Investigating the gut and the heart in PTSD-like mice

Post-traumatic stress disorder (PTSD) is associated with increased risk for cardiovascular disease, but the mechanism is unclear. Using the inescapable foot shock (IFS) model, our lab showed mice that demonstrated PTSD-like behaviors had cardiovascular complications. Research has exhibited a strong connection between cardiovascular and intestinal health, linking the gut microbiome to cardiovascular disease. Whether the gut plays a role in PTSD-induced cardiovascular pathology has largely not been studied. We hypothesize that PTSD-induced changes to the gut microbiome stimulate adverse cardiac remodeling. To induce experimental PTSD, male and female C57BL/6J mice (n=3-6/group) were placed in chambers where they were exposed to 5 random foot-shock incidences (IFS; 1.0 mA, 1 sec duration) in 6 min. Behavioral testing designed to mimic the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was performed to characterize mice as non-responders (NR; do not demonstrate PTSD-like characteristics) and PTSD-like. Control mice were also placed in IFS chambers for the same duration but without foot shocks. Stool pellets were serially collected at baseline (pre-IFS), 4-weeks, and 8-weeks post-IFS, and gDNA was isolated and analyzed via 16S sequencing, to identify potential shifts in the gut microbiota. Sex differences were observed at the species level at 8-weeks post-IFS despite no significant differences at the phyla and class levels. Notably, the abundance of Akkermansia muciniphila was increased (p=0.015) and Allobaculum sp was decreased (p=0.031) in PTSD males compared to controls. To assess whether these microbiome differences were accompanied by changes in gut architecture, intestinal barriers were assessed via fluorescein isothiocyanate (FITC) dextran oral gavage and histological staining of the small and large intestine. Quantification of staining demonstrated male PTSD had shorter crypts (p=0.001) and a trend towards shorter villi (p=0.104) compared to control. Further assessment of the intestines using PCR suggested differences in serotonin production as male PTSD mice had a 2-fold decrease in Tph-1 compared to control (p=0.023) and a 5-fold decrease compared to female PTSD mice (p=0.001) in the small intestine. In conclusion, these data indicate that changes in the gut microbiome of male PTSD mice were accompanied by changes in gut architecture and Tph-1 expression. These findings lay the foundation for future studies on the gut-heart axis in PTSD, as serotonin plays a significant role in contraction and relaxation of the heart. This work was supported by the National Institutes of Health R25GM072643, T32GM1523862, F31HL170740, T32GM123055, HL173273; the American Heart Association 24PRE1188095; the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award I01BX00584; and South Carolina Translational Research Center UL1TR001450 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.