The beneficial effects of probiotic consumption on age-related decline in cerebral function have been previously reported in the literature; however, the mechanistic link between gut and brain interactions has not yet been fully elucidated. Therefore, this study aimed to identify the role of gut microbiota-derived metabolites in gut-brain interactions via blood metabolomic profiling analysis in clinical trials and in vitro mechanistic studies. A randomized, double-blind, placebo-controlled, multicenter clinical trial was conducted in 63 healthy elderly individuals (≥65 years of age). Participants were administered either placebo (placebo group, N = 31) or probiotic capsules (Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI; probiotics group, N = 32) for 12 weeks. Global and targeted metabolomic profiling analyses of their blood samples were then performed using ¹H nuclear magnetic resonance and liquid chromatography-mass spectrometry methods, both at baseline and at the end of the trial. Gut microbial analysis was conducted using the 16S ribosomal ribonucleic acid gene sequencing method. Subsequently, microglial BV2 cells were treated in vitro with indole-3-propionic acid (IPA) following lipopolysaccharide stimulation, and neuronal SH-SY5Y cells were treated with conditioned media from the BV2 cells. Finally, the levels of pro-inflammatory cytokines in BV2 cells and neurotrophins in SH-SY5Y cells were quantified using a real-time polymerase chain reaction or enzyme-linked immunosorbent assay. The metabolomic profiling analyses showed that probiotic consumption significantly altered the levels of metabolites involved in tryptophan metabolism (P < 0.01). Among these metabolites, gut microbiota-produced IPA had a 1.91-fold increase in the probiotics group (P < 0.05) and showed a significant relation to gut bacterial profiles (P < 0.01). Elevated IPA levels were also positively associated with the level of serum brain-derived neurotropic factor (BDNF) in the probiotics group (r = 0.28, P < 0.05), showing an inverse trend compared to the placebo group. In addition, in vitro treatment with IPA (5 μM) significantly reduced the concentration of proinflammatory TNF-α in activated microglia (P < 0.05), and neuronal cells cultured with conditioned media from IPA-treated microglia showed a significant increase in BDNF and nerve growth factor production (P < 0.05). These results show that gut microbiota-produced IPA plays a role in protecting the microglia from inflammation, thus promoting neuronal function. Therefore, this suggests that IPA is a significant mediator linking the interaction between the gut and the brain in the elderly with probiotic supplementation.

Gut microbiota have crucial effects on brain function via the gut–brain axis. Growing evidence suggests that this interaction is mediated by signaling molecules derived from dietary components metabolized by the intestinal microbiota. Although recent studies have provided a substantial understanding of the cell-specific effects of gut microbial molecules in gut microbiome–brain research, further validation is needed. This review presents recent findings on gut microbiota-derived dietary metabolites that enter the systemic circulation and influence the cell-to-cell interactions between gut microbes and cells in the central nervous system (CNS), particularly microglia, astrocytes, and neuronal cells, ultimately affecting cognitive function, mood, and behavior. Specifically, this review highlights the roles of metabolites produced by the gut microbiota via dietary component transformation, including short-chain fatty acids, tryptophan metabolites, and bile acid metabolites, in promoting the function and maturation of brain cells and suppressing inflammatory signals in the CNS. We also discuss future directions for gut microbiome–brain research, focusing on diet-induced microbial metabolite-based therapies as possible novel approaches to mental health treatment.

It has been suggested that probiotics have beneficial effects on a variety of health problems including immunologic diseases and metabolic disorders, however, the effects on brain function are yet to be fully studied. The aim of this study was to evaluate the association between probiotic food consumption and depression status through a cross-sectional analysis of a nationwide, large population-based data. The study population included 26 118 individuals 19 to 64 y of age who participated in the Korean National Health and Nutrition Examination Survey (KNHANES, 2012-2016). A food frequency questionnaire was used to assess probiotic food consumption. Depression status was determined by two different methods including a Patient Health Questionnaire (PHQ-9) and self-reported clinical diagnosis. Compared with the lowest tertile of probiotic food consumption, the highest tertile had significantly lower odds in PHQ-9 depression severity (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.28-0.81; P = 0.0065) and self-reported clinical depression (OR, 0.59; 95% CI, 0.35-0.96; P = 0.0129). Although there was no significant association between probiotic food consumption and clinical depression in women (OR, 0.85; 95% CI, 0.47-1.54; P = 0.3081), men showed a significantly lower prevalence of clinical depression (OR, 0.24; 95% CI, 0.06-0.92; P = 0.0256) in the highest tertile. These results suggest that probiotic food consumption might have beneficial effects on depression, particularly in men. Further studies are required to identify the mechanistic relations between probiotics and depression.

Gut microbiota is suggested to regulate the host’s mental health via the gut-brain axis. In this study, we investigated the relationship between the microbiome and psychological pain due to social exclusion. Adult individuals with (n = 14) and without (n = 25) social exclusion experience were assessed for the psychological status using self-reported questionnaires: Beck Anxiety Inventory (BAI), Beck Depression Inventory, and the UCLA Loneliness Scale. The gut microbiota was analyzed by 16 S rRNA gene sequencing and bioinformatics. The exclusion group had a 1.70-fold higher total BAI score and 2.16-fold higher levels of anxiety-related physical symptoms (p < 0.05). The gut microbial profiles also differed between the two groups. The exclusion group showed higher probability of having Prevotella-enriched microbiome (odds ratio, 2.29; 95% confidence interval, 1.65–2.75; p < 0.05), a significantly reduced Firmicutes/Bacteroidetes ratio, and decreased abundance of Faecalibacterium spp. (p < 0.05) which was associated with the duration and intensity of social exclusion (p < 0.05). Our results indicate that the psychological pain due to social exclusion is correlated with the gut microbiota composition, suggesting that targeting social exclusion-related microorganisms can be a new approach to solving psychological problems and related social issues.

Dietary fiber has been actively studied for its profound impacts on mental health by affecting the gut–brain axis communication. However, the association between dietary fiber intake and depression has been inconsistent, partly due to the lack of consideration of the fiber source. Therefore, this study aimed to examine the association between various sources of dietary fiber and depression in Korean adults through a nationwide cross-sectional study. The study population was a total of 2960 adults between 19 and 64 years of age who participated in the Korean National Health and Nutrition Examination Survey (KNHANES, 2012–2016). Dietary fiber intake from each fiber subtype (crude, cereal, vegetable, fruit, seaweed, and mushroom) was calculated using the Food Frequency Questionnaire (FFQ). Depression prevalence was assessed using a Patient Health Questionnaire (PHQ-9) and self-reported clinical diagnosis by a physician. We found that seaweed (odds ratio (OR) = 0.38; 95% confidence interval (CI): 0.20–0.72; p < 0.05) and mushroom fiber intake (OR = 0.18; 95% CI: 0.01–0.37; p < 0.05) were inversely associated with depressive symptoms assessed using the PHQ-9 parameters. Moreover, seaweed fiber intake was inversely associated with clinical depression diagnosed by a physician (OR = 0.45; 95% CI: 0.23–0.88; p < 0.05). This was the first study to find that higher intakes of seaweed and mushroom fiber were associated with a lower likelihood of depression in a representative cohort of Korean adults, indicating that the specific source of dietary fiber may be an important dietary factor in modulating depression.

Kim CS, et al. Nutr Res Pract. 2023 Oct;17(5):883-898. https://doi.org/10.4162/nrp.2023.17.5.883