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Brain-gut-microbiota axis in depression: A historical overview and future directions.
Depression is the most common mental disorder and a leading cause of disability worldwide. Despite abundant research, the precise mechanisms underlying the pathophysiology of depression remain elusive. Accumulating evidence from preclinical and clinical studies suggests that alterations in the gut microbiota, microbe-derived short-chain fatty acids, D-amino acids and metabolites play a key role in the pathophysiology of depression via the brain-gut-microbiota axis, including the neural and immune systems. Notably, the brain-gut-microbiota axis might play a crucial role in susceptibility versus resilience in rodents exposed to stress. Vagotomy is reported to block depression-like phenotypes in rodents after fecal microbiota transplantation of "depression-related" microbiome, suggesting that the vagus nerve influences depression through the brain-gut-microbiota axis. In this article, we review recent findings regarding the brain-gut-microbiota axis in depression and discuss its potential as a therapeutic target for depression.
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Meranzin Hydrate ameliorates "atherosclerotic depression" in ApoE-/- mice by restoring gut microbiota-driven microbial-inflammatory circuitry.
BACKGROUND: Depression and atherosclerosis frequently co-occur, with disrupted gut microbiota-driven inflammatory circuitry emerging as a shared pathogenic mechanism. To address this, we operationally define "atherosclerotic depression" as depression comorbidity with atherosclerosis. Despite its clinical significance, integrated therapeutic strategies remain lacking. METHODS: An ApoE-/- mouse model combining high-fat diet feeding and acute restraint stress was established to mimic atherosclerosis-associated depression. Animals received Meranzin Hydrate (MH) treatment, followed by comprehensive assessments. Metabolic and vascular endpoints included body weight, serum lipid profiles, and aortic plaque burden (Oil Red O staining). Depressive-like behaviors were evaluated through standardized behavioral tests. BOLD-fMRI with regional homogeneity (ReHo) analysis measured brain functional activity. Gut microbiota profiling was performed by 16S rRNA sequencing to assess α-/β-diversity, Firmicutes/Bacteroidetes ratio, and keystone taxa. Inflammatory and neurotrophic markers were examined via ELISA (5-hydroxytryptamine, brain-derived neurotrophic factor, interleukin-6, endothelial nitric oxide synthase, and ghrelin), while protein and mRNA levels of vascular cell adhesion molecule-1, interleukin-1β, tumor necrosis factor-α, and ghrelin were analyzed by Western blot and RT-PCR. RESULTS: MH significantly reduced aortic plaque formation, improved lipid profiles, and alleviated depressive-like behaviors. MH restored gut microbiota homeostasis by enhancing α-diversity, normalizing the Firmicutes/Bacteroidetes ratio, and enriching beneficial taxa such as Akkermansia and Allobaculum. These microbiota changes paralleled the reversal of stress- and diet-induced BOLD-fMRI alterations in emotion-regulation regions (hippocampus and prefrontal cortex). Inflammatory circuitry was rebalanced, as evidenced by reduced IL-6, TNF-α, IL-1β, and VCAM-1, alongside restored hippocampal and cardiac 5-HT, BDNF, and ghrelin levels. CONCLUSION: MH demonstrates therapeutic potential in alleviating atherosclerosis co-depression by modulating acute mental stress-induced vascular inflammation, neurotrophic factors, brain function, and gut microbiota.
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Probiotic supplementation can positively affect anxiety and depressive symptoms: a systematic review of randomized controlled trials.
Gastrointestinal microbiota, consisting of microbial communities in the gastrointestinal tract, play an important role in digestive, metabolic, and immune functioning. Preclinical studies on rodents have linked behavioral and neurochemical changes in the central nervous system with deficits or alterations in these bacterial communities. Moreover, probiotic supplementation in rodents has been shown to markedly change behavior, with correlated changes in central neurochemistry. While such studies have documented behavioral and mood-related supplementation effects, the significance of these effects in humans, especially in relation to anxiety and depression symptoms, are relatively unknown. Thus, the purpose of this paper was to systematically evaluate current literature on the impact of probiotic supplementation on anxiety and depression symptoms in humans. To this end, multiple databases, including Medline, PsycINFO, PubMed, Scopus, and Web of Science were searched for randomized controlled trials published between January 1990 and January 2016. Search results led to a total of 10 randomized controlled trials (4 in clinically diagnosed and 6 in non-clinical samples) that provided limited support for the use of some probiotics in reducing human anxiety and depression. Despite methodological limitations of the included trials and the complex nature of gut-brain interactions, results suggest the detection of apparent psychological benefits from probiotic supplementation. Nevertheless a better understanding of developmental, modulatory, and metagenomic influences on the GI microbiota, specifically as they relate to mood and mental health, represent strong priorities for future research in this area.
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Edible and Medicinal Fungi as Candidate Natural Antidepressants: Mechanisms and Nutritional Implications.
This systematic review examines the antidepressant potential of edible medicinal fungi (EMFs), focusing on their bioactive compounds and mechanisms of action. EMFs modulate neurotransmitter systems, including serotonin (5-HT) and dopamine (DA), alleviating depressive symptoms. Extracts from EMFs, such as Ganoderma lucidum, Hericium erinaceus, Poria cocos, and Cordyceps militaris, demonstrate significant antidepressant-like effects in preclinical studies. Their bioactive compounds influence the tryptophan-kynurenine (KYN) pathway, regulate the hypothalamus-pituitary-adrenal (HPA) axis, and reduce neuroinflammation, all of which are linked to stress response and mood regulation. The review also explores the gut-brain axis, highlighting how EMF-derived polysaccharides improve gut health by modulating microbiota, potentially mitigating depressive symptoms. Additionally, it discusses the use of EMFs in functional foods and dietary supplements, innovations like 3D food printing for depression-related issues, and synthetic biology for enhancing compound production. Artificial intelligence is used to model complex mechanisms. However, challenges remain, such as standardization and lack of clinical validation. Future research should address these gaps, emphasizing personalized interventions and advanced technologies for next-generation antidepressant foods.
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Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice.
The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-induced experimental dysbiosis. Inflammation of the small intestine was also assessed. Mice were exposed to a mixture of antimicrobials for 2weeks. Afterwards, they received Lactobacillus casei DG (LCDG) or a vehicle for up to 7days via oral gavage. Perturbation of microbiota was accompanied by a general inflammatory state and alteration of some endocannabinoidome members in the gut. Behavioural changes, including increased immobility in the tail suspension test and reduced social recognition were observed, and were associated with altered BDNF/TrkB signalling, TRPV1 phosphorylation and neuronal firing in the hippocampus. Moreover, morphological rearrangements of non-neuronal cells in brain areas controlling emotional behaviour were detected. Subsequent probiotic administration, compared with vehicle, counteracted most of these gut inflammatory, behavioural, biochemical and functional alterations. Interestingly, levels of Lachnospiraceae were found to significantly correlate with the behavioural changes observed in dysbiotic mice. Our findings clarify some of the biomolecular and functional modifications leading to the development of affective disorders associated with gut microbiota alterations.
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Effects of regulating gut microbiota by electroacupuncture in the chronic unpredictable mild stress rat model.
OBJECTIVE: This study aims to investigate the effect of electroacupuncture (EA) treatment on depression, and the potential molecular mechanism of EA in depression-like behaviors rats. METHODS: A total of 40 male Sprague Dawley rats were divided into three groups: normal control, chronic unpredictable mild stress (CUMS), and EA (CUMS + EA). The rats in CUMS and EA groups underwent chronic stress for 10 weeks, and EA group rats received EA treatment for 4 weeks starting from week 7. Body weight and behavioral tests, including the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were monitored. Gut microbiota composition was assessed via 16S rDNA sequencing, and lipid metabolism was analyzed by using UPLC-Q-TOF/MS technology. RESULTS: In comparison to CUMS group, EA could improve the behavior including bodyweight, immovability time, sucrose preference index, crossing piece index and rearing times index. After 4 weeks of EA treatment, 5-HT in hippocampus, serum and colon of depressive rats were simultaneously increased, indicating a potential alleviation of depression-like behaviors. In future studies revealed that EA could regulate the distribution and functions of gut microbiota, and improve the intestinal barrier function of CUMS rats. The regulation of intestinal microbial homeostasis by EA may further affect lipid metabolism in CUMS rats, and thus play an antidepressant role. CONCLUSION: This study suggested that EA has potential antidepressant effects by regulating gut microbiota composition and abundance, subsequently affecting lipid metabolism.
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Infantile Functional Gastrointestinal Disorders and Maternal Psychological Status: A Narrative Review.
BACKGROUND: Functional gastrointestinal disorders are often extremely distressing for the infant and parents, leading to infant discomfort and crying, parental anxiety, repeated healthcare consultations, and escalating healthcare costs. AIM: In this narrative review, we analyzed the relationship between maternal psychological status during pregnancy and postpartum and the main infantile functional gastrointestinal disorders. MATERIALS AND METHODS: The narrative review was conducted searching scientific databases for articles reporting on infantile functional gastrointestinal disorders in association with maternal depressive or anxiety disorders. RESULTS: Seven studies were suitable. DISCUSSION: Maternal psychological disorders may be correlated to infantile functional gastrointestinal disorders. Whether it is the excessive crying that favors the onset of maternal psychological disorders or, in contrast, an altered attachment style due to the maternal status that facilitates the onset of functional gastrointestinal disorders in the infant is still an open question. Recent findings revealed that both anxious and depressed mothers are more likely to have an adverse gut microbiome. CONCLUSION: A healthy interaction of the mother-baby dyad is advantageous in ensuring the mental and physical development of the offspring. Gynecologists, general practitioners and pediatricians should be alert for early identification of mothers at risk with the aim to initiate timely targeted interventions. Further research on the role of microbiota and the possible therapeutic approaches with probiotics is required.
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Acupuncture ameliorates depression-like behavior of poststroke depression model rats through the regulation of gut microbiota and NLRP3 inflammasome in the colon.
This study was conducted to examine the effects of acupuncture on gut microbiota and expression of NLRP3 inflammasome in the colon in poststroke depression (PSD) model rats. Sprague-Dawley male rats were randomized into four groups: sham surgery group, poststroke depression group, acupuncture group, and probiotics group. Acupuncture therapy at Baihui (GV20), Shenting (GV24), bilateral Zusanli (ST36) acupoints in the acupuncture group and probiotic gavage therapy in the probiotics group were performed once per day for 2 weeks. Behaviors of depression were assessed by using weight measurements, sucrose preference test, open field test, and forced swimming test. Histopathological alterations in the colon were determined by hematoxylin-eosin staining, the expression of NLRP3/ASC/caspase-1 pathway-related proteins was analyzed by western blotting. Serum levels of IL-1β and IL-18 were derived from ELISA. The 16S rRNA gene sequencing was performed to examine and analyze the differences of gut microbiota of rats among all groups. Acupuncture was effective to increase weight and ameliorate depressive-like behaviors in PSD rats. Acupuncture increased the diversity of gut microbiota, upregulated the abundance of Bifidobacteriaceae and Lactobacillaceae, and decreased the relative abundance of Peptostreptococcaceae, Rikenellaceae, Eggerthellaceae, and Streptococcaceae at family level. Acupuncture effectively improved the pathological changes in the colon. Meanwhile, acupuncture reduced NLRP3, ASC, caspase-1 protein expressions in the colon, and serum levels of IL-18 and IL-1β. Acupuncture may reduce depressive-like behaviors of PSD by regulating the gut microbiota and suppressing hyperactivation of NLRP3 inflammasome in the colon. Microbiota-gut-brain axis may be an effective target pathway for acupuncture treatment of PSD.
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Seasonal Affective Disorder and the Microbiota-Gut-Brain Axis: Circadian Disruption, Tryptophan Metabolism, and Psychobiotic Potential of Lacticaseibacillus rhamnosus GG.
Seasonal affective disorder (SAD) is a recurrent mood disorder associated with reduced photoperiod exposure and circadian disruption during autumn and winter. Emerging evidence links SAD to alterations in serotonergic signaling, neuroimmune activity, metabolism, and the microbiota-gut-brain axis; however, the causal relationships among these systems remain incompletely understood. A structured search of PubMed, Web of Science, and Scopus identified relevant publications from 2000 to 2025, with clinical and preclinical evidence evaluated separately. Proposed links between circadian misalignment, inflammatory signaling, and tryptophan metabolism toward the kynurenine pathway are based largely on associative and preclinical findings rather than confirmed mechanisms in SAD. The microbiota-gut-brain axis in SAD is likely bidirectional, as seasonal changes in feeding behavior, physical activity, and circadian phase may themselves influence gut microbial composition and function. Accordingly, microbiome alterations in affective disorders may reflect both potential upstream modulators and downstream consequences of disease-related behavior. Psychobiotics have been proposed as modulators of gut-brain communication in affective disorders. Among candidate strains, Lacticaseibacillus rhamnosus GG (formerly Lactobacillus rhamnosus GG; LGG) has shown effects on intestinal barrier function, immune signaling, and host tryptophan metabolism in preclinical studies. However, evidence derives largely from animal or non-seasonal depression models, and direct evidence in SAD is lacking. Thus, LGG should be considered a mechanistically plausible candidate for future investigation rather than an established therapy. This review synthesizes evidence on circadian regulation, serotonergic and tryptophan metabolism, and microbiota-gut-brain interactions in SAD, and highlights mechanistic gaps for future studies.
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Perinatal exposure to polystyrene nanoplastics alters socioemotional behaviors via the microbiota-gut-brain axis in adult offspring mice.
Polystyrene nanoplastics (PS-NPs), ubiquitous environmental contaminants, have been detected in various tissues of humans and animals, raising significant concerns regarding their potential health hazards. The long-term consequences of PS-NPs exposure during early developmental stages remain inadequately characterized. In this study, we established a murine model to investigate the chronic oral administration of PS-NPs via drinking water during the perinatal period, with a focus on elucidating the impact of PS-NPs ingestion on the social behaviors of adult offspring and the underlying mechanisms, particularly those involving the gut-brain axis. Our findings revealed that perinatal PS-NPs exposure elicited depression-like behaviors, diminished social dominance, and reduced social interactions in adult offspring. Additionally, we observed a decrease in dendritic spine density within hippocampal neurons, along with ultrastructural damage to hippocampal neurons and synapses in the adult offspring. PS-NPs exposure also led to a reduction in the richness and evenness of gut microbiota species composition in both male and female mice, with gut dysbiosis being particularly pronounced in adult males. Furthermore, alterations in metabolite abundance and metabolic pathways were detected in the hippocampus of both male and female adult offspring. Notably, a significant correlation was identified between the relative abundance of intestinal microorganisms and hippocampal metabolites. These results offer new insights into the association between early-life PS-NPs exposure and adult social behaviors, mediated through the microbiota-gut-brain axis.