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Effect of Mediterranean diet on mental health outcomes: a systematic review.
Growing evidence has linked both the onset and symptoms of various mental disorders to lifestyle factors such as diet, exercise and sleep. The link between diet and mental health, in particular in depressive disorders, has gained interest in recent years. Previous reviews assessing the link between the Mediterranean diet (MedDiet) and mental health predominantly focused on depression, whilst others failed to integrate a summary of possible underlying mechanisms related to a link between MedDiet and mental health to complement their findings. In the present review, we provide a comprehensive synthesis of evidence on the MedDiet and diverse mental health outcomes complemented by narration of the potential mechanisms involved. A literature search was conducted across MEDLINE, PsycINFO, Scopus, Cochrane library, Google Scholar, CINAHL and Embase databases. A total of 10 249 articles were found through the primary literature search and 104 articles (88 observational and 16 interventional studies) were eligible for inclusion. The MedDiet has been associated with favourable mental health outcomes in adult populations, including reduced depressive and anxiety symptoms, lower perceived stress, and improved quality of life and overall wellbeing, both in healthy individuals and those with comorbidities, across diverse geographical settings. Mechanisms involved include the antioxidant, anti-inflammatory potential of the MedDiet and its effect on gut microbiota. Further research is warranted to rigorously establish causal inferences and to guide the optimal incorporation of Mediterranean diet principles into comprehensive prevention and treatment strategies aimed at improving mental health outcomes.
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Resilience and immunity.
Resilience is the process that allows individuals to adapt to adverse conditions and recover from them. This process is favored by individual qualities that have been amply studied in the field of stress such as personal control, positive affect, optimism, and social support. Biopsychosocial studies on the individual qualities that promote resilience show that these factors help protect against the deleterious influences of stressors on physiology in general and immunity in particular. The reverse is also true as there is evidence that immune processes influence resilience. Most of the data supporting this relationship comes from animal studies on individual differences in the ability to resist situations of chronic stress. These data build on the knowledge that has accumulated on the influence of immune factors on brain and behavior in both animal and human studies. In general, resilient individuals have a different immunophenotype from that of stress susceptible individuals. It is possible to render susceptible individuals resilient and vice versa by changing their inflammatory phenotype. The adaptive immune phenotype also influences the ability to recover from inflammation-induced symptoms. The modulation of these bidirectional relationships between resilience and immunity by the gut microbiota opens the possibility to influence them by probiotics and prebiotics. However, more focused studies on the reciprocal relationship between resilience and immunity will be necessary before this can be put into practice.
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The dual-sensitive period gut-brain crosstalk, neuroinflammation, and the biological roots of adolescent depression.
The increasing burden of adolescent depression underscores the need to identify developmental vulnerabilities and biologically informed strategies for prevention and intervention. This review synthesizes evidence supporting adolescence as a "dual-sensitive period" during which concurrent maturation of the brain and gut microbiota may create a window of susceptibility to perturbations of the microbiota-gut-brain axis (MGBA). During this stage, dysregulated gut-brain communication may contribute to low-grade inflammation, impaired barrier function, altered HPA-axis responsivity, and changes in tryptophan-, short-chain fatty acid-, and neurotransmitter-related metabolism. In particular, inflammatory signaling and microglial activation may link gut dysbiosis to maladaptive synaptic remodeling, although direct causal evidence in adolescents remains limited. The review also examines the "microgenderome" framework as a lens for understanding potential sex-related differences in depression, and considers environmental exposures such as diet, antibiotics, and sleep disruption as perturbing influences on MGBA homeostasis. Translationally, psychobiotics, dietary optimization, and related microbiota-informed approaches may hold promise as adjunctive or preventive strategies, but they are not yet established standalone treatments for adolescent depression. Future studies integrating longitudinal design, multi-omics profiling, biomarkers, and adolescent-specific intervention trials will be essential to clarify causality and guide precision prevention.
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Evaluation of antibiotic-induced behavioral changes in mice.
Gut microbiota (GM) plays a critical role in health maintenance. Previous reports connected GM with metabolic, immunologic and neurologic pathways. The main purpose of the current investigation was to study whether antibiotic-induced disturbances of GM affects psychological or behavioral conditions on mice as animal model. Mice were exposed to clindamycin or amoxicillin, and their behaviors were evaluated. Antibiotic-treated groups displayed reduced recognition memory and increased depression. No significant changes in the locomotor activity and anxiety were observed. Our data suggested that changes in GM composition by antibiotics may lead to the cognitive and behavioral deficit.
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Effects of Fermented Milk Containing Lacticaseibacillus paracasei Strain Shirota on Constipation in Patients with Depression: A Randomized, Double-Blind, Placebo-Controlled Trial.
Probiotics have been shown to benefit patients with constipation and depression, but whether they specifically alleviate constipation in patients with depression remains unclear. The aim of this study was to investigate the effect of Lacticaseibacillus paracasei strain Shirota (LcS), formerly Lactobacillus casei strain Shirota, on constipation in patients with depression with specific etiology and gut microbiota and on depressive regimens. Eighty-two patients with constipation were recruited. The subjects consumed 100 mL of a LcS beverage (108 CFU/mL) or placebo every day for 9 weeks. After ingesting beverages for this period, we observed no significant differences in the total patient constipation-symptom (PAC-SYM) scores in the LcS group when compared with the placebo group. However, symptoms/scores in item 7 (rectal tearing or bleeding after a bowel movement) and items 8-12 (stool symptom subscale) were more alleviated in the LcS group than in the placebo group. The Beck Depression Index (BDI) and Hamilton Depression Rating Scale (HAMD) scores were all significantly decreased, and the degree of depression was significantly improved in both the placebo and LcS groups (p < 0.05), but there was no significant difference between the groups. The LcS intervention increased the beneficial Adlercreutzia, Megasphaera and Veillonella levels and decreased the bacterial levels related to mental illness, such as Rikenellaceae_RC9_gut_group, Sutterella and Oscillibacter. Additionally, the interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) levels were significantly decreased in both the placebo and LcS groups (p < 0.05). In particular, the IL-6 levels were significantly lower in the LcS group than the placebo group after the ingestion period (p < 0.05). In conclusion, the daily consumption of LcS for 9 weeks appeared to relieve constipation and improve the potentially depressive symptoms in patients with depression and significantly decrease the IL-6 levels. In addition, the LcS supplementation also appeared to regulate the intestinal microbiota related to mental illness.
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A study on the efficacy and safety of fecal microbiota transplantation as an adjunctive therapy for treating depressive episodes.
This study aimed to evaluate the efficacy and safety of fecal microbiota transplantation (FMT) as an adjunctive therapy for depressive episodes. This study recruited 46 participants aged 18–65 from January 2022 to December 2023 who were diagnosed with depression according to the International Classification of Diseases, 10th edition. They were randomly divided into two groups to receive different treatments, including FMT combined with medication group (test group, n = 23) and the medication-only group (control group, n = 23). Assessments were performed before and two weeks after treatment. Ten predominant gut microbiota species were analyzed, and the Hamilton’s Depression Scale-24(HAMD-24) was used to evaluate depressive symptoms. Adverse events related to treatment were assessed using an adverse event scale and laboratory tests. The main evaluation indicators included the reduction rate of HAMD-24 scores, treatment efficacy rate, and changes in the indicators of the ten predominant intestinal bacteria before and after transplantation. Safety assessment indicators included adverse events, blood routine, biochemistry, electrocardiogram, immunological parameters (immunoglobulins and complement), hypersensitive C-reactive protein(hs-CRP), thyroid function, and glycated hemoglobin. The rank-sum test was performed to compare differences in microbiota before and after FMT treatment. The relationship between gut microbiota and depression severity was examined by means of correlation analysis. The baseline HAMD-24 scores showed no significant difference between the test and control groups (P > 0.05). After two weeks treatment, the reduction in HAMD-24 scores (P = 0.048) and the HAMD-24 reduction rate (P = 0.016) were significantly higher in the test group than control group (P < 0.05). Following FMT treatment, Enterococcus, Lactobacillus, Bifidobacterium, and Butyricicoccus levels significantly increased compared to baseline (P < 0.05). Linear discriminant analysis(LDA) revealed a significant post-treatment increase in Enterococcus relative abundance (P = 0.02). In the test group, baseline-enriched Clostridium prausnitzii (P = 0.040), Butyricicoccus (P = 0.029), and Eubacterium rectale (P = 0.004) showed significant negative correlations with HAMD-24 scores, whereas post-treatment Enterococcus was correlated with HAMD-24 scores (P = 0.030). Adverse event incidence was 28.6% in the test group and 30% in the control group, with no significant difference (P = 0.928). Reported discomforts during FMT treatment—nausea, vomiting, and nasopharyngeal discomfort—were mild and self-resolving, with no serious adverse events observed. The administration of FMT as an adjunctive therapy demonstrates superior improvement in depressive symptoms and is deemed safe with no apparent adverse reactions. There was no change in the composition of gut microbiota structure before and after FMT in patients with depression. Enterococcus showed a significant relative abundance increase in the gut after FMT. The post-treatment Enterococcus was correlated with HAMD-24 scores.
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Xiaoyao Pill Regulates Gut Microbiota and Tryptophan Metabolism to Alleviate Depression Induced by Chronic Stress in Rats.
OBJECTIVE: To investigate the antidepressant effects of Xiaoyao Pill (XYP) by exploring its interactions with gut microbiota and tryptophan metabolism. METHODS: Utilizing network pharmacology, the functional substance groups, key targets, and pathways of XYP in the treatment of depression were identified. The chronic unpredictable mild stress (CUMS) protocol was implemented in male Sprague-Dawley rats to establish depression model. Thirty rats were randomly divided into 3 groups according to their body weight (10 for each): control, CUMS and XYP groups (1.8 g/kg). After 28-day interventions, behavioral phenotyping including sucrose preference test (SPT) and open field test (OFT) were performed. Biochemical validation encompassed enzyme-linked immunosorbent assay for serum cortisol, hematoxylin-eosin histopathology, and immunohistochemistry. Liquid chromatography-mass spectrometry was utilized to profile serum metabolites, while fecal samples underwent metagenomic sequencing for gut microbiota characterization. RESULTS: Network pharmacology studies predicted that key components can protect the nervous system by regulating inflammatory pathways through the blood-brain barrier. SPT and OFT showed that XYP treatment significantly ameliorated depressive-like behaviors (all P<0.05). XYP treatment also restored hippocampal neuronal density, increased serum neurotransmitter levels of neurotransmitters such as 5-hydroxytryptamine and vasoactive intestinal peptide, and while suppressing inflammatory markers such as tumor necrosis factor-alpha, interleukin-1 beta (IL-1 β), and IL-6 (all P<0.05). Metagenomics revealed significant restructuring of gut microbiota, notably the regulation of Parabacteroides distasonis (P<0.05). Non-targeted metabolomics analysis showed that the level of metabolites in the tryptophan and kynurenine pathway significantly changed (variable importance in the projection >1, P<0.05), and the change of metabolic flux was significantly correlated with behavioral improvement (P<0.05). CONCLUSIONS: XYP exerts antidepressant effects by increasing neurotransmitter levels, reducing inflammatory makers and modulating Parabacteroides distasonis. Through further exploration of metabolomics, we found that XYP may play a protective role in depression by regulating tryptophan metabolism.
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Chronic Exposure to Environmentally Relevant Doses of Triphenyl Phosphate Induces Anxiety- and Depression-Like Behaviors in Mice via the Gut-Brain Axis.
Triphenyl phosphate (TPHP) is an emerging endocrine-disrupting chemical that has been widely used as a flame retardant. Although the neurotoxicity of TPHP to aquatic animals had been highlighted in previous studies, its effects on mammals, particularly at environmentally relevant doses (ERDs), have remained largely unknown. In this study, a 28-week mouse model was established to investigate the potential neurotoxicity induced by ERDs of TPHP (0.89 and 9.19 μg/kg/day). The mechanisms underlying gut-brain axis communication were explored using behavioral tests, 16S rRNA sequencing, and multiomics analysis. The results demonstrated that chronic exposure to an ERD of TPHP (9.19 μg/kg/day) significantly reduced the abundance of Lactobacillus in the gut microbiota of mice and led to an increase in pro-inflammatory bacterium. These alterations activated the NF-κB signaling pathway in the prefrontal cortex, resulting in the accumulation of quinolinic acid and glutamate. Ultimately, these changes induced anxiety- and depression-like behaviors in mice. This study provides novel insights into the indirect neurotoxic effects of TPHP exposure at ERDs in mammals and emphasizes the need for more stringent regulatory policies regarding the use of TPHP.
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[Effect of Zuogui Jiangtang Jieyu Formula on intestinal flora and short-chain fatty acid metabolism in rats with diabetes mellitus complicated with depression].
This study aimed to investigate the regulatory effects of Zuogui Jiangtang Jieyu Formula(ZJJ) on the intestinal flora, short chain fatty acids(SCFAs), and neuroinflammation in rats with diabetes mellitus complicated depression(DD). The DD model was established in rats and model rats were randomly divided into a model group, a positive drug(metformin + fluoxetine) group, a ZJJ low-dose group, and a ZJJ high-dose group, with eight rats in each group. Another eight rats were assigned to the blank group. Subsequently, depressive-like behavior test was conducted on the rats, and cerebrospinal fluid samples were collected to measure pro-inflammatory cytokines [interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α)]. Blood serum samples were collected to measure proteins related to the hypothalamic-pituitary-adrenal axis(HPA axis), including corticotropin-releasing hormone(CRH), adrenocorticotropic hormone(ACTH), and cortisol(CORT), as well as glucose metabolism. Gut contents were collected from each group for 16S rRNA sequencing analysis of intestinal flora and SCFAs sequencing. The results indicated that ZJJ not only improved glucose metabolism in DD rats(P<0.01) but also alleviated depressive-like behavior(P<0.05) and HPA axis hyperactivity(P<0.05 or P<0.01). Besides, it also improved the neuroinflammatory response in the brain, as evidenced by a significant reduction in pro-inflammatory cytokines in cerebrospinal fluid(P<0.05 or P<0.01). Additionally, ZJJ improved the intestinal flora, causing the intestinal flora in DD rats to resemble that of the blank group, characterized by an increased Firmicutes abundance. ZJJ significantly increased the levels of SCFAs(acetic acid, butyric acid, valeric acid, and isovaleric acid)(P<0.01). Therefore, it is deduced that ZJJ can effectively ameliorate intestinal flora dysbiosis, regulate SCFAs, and thereby improve both glucose metabolism disturbances and depressive-like behavior in DD.
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Gut microbiota and gut tissue metabolites involved in development and prevention of depression.
Depression is a prevalent, life-threatening, and highly recurrent psychiatric illness. Several studies have shown that depression is associated with endogenous metabolites and the gut microbiota. However, it is unclear whether metabolites in different gut tissues play a role in the pathogenesis of depression and whether the gut microbiota has an impact on depression. Here, we investigated the metabolic signatures in the jejunum, ileum, and colorectum using metabolomics and explored the influence of the gut microbiota on both the development of chronic variable stress (CVS)-induced depression rat model and variations in gut tissue metabolites using a gnotobiotic rat model. The results showed that CVS induced disturbances in gut metabolites (29 differential metabolites) and had different effects on the different segments. When CVS rats were treated with antibiotics, depression-like ethological disorders disappeared, and the decreased catecholamine levels almost normalized. The depression recovery was attributed to the influence of antibiotics on the gut microbiota, especially inhibiting Clostridiaceae (F1), Candidatus arthromitus (G2), Lactobacillus (G6), and elevating Pseudomonadaceae (F6). Moreover, 16 of 29 varied metabolites in CVS rats were reversed with antibiotic treatment. Among them, 12 increased metabolites were decreased, suggesting a trigger for depression. However, four decreased metabolites were increased, indicating a potential therapeutic effect on depression. Based on the Pearson's correlation analysis, hypoxanthine, 3-hydroxypristanic acid, threonic acid, and L-carnitine were strongly associated with F6, F1, G2, and G6, which are involved in the development and prevention of depression. These findings provide a possibility for further exploration of the pathogenesis and prevention of depression.