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Gut microbiota and metabolic characteristics in subthreshold depression based on multi-omics.
BACKGROUND: Subthreshold depression (SD) is an intermediate state between normal mood and major depressive disorder (MDD), but its biological underpinnings remain insufficiently understood. Increasing evidence suggests that gut microbiota and host metabolic alterations may contribute to early depressive pathophysiology. METHODS: We performed full-length 16S rRNA gene sequencing and LC-MS-based untargeted metabolomics on stool and plasma samples obtained from SD subjects and healthy controls. Microbial diversity, taxonomic composition, metabolic pathway alterations, and gut microbiota-metabolite associations were analyzed using bioinformatics pipelines, KEGG annotation, and Spearman correlation analysis. RESULTS: SD patients exhibited marked gut microbial disturbances, including reduced microbial diversity and altered abundances of key genera such as decreased Eubacterium hallii group, Blautia, Dorea, and Agathobacter, and increased Escherichia-Shigella, Monoglobus, and Lachnoclostridium. Metabolomic profiling identified widespread metabolic perturbations, mainly affecting lipid metabolism, steroid hormone biosynthesis, and amino acid pathways. Exploratory correlation analysis indicated that beneficial taxa (e.g., Eubacterium hallii group and Blautia) were positively associated with specific glycerophospholipid and steroid hormone metabolites, whereas inverse associations were observed for other lipid-related metabolites. CONCLUSION: This integrative microbiome-metabolome analysis demonstrates that SD is accompanied by early disruptions in gut microbial composition and systemic metabolism, particularly within lipid-related pathways. These findings suggest that gut microbiota dysbiosis may reflect early metabolic dysregulation and depression-related biological vulnerability in SD and highlight the gut microbiota as a candidate biological target for early identification and intervention.
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Efficacy of Gut Microbiome-Targeted Interventions on Mental Health Symptoms in Women Across Key Hormonal Life Stages: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Background: Women are disproportionately affected by depression and generalized anxiety disorder compared to men throughout their lives. Hormonal changes during the menstrual cycle, pregnancy, postpartum, and menopause are often associated with mood disturbances. Evidence suggests that modulating the gut microbiome through gut-targeted interventions may offer a novel therapeutic approach for various mental health conditions. Objective: This systematic review and meta-analysis aimed to synthesize evidence from randomized controlled trials (RCTs) on the efficacy of gut microbiome-targeted interventions in improving mental health symptoms in women during key hormonal transitions. Methods: A systematic search was conducted from inception to August 2025 across Embase, MEDLINE (PubMed), Web of Science, PsycINFO, CINAHL, Scopus, FSTA, CENTRAL, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. Two reviewers independently screened, extracted data, and assessed study quality. Methodological quality was evaluated using Cochrane's risk-of-bias tool (RoB 2.0). Statistical analyses were performed with Comprehensive Meta-Analysis software (version 4). Results: Eleven RCTs were included, of which eight were used in the meta-analyses. Gut microbiome-targeted interventions significantly reduced depressive symptoms (Standardized Mean Difference (SMD) = -0.848; 95% Confidence Interval (CI): -1.470 to -0.226; p = 0.008) and anxiety symptoms (SMD = -0.997; 95% CI: -1.684 to -0.311; p = 0.004) versus controls. Heterogeneity was high (depression: Cochran's Q = 87.1, I2 = 92%, τ2 = 0.729; anxiety: Q = 35.3, I2 = 89%, τ2 = 0.535), but sensitivity analyses confirmed robustness. Meta-regressions indicated that treatment duration was not a significant moderator (depression: p = 0.12; anxiety: p = 0.28). Conclusions: Gut-targeted interventions significantly reduced symptoms of both depression and anxiety, highlighting their potential as complementary therapeutic strategies for managing mood disorders in women across hormonal life stages. However, high heterogeneity limits the ability to determine optimal standardized clinical recommendations, highlighting the need for further research to guide clinical applications and inform individualized approaches to treatment.
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A1 protein free milk benefits mood and subjective cognition in free-living Australian adults: a pragmatic, exploratory, open label randomised controlled trial.
BACKGROUND: Adverse effects of milk containing A1-type β-casein on digestion, immune response, and cognition have been identified in milk-intolerant individuals, but health effects in healthy individuals without symptoms of milk intolerance are yet to be examined. OBJECTIVE: The objective was to explore the impact of reducing A1 type β-casein intake via switching milk type from conventional A1/A2-type β-casein milk (A1/A2 milk) to A1-type β-casein protein free milk (A1PF) on brain, immune response, gastrointestinal, and skin (BIGS) outcomes in a real-world setting. METHODS: An open-label, pragmatic, exploratory randomised controlled trial was conducted in 997 healthy, free-living Australian older adolescents and adults (16-65 years) who regularly consume A1/A2 protein-containing milk and milk products. Participants were randomised into two groups, to consume ≥250 mL/day of A1/A2 milk (control) or to switch to ≥250 mL/day of A1PF milk (intervention) for 28 days, while continuing to follow their usual diet (including up to 1 serve a day of A1/A2 dairy products). A sub-group of 265 participants conducted stool, saliva and cognitive testing on days 0 and 28. All participants completed subjective questionnaires on days 0, 14, and 28. RESULTS: No differences in gut microbiome composition, alpha-diversity, or function were found by switching milk type. After switching to A1PF milk, a small increase in stool consistency was reported (-0.16, p = 0.007), and females experienced a marginal reduction in gastrointestinal symptoms (p = 0.015) and improved subjective cognition (p = 0.03). Switching to A1PF milk reduced anxiety (-0.61; p = 0.002), depression (-0.56; p = 0.023), stress (-0.70, p = 0.012) and fatigue (p = 0.001; females only), compared to drinking A1/A2 milk, with stronger effects in females. No consistent effects on markers of immune response or skin health were identified. CONCLUSION: Switching from conventional A1/A2 milk to A1PF milk may benefit mood and subjective cognition, particularly in females, without the need for complete elimination of A1 β-casein from the diet. Further investigations are warranted. CLINICAL TRIAL REGISTRATION: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385966, identifier ACTRN12623000628640.
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The mind, brain, and body study: A protocol for examining the effects of the gut-brain-immune axis on internalizing symptoms in youth exposed to caregiving-related early adversity.
Experiences of caregiving-related adversity are common and one of the strongest predictors of internalizing psychopathology (i.e., anxiety and depression). Specifically, individuals who have been exposed to such early adversities have altered affective neurodevelopment, impaired memory systems, increased risk of developing internalizing disorders, greater inflammation, and differences in gastrointestinal (gut) microbiome composition. Crucially, the gut microbiome undergoes a sensitive period of development that precedes neural and immune sensitive periods, thus making it a potentially fruitful target for intervention. Though previous work has assessed neural, immune, and gut microbiome systems in individuals exposed to early adversity, studies have primarily looked at these biological systems independently. The Mind, Brain, and Body study (MBB) implements multimodal and longitudinal design to assess how changes in the gut microbiome following caregiving-related adversity may underlie altered affective neurodevelopment, memory, and immune functioning in youth and contribute to internalizing symptoms. Across three waves, spread approximately 12-18 months apart, youth with and without previous experiences of caregiving-related adversity completed self-report measures of mental and physical health, provided stool, saliva, hair, and blood samples, and completed an MRI scan. Results of this study will expand our knowledge on how the gut microbiome shapes several biological and cognitive systems and motivate future work investigating the gut microbiome as potential target for intervention.
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The role of microbiome in central nervous system disorders.
Mammals live in a co-evolutionary association with the plethora of microorganisms that reside at a variety of tissue microenvironments. The microbiome represents the collective genomes of these co-existing microorganisms, which is shaped by host factors such as genetics and nutrients but in turn is able to influence host biology in health and disease. Niche-specific microbiome, prominently the gut microbiome, has the capacity to effect both local and distal sites within the host. The gut microbiome has played a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities, and thus the concept of microbiome-gut-brain axis is emerging. Studies are revealing how diverse forms of neuro-immune and neuro-psychiatric disorders are correlated with or modulated by variations of microbiome, microbiota-derived products and exogenous antibiotics and probiotics. The microbiome poises the peripheral immune homeostasis and predisposes host susceptibility to CNS autoimmune diseases such as multiple sclerosis. Neural, endocrine and metabolic mechanisms are also critical mediators of the microbiome-CNS signaling, which are more involved in neuro-psychiatric disorders such as autism, depression, anxiety, stress. Research on the role of microbiome in CNS disorders deepens our academic knowledge about host-microbiome commensalism in central regulation and in practicality, holds conceivable promise for developing novel prognostic and therapeutic avenues for CNS disorders.
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Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities.
Mood disorders such as depression are among the most prevalent psychiatric disorders in the United States, but they are inadequately treated in a substantial proportion of patients. Accordingly, neuropsychiatric research has pivoted from investigation of monoaminergic mechanisms to exploration of novel mediators, including the role of inflammatory processes. Subsets of mood disorder patients exhibit immune-related abnormalities, including elevated levels of proinflammatory cytokines, monocytes, and neutrophils in the peripheral circulation; dysregulation of neuroglia and blood-brain barrier function; and disruption of gut microbiota. The field of psychoneuroimmunology is one of great therapeutic opportunity, yielding experimental therapeutics for mood disorders, such as peripheral cytokine targeting antibodies, microglia and astrocyte targeting therapies, and probiotic treatments for gut dysbiosis, and producing findings that identify therapeutic targets for future development.
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Microbial metabolites and immune regulation: New targets for major depressive disorder.
Treatments for depression and mood disorders have been singularly targeted at the brain without consideration for the context of the rest of the body. As evidence mounts for a role of autoimmunity and inflammation as risk factors and contributors to mood disorders, attention has shifted to one of the primary immunoregulatory organs in the body--the gut. Gut-brain interactions have been established and correlative links between the microbiome and mood have been examined, but with novel tools and a base of understanding, focus shifts to the mechanisms of these communications. In this review, we examine how the small molecules produced by metabolic processes of bacteria in the gut influence the host immune system. The gaps in knowledge discussed here include the under characterized diversity of small molecules crossing the gut walls, as well as the need to close the logical loop connecting the microbiome to the immune system, and the immune system to behavior and mood. As we move past the dawn of this field, more precise understanding using novel tools and techniques will help move toward a more informed and systematic process for clinically evaluating the efficacy of probiotics and bacterially derived compounds as antidepressants and mood regulators.
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Bibliometric analysis of research hotspots and trends on the relationship between the gut microbiota and depression from 2020 to 2024.
INTRODUCTION: In recent years, an increasing body of research has illustrated a strong correlation between gut microbiota and depression. However, there has yet to be a comprehensive discussion or summary of the latest advancements and trends in this field. METHODS: We retrieved research articles focused on gut microbiota and depression through the WOS database from 2020 to 2024, using visual text analysis tools such as CiteSpace and VOSviewer. RESULTS: The literature on the relationship between gut microbiota and depression surged from 396 papers in 2020 to 711 by 2024. During this period, the journal with the highest publication rate was Nutrients. China led the countries in contributions, while University College Cork topped the institutions. Kenji Hashimoto emerged as the most prolific author. The most cited paper was authored by Cryan JF et al., published in 2019 in Physiol Rev. The keywords "gut microbiota," "depression," and "anxiety" appeared most frequently, while recent years saw explosive increases in terms such as "growth performance," "receptors," "depression-like phenotypes," "stress response," "gastrointestinal symptoms," "reliability," and "neurogenesis." DISCUSSION: Our article displayed the overview of the relationship between the gut microbiome and depression from 2020 to 2024 using bibliometric methods, providing perspectives and research hotspots for studies exploring the correlation between the gut microbiome and depression.
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Gut microbiome characteristics of comorbid generalized anxiety disorder and functional gastrointestinal disease: Correlation with alexithymia and personality traits.
OBJECTIVE: The aim of this study was to investigate the characteristics of intestinal flora in patients with functional gastroenteropathy and generalized anxiety disorder (GAD) and the relationship between intestinal flora and psychological factors. MATERIALS AND METHODS: From March 2020 to December 2020, a total of 35 patients with functional gastroenteropathy and generalized anxiety disorder, 30 healthy controls, 16 patients with functional gastroenteropathy, and 44 patients with generalized anxiety disorder were selected from the Affiliated Hospital of Guizhou Medical University. Fecal samples were collected from each group, and the related psychophysiological factors scales (Hamilton Anxiety Scale, Hamilton Depression Scale, Neurotic Personality Questionnaire, concept of illness questionnaire, Toronto Alexithymia Scale, Severity of Physical Symptoms Scale, and Cognitive Emotion Regulation Questionnaire) were improved. 16S rRNA high-pass sequencing was used to determine the correlation between intestinal flora changes and functional gastroenteropathy with generalized anxiety disorder. Then, the scale and gut microbiota results were analyzed for correlation to determine the correlation between personality traits and gut microbiota. RESULTS: We found similar intestinal microbiota in patients with functional gastroenterology, generalized anxiety disorder, and functional gastroenteropathy with generalized anxiety disorder. But the relative abundance of Clostridium was significantly increased in patients with functional gastrointestinal disease (FGID) and generalized anxiety. The relative abundance of Haemophilus influenzae was significantly increased in patients with functional gastrointestinal disease without a generalized anxiety disorder. The intestinal microecological composition was significantly correlated with personality traits. CONCLUSION: Functional gastrointestinal disease comorbidity GAD may be related to an increase in the relative abundance of Fusobacterium. FGID non-comorbidity GAD may be related to the increased relative abundance of Hemophilus. The increased relative abundance of Fusobacterium and Megamonas is associated with personality traits such as difficulty describing feelings and difficulty identifying feelings, neuroticism, and negative cognition of disease.
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Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders.
Chronic inflammation of the central nervous system (CNS) is critical to the pathogenesis of neuropsychiatric disorders (NPDs) that affect the global population. Current therapeutics for NPDs are limited to relieving symptoms and induce many adverse effects. Therefore, the discovery of novel therapeutic agents from natural sources is urgently needed. Intriguingly, the immune responses of peripheral organs are closely linked through the molecular communication between resident and blood-borne cellular components, which shape the neuroinflammatory phenotypes of NPDs. Since the gut and spleen are the two largest immunological organs of the body, the brain-gut-microbiome and brain-spleen axes have been implicated in the connection between the CNS and the peripheral immune system. Accordingly, it has been proposed that the local CNS inflammation observed in NPDs is regulated via the manipulation of the systemic immune system by targeting the gut and spleen. Additionally, the complexity of the signalling network underlying the communication between the CNS and the systemic immune system suggests a strong potential for treating NPDs through a polypharmacological approach. The close association between systemic immunity and the homeostasis of the CNS points to the concept of repurposing interventions for systemic immune disorders to treat NPDs. Notably, natural products represent a promising source of such effective compounds due to both their pharmacological potency and safety. This review discusses the complex implications of dysregulated systemic immunity mediated by the brain-spleen and brain-gut-microbiome axes in NPDs, such as Alzheimer's disease, Parkinson's disease, schizophrenia and major depressive disorder. In addition, the potential of repurposing natural product-based bioactive compounds for treating NPDs via modulating systemic immune disorders is intensively discussed.