Toward hybrid mental health care: an early health technology assessment based on stakeholder analysis and economic simulations.

Post-traumatic stress disorder (PTSD) is a heterogeneous psychiatric disease that may develop following exposure to a severe traumatic event (i.e., death or threatened death, actual or threatened serious injury, actual or threatened sexual violence) and is characterized by re-experiencing the event, avoidance of trauma-related cues, numbing, or hyperarousal. Alterations in neuroendocrine, psychophysiological, and neurobiological systems play a role in the etiology and maintenance of PTSD []. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-established biological feature of PTSD that results in altered cortisol/corticosterone (CORT) plasma levels, activity, and consequently in insufficient regulation of immune function and excessive inflammation [–]. An increasing number of studies have shown that individuals with PTSD exhibit significantly elevated blood levels of inflammatory markers, such as interleukin-1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNFα), and C-reactive protein []. The signaling network among the brain, spleen, and gut seems to represent an important interaction pathway impacting multiple aspects of immune functions and diseases. Changes in the spleen induced by stress are accompanied by alterations of immune cells, cytokine levels, and other molecules released into circulation and other organs in the body. Moreover, changes in the spleen’s immune cell activity appear to be linked with PTSD, too [, ]. The spleen is a primary source of T-lymphocytes producing interleukin 17 A (IL-17 A), which has emerged as a key player in the dysregulation of the immune system associated with PTSD. Human and animal PTSD studies point to increased plasma levels of inflammatory T helper 17 (Th17) cells, their main pro-inflammatory cytokine derivative IL-17 A, and the importance of neural and immune-derived adrenergic signaling in IL-17 A production from T-lymphocytes []. Moreover, it was shown that in PTSD patients, increased plasma IL-17 A levels and cluster of differentiation 4⁺ (CD4⁺) Th17 phenotypes correlate with PTSD severity []. Growing evidence reports gut microbiota alterations in individuals with PTSD [–]. Stress has been shown to cause imbalance in microbial composition, stimulate the intestinal epithelium to produce pro-inflammatory cytokines, and lead to altered permeability in the intestinal tract and excessive antigen trafficking and inflammation []. This “leaky gut syndrome” is associated with increased translocation of gut bacteria, which consequently reaches the liver, spleen, or other tissues. Microbial products like lipopolysaccharide (LPS) enter the bloodstream and trigger systemic inflammation, with the suggested role of the spleen in amplifying the immune responses. Thus, intestinal bacteria, individually, as consortia, as well as through their metabolites, modulate the immune response and thus contribute to the development and maintenance of PTSD symptoms [].