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.

Dysimilarities In The Gut Metabolome Of Rabbits With Genetic Differences In Their Resilient Potential

“…As AAA metabolism can control health and disease [37] 1) in individuals under stress with in ammation [42], which agrees with the higher levels of CRP (an in ammation biomarker) identi ed in the non-resilient animals [11]. As the animals were sacri ced after their rst parity, these results could pinpoint higher susceptibility to stress in the non-resilient animals.…”

Revisiting the seven pillars of RDoC

“…New discoveries linking other biological systems to behavior and psychiatric symptoms present expanded opportunities in the mind-body space. For example, new understanding about how immune and inflammatory processes relate to a wide spectrum of psychiatric symptoms via central-peripheral interactions informs models that link experiential and environmental factors such as stress to changes in the blood-brain barrier and gut permeability, impacting cognition and mood [ 74 ]. The importance of development to these processes is reflected in data showing that depleting the gut microbiota in rodents leads to persistent effects on neuronal function and learning-related plasticity involved in fear-related behaviors and that restoring the microbiota reversed these effects — but only when the restoration was done during the neonatal period [ 75 ].…”

The Effects of Stress and Diet on the “Brain–Gut” and “Gut–Brain” Pathways in Animal Models of Stress and Depression

“…Furthermore, the neuroinflammation in the reported studies associated with chronic activation of the HPA axis may be due to impaired intestinal barrier integrity inducing systemic inflammation and exposing the brain to inflammatory cytokines (see Section 3.2.1 Intestinal Barrier Integrity Pathways). Although beyond the scope of this review, this vulnerable state of the brain during stress is brought about by direct modulation of the blood-brain barrier by inflammatory cytokines derived from the central immune system and microglia, a process well-described in the review by Doney et al [44]. Another explanation may be due to increased neurotoxicity driven by increased output from the neurotoxic branch of the kynurenine pathway (see Section 3.1.3 Serotonin and Tryptophan Pathways).…”