Depression is considered a major public health concern, where existing pharmacological treatments are not equally effective across all patients. The pathogenesis of depression involves the interaction of complex biological components, such as the immune system and the microbiota‐gut‐brain axis. Adjunctive lifestyle‐oriented approaches for depression, including physical exercise and special diets are promising therapeutic options when combined with traditional antidepressants. However, the mechanisms of action of these strategies are incompletely understood. Accumulating evidence suggests that physical exercise and specific dietary regimens can modulate both the immune system and gut microbiota composition. Here, we review the current information about the strategies to alleviate depression and their crosstalk with both inflammatory mechanisms and the gut microbiome. We further discuss the role of the microbiota‐gut‐brain axis as a possible mediator for the adjunctive therapies for depression through inflammatory mechanisms. Finally, we review existing and future adjunctive strategies to manipulate the gut microbiota with potential use for depression, including physical exercise, dietary interventions, prebiotics/probiotics, and fecal microbiota transplantation.

Recent investigations in neuroscience implicate the role of microbial-derived metabolites, such as short-chain fatty acids (SCFAs) in brain health and disease. The SCFAs acetate, propionate and butyrate have pleiotropic effects within the nervous system. They are crucial for the maturation of the brain's innate immune cells, the microglia, and modulate other glial cells through the aryl-hydrocarbon receptor. Investigations in preclinical and clinical models find that SCFAs exert neuroprotective and antidepressant affects, while also modulating the stress response and satiety. However, many investigations thus far have not assessed the impact of sex on SCFA activity. Our novel investigation tested the impact of physiologically relevant doses of SCFAs on male and female primary cortical astrocytes. We find that butyrate (0–25 ​μM) correlates with increased Bdnf and Pgc1-α expression, implicating histone-deacetylase inhibitor pathways. Intriguingly, this effect is only seen in females. We also find that acetate (0–1500 ​μM) correlates with increased Ahr and Gfap expression in males only, suggesting immune modulatory pathways. In males, propionate (0–35 ​μM) correlates with increased Il-22 expression, further suggesting immunomodulatory actions. These findings show a novel sex-dependent impact of acetate and butyrate, but not propionate on astrocyte gene expression.

Polyphenols are phytochemicals that have been associated with therapeutic effects in stress-related disorders. Indeed, studies suggest that polyphenols exert significant neuroprotection against multiple neuronal injuries, including oxidative stress and neuroinflammation, but the mechanisms are unclear. Evidence indicates that polyphenol neuroprotection may be mediated by activation of Nrf2, a transcription factor associated with antioxidant and cell survival responses. On the other hand, in stress-linked disorders, Fkbp5 is a novel molecular target for treatment because of its capacity to regulate glucocorticoid receptor sensitivity. However, it is not clear the role Fkbp5 plays in polyphenol-mediated stress modulation. In this study, the neuroprotective effects and mechanisms of the naturally derived polyphenols xanthohumol and quercetin against cytotoxicity induced by corticosterone were investigated in primary cortical cells. Primary cortical cells containing both neurons and astrocytes were pre-incubated with different concentrations of quercetin and xanthohumol to examine the neuroprotective effects of polyphenols on cell viability, morphology, and gene expression following corticosterone insult. Both polyphenols tested prevented the reduction of cell viability and alterations of neuronal/astrocytic numbers due to corticosterone exposure. Basal levels of Bdnf mRNA were also decreased after corticosterone insult; however, this was reversed by both polyphenol treatments. Interestingly, the Nrf2 inhibitor blocked xanthohumol but not quercetin-mediated neuroprotection. In contrast, we found that Fkbp5 expression is exclusively modulated by quercetin. These results suggest that naturally derived polyphenols protect cortical cells against corticosterone-induced cytotoxicity and enhance cell survival via modulation of the Nrf2 pathway and expression of Fkbp5.

Background: Early life stress is a key predisposing factor for depression and anxiety disorders. Selective serotonin re-uptake inhibitors (SSRI) are frequently used as the first line of pharmacology treatment for depression but have several negative qualities, i.e. a delay or absence of effectiveness and negative side-effects. Therefore, there is a growing need for new nutraceutical-based strategies to blunt the effects of adverse-life events. Objectives: This study aimed to use the maternal separation model in rats to test the efficacy of fish oil dietary supplementation, on its own and in conjunction with the SSRI anti-depressant fluoxetine, as a treatment for depressive and anxiety-like symptoms associated with early life stress. Methods: Behavioural tests (open field test, elevated plus maze test and forced swim test) and biochemical markers (corticosterone, BDNF, brain fatty acids and short chain fatty acids) were used to analyse the effects of the dietary treatments. Gut microbial communities and relating metabolites (SCFA) were analysed to investigate possible changes in the microbiota-gut-brain axis. Results: Maternally separated rats showed depressive-like behaviours in the forced swim and open field tests. These behaviours were prevented significantly by fluoxetine administration and in part by fish oil supplementation. Associated biochemical changes reported include altered brain fatty acids, significantly lower plasma corticosterone levels (AUC) and reduced brain stem serotonin turnover, compared to untreated, maternally separated (MS) rats. Untreated MS animals had significantly lower ratios of SCFA producers such as Caldicoprobacteraceae, Streptococcaceae, Rothia, Lachnospiraceae_NC2004_group, and Ruminococcus_2, along with significantly reduced levels of total SCFA compared to non-separated animals. Compared to untreated MS animals, animals fed fish oil had significantly higher Bacteroidetes and Prevotellaceae and reduced levels of butyrate, while fluoxetine treatment resulted in significantly higher levels of Neochlamydia, Lachnoclostridium, Acetitomaculum and Stenotrophomonas and, acetate and propionate. Conclusion: Despite the limitations in extrapolating from animal behavioural data and the notable differences in pharmacokinetics between rodents and humans, the results of this study provide a further advancement into the understanding of some of the complex systems within which nutraceuticals and pharmaceuticals effect the microbiota-gut-brain axis.

Nutrition is a crucial component for maintenance of brain function and mental health. Accumulating evidence suggests that certain molecular compounds derived from diet can exert neuroprotective effects against chronic stress, and moreover improve important neuronal processes vulnerable to the stress response, such as plasticity and neurogenesis. Phospholipids are naturally occurring amphipathic molecules with promising potential to promote brain health. However, it is unclear whether phospholipids are able to modulate neuronal function directly under a stress-related context. In this study, we investigate the neuroprotective effects of phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylglycerol (PG), phosphatidic acid (PA), sphingomyelin (SM) and cardiolipin (CL) against corticosterone (CORT)-induced cytotoxicity in primary cultured rat cortical neurons. In addition, we examine their capacity to modulate proliferation and differentiation of hippocampal neural progenitor cells (NPCs).