphically represent the significant taxa in their taxonomic tree; LEfSe was not used for analysis. (A) Day 10: Acute Stress. (B) Week 1: Post-stress. (C) Week 4: Post-stress. (D) Significant taxa at time points for Agg-E SS versus Control mice, normalized by baseline from Deseq2 (padj < 0.1). Taxa exclusive to a particular time point are listed above the center timeline, whereas taxa in common between time points are listed below the timeline. (light red, decreased abundance in Agg-E SS; light green, increased abundance in Agg-E SS; Agg-E SS, aggressor-exposed social stress; Ctrl, control).
Figure 4
Figure 4
Significant pathways between Agg-E SS vs Control mice, normalized by baseline from Deseq2 (padj < 0.1). Those pathways exclusive to a particular time point are listed above the center timeline, whereas pathways in common between time points are listed below the timeline (light red, inhibited in Agg-E SS; light green, activated in Agg-E SS; Agg-E SS, aggressor-exposed social stress).
Figure 5
Figure 5
Intestinal Permeability Markers Fold Change at Week 4 post-stress in Aggressor-exposed social stress ileal samples. The qPCR for intestinal permeability markers were normalized by the housekeeping genes, and fold change of each Agg-E SS sample expression relative to the expression in healthy controls was calculated by the 2^(-ΔΔCt) method. Error bars are mean with the SEM (Standard Error of Mean). (#p-value 0.1<#<0.05, *p-value<0.05, **p-value<0.01).
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References

    1. Aguayo FI, Pacheco A., García-Rojo G. J., Pizarro-Bauerle J. A., Doberti A. V., Tejos M., et al. . (2018). Matrix Metalloproteinase 9 Displays a Particular Time Response to Acute Stress: Variation in its Levels and Activity Distribution in Rat Hippocampus. ACS Chem. Neurosci. 9 (5), 945–956. doi: 10.1021/acschemneuro.7b00387 - DOI - PubMed
    1. Al-Sadi R., Youssef M., Rawat M., Guo S., Dokladny K., Haque M., et al. . (2019). MMP-9-Induced Increase in Intestinal Epithelial Tight Permeability is Mediated by P38 Kinase Signaling Pathway Activation of MLCK Gene. Am. J. Physiol. Gastrointest Liver Physiol. 316 (2), G278–G290. doi: 10.1152/ajpgi.00126.2018 - DOI - PMC - PubMed
    1. Amir A., McDonald D., Navas-Molina J. A., Kopylova E., Morton J. T., Zech Xu Z., et al. . (2017). Deblur Rapidly Resolves Single-Nucleotide Community Sequence Patterns. mSystems 2 (2), e00191–16. doi: 10.1128/mSystems.00191-16 - DOI - PMC - PubMed
    1. Anderson M. J. (2001). A New Method for non-Parametric Multivariate Analysis of Variance. Austral Ecol. 26, 32–46. doi: 10.1111/j.1442-9993.2001.01070.pp.x - DOI
    1. Auxemery Y. (2018). Post-Traumatic Psychiatric Disorders: PTSD is Not the Only Diagnosis. Presse Med. 47 (5), 423–430. doi: 10.1016/j.lpm.2017.12.006 - DOI - PubMed

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