Psychobiotics and the Microbiota-Gut-Brain Axis: Where Do We Go from Here?

The bidirectional relationship between the gut microbiota and the nervous system is known as the microbiota-gut-brain axis (MGBA). The MGBA controls the complex interactions between the brain, the enteric nervous system, the gut-associated immune system, and the enteric neuroendocrine systems, regulating key physiological functions such as the immune response, sleep, emotions and mood, food intake, and intestinal functions. Psychobiotics are considered tools with the potential to modulate the MGBA through preventive, adjunctive, or curative approaches, but their specific mechanisms of action on many aspects of health are yet to be characterized. This narrative review and perspectives article highlights the key paradigms needing attention as the scope of potential probiotics applications in human health increases, with a growing body of evidence supporting their systemic beneficial effects. However, there are many limitations to overcome before establishing the extent to which we can incorporate probiotics in the management of neuropsychiatric disorders. Although this article uses the term probiotics in a general manner, it remains important to study probiotics at the strain level in most cases.

The Bioactive Dietary Polyphenol Preparation Alleviates Depression and Anxiety-Like Behaviors by Modulating the Regional Heterogeneity of Microglia Morphology.

SCOPE: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. METHODS AND RESULTS: The study finds that treatment with BDPP significantly decreases depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. The study also finds that BDPP treatment reverses microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. CONCLUSION: The findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway may provide a new avenue for preventing the manifestation of psychiatric impairments including stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

The bioactive dietary polyphenol preparation alleviates depression and anxiety-like behaviors by modulating the regional heterogeneity of microglia morphology.

Scope: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. Methods and results: We find that treatment with BDPP significantly decreased depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. We also find that BDPP treatment reversed microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. Conclusion: Our findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway might provide a new avenue for therapeutic intervention in stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.

Inflammasome-Mediated Neuronal-Microglial Crosstalk: a Therapeutic Substrate for the Familial C9orf72 Variant of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis.

Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly (GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS, we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1ß, and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits, and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

Changes in polyphenol serum levels and cognitive performance after dietary supplementation with Concord grape juice in veterans with Gulf War Illness.

AIMS: We investigated whether the consumption of Concord grape juice (CGJ) was associated with increased bioavailability of serum metabolites and their potential impact on cognitive performance in Veterans with Gulf War Illness (GWI). MAIN METHODS: Twenty-six veterans were selected from a cohort of 36 enrolled in a 24-week randomized, double-blind, Phase I/IIA clinical trial exploring whether the consumption of Concord grape juice (CGJ) was tolerable and safe in Veterans with GWI and improved cognitive function and fatigue. These 26 veterans were selected based on their completion of the entire 24-week protocol and documented adherence to the study beverage ≥80%. Differences in serum metabolite levels between CGJ and placebo at midpoint and endpoint were evaluated using two-way repeated measures ANOVA with post hoc Sidak's multiple comparison test. Bivariate correlations to assess for possible relationships between change in serum metabolite levels and change in cognitive function as measured by the Halstead Category Test-Russell Revised Version (RCAT) were also conducted. KEY FINDINGS: Seventy-six metabolites were identified and quantified in this study, with three (cyanidin-glucuronide, me-cyanidin-glucuronide, and me-malvidin-glucuronide) found to be significantly higher (p < 0.05) in the CGJ group compared to placebo at 24 weeks. Significant associations between changes in cognitive function and changes in serum levels of epicatechin-sulphate (r = 0.48, p = 0.01) and petunidin-glucuronide (r = 0.53, p < 0.01) from baseline to 24 weeks were also observed. SIGNIFICANCE: Our data suggest that dietary supplementation with CGJ is associated with increased bioavailability of specific phenolic metabolites, some of which may be correlated with cognitive performance.

Anxiolytic effects of NLRP3 inflammasome inhibition in a model of chronic sleep deprivation.

Sleep deprivation is a form of stress that provokes both inflammatory responses and neuropsychiatric disorders. Because persistent inflammation is implicated as a physiological process in anxiety disorders, we investigated the contributions of NLRP3 inflammasome signaling to anxiety and anxiolytic properties of flavanol diets in a model of chronic sleep deprivation. The results show a flavanol-rich dietary preparation (FDP) exhibits anxiolytic properties by attenuating markers of neuroimmune activation, which included IL-1ß upregulation, NLRP3 signaling, and microglia activation in the cortex and hippocampus of sleep-deprived mice. Production of IL-1ß and NLRP3 were critical for both anxiety phenotypes and microglia activation. Individual FDP metabolites potently inhibited IL-1ß production from microglia following stimulation with NLRP3-specific agonists, supporting anxiolytic properties of FDP observed in models of sleep deprivation involve inhibition of the NLRP3 inflammasome. The study further showed sleep deprivation alters the expression of the circadian gene Bmal1, which critically regulated NLRP3 expression and IL-1ß production.

Novel microencapsulated probiotic blend for use in metabolic syndrome: design and in-vivo analysis.

The increasing prevalence of the metabolic syndrome has made it a medical issue that currently affects 1 in 5 Canadians. The metabolic syndrome is defined by risk factors that predispose an individual to diabetes and cardiovascular disease. Current forms of interventions have been inadequate as substantiated by the fact that the prevalence of metabolic syndrome has not reduced over the years. The objective of this study was to investigate the therapeutic benefits of a novel microencapsulated probiotic blend in treating the metabolic syndrome. Three probiotic strains were microencapsulated into alginate-polylysine-alginate (APA) microcapsules: L. rhamnosus NCIMB 6375, L. plantarum NCIMB 8826 and L. fermentum NCIMB 5221. From the results, it was observed that the microencapsulated probiotic blend significantly reduced serum total cholesterol, LDL cholesterol and triglyceride levels (reducing from 516 mg/dL to 379 mg/dL, 314 mg/dL to 231 mg/dL and 580 mg/dL to 270 mg/dL, respectively). In addition, the administration of the microencapsulated probiotic blend was found to favourably influence the gut microbiota, decreasing Firmicutes levels and increasing Bacteroidetes levels. Overall, this work demonstrates the potential a microencapsulated probiotic blend could have in targeting multiple risk factors of the metabolic syndrome; however, greater research is still needed.