The gut-microbiota's role in brain processes, mental health, and cognitive function has spurred interest in manipulating the microbiota to benefit brain function. The term "psychobiotic" describes interventions impacting the brain via bacteria. Probiotics and prebiotics show promise as psychobiotic agents. Diet significantly influences microbiota composition and function, with links between healthy dietary patterns and reduced mental illness risk. Studies on single foods show promise, but whole dietary approaches are more realistic for developing psychobiotic interventions. Animal models suggest microbiota-mediated mechanisms (immune system, HPA axis, tryptophan metabolism) underlie the diet-brain connection. However, human studies are limited, with most clinical trials focusing on diet's impact on anxiety, depression, or cognition without exploring microbiota changes. A few studies show promise in improving mental health or cognition using microbiota-targeted diets, such as increasing dietary fiber, vegetable dishes, and milk products which shifted the microbiota composition to higher abundance of beneficial microbes and decreased depression score in obese females, and improvement in global cognition and episodic memory in the elderly population following adherence to the Mediterranean diet. This study aimed to investigate a whole-diet psychobiotic approach's potential to modulate microbiota composition and function, influence stress responses, and improve mood in a healthy population.

Existing research highlights the gut-brain axis and its connection to mental health. Studies using probiotics and prebiotics as psychobiotics have shown promising results in both animal and human studies. The significant influence of diet on the gut microbiome composition and function is well established, with a growing body of evidence linking dietary patterns to mental health outcomes. While studies focusing on individual foods offer valuable insights, a more holistic approach considering the synergistic effects of various food groups is needed. Animal studies provide clues about the potential mechanisms, such as immune system modulation, HPA axis influence, and tryptophan metabolism. However, robust human trials are scarce, with most lacking detailed microbiota analysis. A few studies examining microbiota-targeted dietary approaches demonstrate potential benefits for mental health, but further evidence is needed to confirm these findings and translate them into clinical practice. This study aimed to address this gap by investigating the effects of a comprehensive psychobiotic diet on both microbiota and mental health.

This single-blind, randomized, controlled trial involved 45 healthy adults (18-59 years) from Cork, Ireland, recruited between February 2018 and March 2019. Participants were randomized to either a psychobiotic diet group (n=24) or a control group (n=21) for four weeks. The psychobiotic diet emphasized whole grains, prebiotic fruits and vegetables, fermented foods, and legumes, while limiting unhealthy foods. Dietary intervention involved an initial 30-minute education session and a 15-minute refresher session with a registered dietitian. Dietary intake was assessed using 7-day food records and a food frequency questionnaire. The control group received similar education sessions but focused on general dietary guidelines. Baseline and post-intervention assessments included questionnaires (Cohen's Perceived Stress Scale (PSS), Bristol Stool Chart, Pittsburgh Sleep Quality Index (PSQI), etc.) and biological sample collection (fecal, blood, urine, saliva). Fecal microbiota composition and function were analyzed using shotgun sequencing, and metabolic profiling was performed on plasma, urine, and fecal samples. Statistical analyses included linear mixed effect models, regression analyses, and appropriate non-parametric tests. Bioinformatics analyses employed FastQC, Trimmomatic, Bowtie2, MetaPhlAn3, and HUMAnN3 for microbiota data processing.

The psychobiotic diet significantly reduced perceived stress (32% vs. 17% in the control group), with higher diet adherence correlating with stronger stress reduction. While the diet induced only subtle changes in gut microbiota composition and function, significant alterations were observed in 40 fecal lipids and 13 urinary tryptophan metabolites in the psychobiotic group. Microbial stability (lower volatility) was positively correlated with greater stress reduction in the psychobiotic diet group. Both groups showed improved bowel habits and sleep quality, but the improvement in subjective sleep quality was statistically significantly greater in the psychobiotic group. No significant changes in cortisol awakening response or immune markers were observed.

The study demonstrates that a psychobiotic diet can effectively reduce perceived stress in healthy adults. The positive correlation between diet adherence and stress reduction highlights the importance of consistent implementation. The lack of substantial changes in microbiota composition suggests that the observed effects may be mediated by other mechanisms, such as changes in fecal lipids and urinary tryptophan metabolites. Alterations in tryptophan metabolism, specifically the reduction of quinolinic acid, are noteworthy, given its potential neurotoxic effects. Changes in fecal lipids could also be related to mood regulation. However, further research is needed to establish causal relationships and determine the precise mechanisms underlying the observed effects. Limitations include the relatively small sample size due to the COVID-19 pandemic, the short intervention duration, and potential limitations in dietary assessment.

This study provides preliminary evidence supporting the use of psychobiotic diets to reduce perceived stress. The significant impact of diet adherence and the observed metabolic changes warrant further investigation. Future research should focus on larger, longer-term studies to confirm these findings, explore underlying mechanisms, and assess the effects in populations with pre-existing mental health conditions. Additional research is needed to determine the optimal composition of psychobiotic diets and to identify potential biomarkers for predicting individual responses.

The study's sample size was limited due to the COVID-19 pandemic, potentially impacting the generalizability of findings. The short four-week intervention duration may not have allowed for maximal microbiota and metabolic changes. Self-reported dietary data and the nature of the nutritional education could introduce some bias and measurement error. The study population consisted of healthy individuals; therefore, extrapolating results to populations with pre-existing mental health conditions requires caution.