Inflammation-driven brain and gut barrier dysfunction in stress and mood disorders

Abstract

Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs. resilience, and emotion-related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder, and post-traumatic stress disorder is increasing in our modern societies. Unfortunately, 30%-50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion-related biology to gain mechanistic insights that could lead to innovative therapies. Here, we provide an overview of inflammation-related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention, and thus, the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation-driven leakiness of the blood-brain and gut barriers in emotion regulation and mood are highlighted. Stress-induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut-brain axis which is central to production of mood-related neurotransmitter serotonin. Novel therapeutic approaches such as anti-inflammatory drugs, the fast-acting antidepressant ketamine, and probiotics could directly act on the mechanisms described here improving mood disorder-associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.

Keywords: PTSD; bipolar; blood-brain barrier; cytokine; depression; emotion; microbiome.

FIGURE 1

Blood‐brain barrier and intestinal barrier leakiness in stress and mood disorders. The blood‐brain barrier (BBB) is formed by endothelial cells, pericytes and astrocyte end‐feet ensheathing the capillary wall (a). The restricted permeability between endothelial cells of the BBB is maintained by junctional complexes, such as TJs, JAMs and adherens junctions (b). MDD, PTSD, and BD have all been associated with increased levels of circulating pro‐inflammatory cytokines, such as IL‐6, TNF‐α, and IL‐1β. These cytokines are trafficked to the brain through different transport mechanisms. Inflammation‐induced increase in VCAM‐1 and ICAM‐1 expression leads to downregulation of TJ gene expression and altered distribution at the endothelium. Together, these inflammation‐induced adaptations lead to increased BBB permeability (c). The gut barrier is formed by the mucosa, composed of an epithelial cell monolayer, a connective tissue layer, and the mucosal muscle (d). Epithelial cells maintain intestinal integrity through TJ and adherens junction complexes, desmosomes, and GAP junctions (e). Increased peripheral inflammation in mood disorders has been linked to increased TJ downregulation and redistribution, as well as decreased ZO expression through activation of the NF‐kB pathway (f). Moreover, MDD, PTSD, and BD are associated with dysbiosis, linked to increased intestinal permeability. Together, these mechanisms induce excessive bacterial translocation to the bloodstream and increased pro‐inflammatory cytokine production by gut‐associated lymphoïd tissue, exacerbating the dysbiosis‐induced inflammation (g). Abbreviations: JAM, junctional adhesion molecules; NF‐kB, nuclear factor kappa‐B; TJ, tight junctions; ZO, zona occludens

FIGURE 2

Effects of peripheral and central inflammation on emotion in stress and mood disorders (a–c.). PTSD, MDD, and BD have been associated with a shift toward a pro‐inflammatory profile in the periphery. However, in BD, the specific cytokines profiles have been found to shift between phases of the disease (d). Increased AMY activation concomitant with decreased volume was reported in PTSD patients vs. healthy controls and reduced hippocampal volume correlated to the severity of the symptoms, such as hypervigilance and memory deficits (e). Decreased volume and connectivity of emotion‐regulating brain regions, namely, the HIPP and the AMY, and increased expression of brain IL‐6, IL‐9, IL‐10, and IL‐12 were reported in MDD patients, possibly contributing to the emergence of symptoms (f). Finally, increased functional connectivity has been reported in BD patients between the mPFC‐HIPP and mPFC‐AMY, as well as decreased gray matter volume in the HIPP, suggesting that different immune and neurophysiological profiles could correlate with the different phases of the disease. Abbreviations: AMY, amygdala; BD, bipolar disorder; CNS, central nervous system; HIPP, hippocampus; IL, interleukin; MDD, major depressive disorder; mPFC, medial prefrontal cortex; PTSD, post‐traumatic stress disorder; sIL‐6R, soluble interleukin 6 receptor; TNF‐α, tumor necrosis factor alpha

FIGURE 3

Tryptophan metabolism alterations in stress and mood disorders. TRP is an essential amino acid involved in the metabolic pathways for serotonin and KYN. In the latter pathway, TRP is first metabolized by IDO1 to KYN. Pro‐inflammatory cytokines, such as IL‐6, TNF‐a, and IFN‐y (pink dots) increase IDO1 expression, thus the KYN pathway. Increased production of KYN metabolite KYNA and picolinic acid provides neuroprotective effects, while increased production of 3‐HK, 3‐OH‐anthranilic, acid and QUIN have neurotoxic effects (a). In stress and mood disorders, characterized by increased peripheral and central inflammation, TRP‐KYN pathway is favored. Macrophages in the periphery and microglia in the central nervous system metabolize TRP through the KYN pathway to QUIN, a potent NMDAR agonist, which increases glutamatergic neurotransmission and has been linked to depressive behaviors (b). Similarly, in the gut, increased stress‐induced inflammation promotes the metabolism of TRP in KYN, diverting serotonin production and contributing to TRP depletion. Serotonergic deficiency has been linked to gastrointestinal symptoms in mood disorders. Moreover, peripheral TRP depletion leads to central reduction in TRP and serotonin, an effect that is linked to mood symptoms in the disorders. Abbreviations: 3‐HK, 3‐OH‐kynurenine; IDO1, indoleamine 2,3‐dioxygenase‐1; KYN, kynurenine; KYNA, kynurenic acid; NMDAR, N‐methyl‐D‐aspartate receptor; QUIN: quinolinic acid; TRP, Tryptophan