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Beneficial Effects of Apple Polyphenol Extract and Time-Restricted Feeding on Ulcerative Colitis and Accompanying Depression-like Behaviors Are Correlated with Gut-Brain Axis Modulation.
Time-restricted feeding (TRF) and apple polyphenol extract (APE) emerged as promising adjuvant strategies for managing inflammation and gut microbiota imbalances. Ulcerative colitis (UC), characterized by recurrent episodes, is difficult to cure and often accompanied by anxiety- and depression-like behaviors. To investigate whether TRF, APE, or their combined intervention could prevent UC and associated behavioral disorders, a dextran sulfate sodium (DSS)-induced UC model in C57BL/6 male mice was employed, and APE (500 mg/kg·body weight·day) was administered via gavage. Through a 36-day treatment, ameliorated UC was observed, along with reduced DAI scores, improved colonic pathological damage, intestinal barrier, and brain barriers by activating intestinal mitophagy with upregulated Parkin/Pink1, and suppressed NLRP3/ASC/Caspase-1 pathway-mediated inflammation. Furthermore, APE and TRF ameliorated UC accompanying behavioral disorders by suppressing astrocytes and microglia activation, preventing synaptic damages through upregulating BDNF and PSD-95 expression and enhancing neurotransmission by increasing the serum levels of 5-Hydroxytryptamine and norepinephrine. Notably, APE and TRF restored gut microbiota composition with increased Firmicutes/Bacterodetes ratio and boosted Akkermansia abundance while reducing the relative abundances of Citrobacter, Bacteroides, and Escherichia-Shigella. In conclusion, APE and TRF, both individually or in combination, significantly prevented DSS-induced UC and associated behavioral disorders, which were strongly associated with coordinated changes of gut-brain axis modulation.
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Semen Sojae Praeparatum alters depression-like behaviors in chronic unpredictable mild stress rats via intestinal microbiota.
A large number of Chinese medical books present that Semen Sojae Praeparatum, a fermented food, possesses antidepressant effect, but the mechanism of this antidepressant effect remains largely unknown. This study aimed to explore the effect of Semen Sojae Praeparatum on rats with chronic unpredictable mild stress (CUMS)-induced depression. The results showed that Semen Sojae Praeparatum improved depression-like behaviors (negative preference of sugar water and increased swimming immobility time and time spent in the dark zone) and effectively reduced cell morphological changes in the dentate gyrus of the hippocampus in CUMS rats. In addition, Semen Sojae Praeparatum significantly promoted the contents of norepinephrine (NE), 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), and gamma-aminobutyric acid (GABA) in the hippocampus and the content of BDNF in the serum (p < 0.05). 16S rRNA sequencing analysis results showed that Semen Sojae Praeparatum increased the abundance of genus Ruminococcaceae_UCG-008 and decreased those of genera Lactobacillus and Bacteroides. Genus Ruminococcaceae_UCG-008 was positively correlated with GABA and BDNF levels in the hippocampus; genus Lactobacillus had a positive correlation with 5-HT; and genus Bacteroides had negative correlations with 5-HT, BDNF, and NE. In addition, Semen Sojae Praeparatum considerably decreased the concentration of short-chain fatty acids (SCFAs). These results indicated that Semen Sojae Praeparatum fermented by Rhizopus chinensis 12 and Bacillus sp. DU-106 alleviated the neurotransmitter levels and structural changes in the neuronal morphology of the hippocampus associated with the modulation of gut microbiota and SCFAs. Therefore, this study confirmed that Semen Sojae Praeparatum could alter depression and provide a theoretical basis for the investigation of the relationship between the microbiota-gut-brain axis and antidepressant.
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The effect of acupuncture on lateral habenular nucleus and intestinal microflora in depression model rats.
BACKGROUND: Depression is a severe emotional condition that significantly affects the quality of life. Acupuncture exerts preventive effects on depression in rats with post-chronic unpredictable mild stress (CUMS). Methods The study involved chronic unpredictable mild stress (CUMS) depression model mice to administer acupuncture as a preventative measure to investigate the mechanism of acupuncture's antidepressant and observe the effect of acupuncture on impact via the Lateral Habenula (LHb) and Gut-Liver-Brain Axis. The researcher investigated molecules correlating with a nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway and assessed inflammation in the LHb and liver. In addition, 16 S rDNA bioinformatics study revealed the quantity and variety of gut microbiota. Rats were randomly divided into five groups: control (CON), CUMS, CUMS + acupuncture (AP), CUMS + fluoxetine (FX) and CUMS + N(G) -nitro -L- arginine methyl ester (LNAME) group. Except for the CON group, other rats were exposed to CUMS condition for 28 days. Simultaneously, manual acupuncture (at Fengfu and Shangxing acupoints, once every other day) and fluoxetine gavage (2.1 mg/kg, 0.21 mg/mL, daily) were conducted to the groups of AP and FX, respectively, after stressors. Rats in LNAME group were treated with LNAME normal saline (10 mg/kg, 1 mg/mL, i.p.) solution. Behavioural tests and biological detection methods were conducted sequentially to evaluate depressionlike phenotype in rats. RESULTS: The results showed CUMS induced depression-like behaviours, hyper-activation of NO/cGMP signaling pathway, inflammation in serum, LHb and liver, and dysbiosis of the gut microbiota. These changes could be prevented and ameliorated by acupuncture to varying extents. CONCLUSION: Acupuncture prevented and attenuated depression-like phenotype induced by CUMS, possibly via regulating the NO/cGMP signaling pathway and thus improving inflammation in serum, LHb and liver, and gut microbiota dysbiosis. In addition, these can be evidence of the existence of the gut-liver-brain axis.
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Antidepressant effects of sulforaphane (SFN) and its derivatives SLL-III-9 and SLL-III-120 and their potential underlying mechanisms based on the microbiota-gut-brain axis.
Broccoli (Brassica oleracea L.) is a vegetable with numerous nutritional properties, with sulforaphane (SFN) being the most abundant and unique bioactive ingredient. SFN has anti-inflammatory, antioxidant, and anti-cancer activities. In this study, a series of SFN derivatives were synthesized and screened for improved antidepressant effects. Among these, the SFN derivatives SLL-III-9 and SLL-III-120 were the best candidates, and the potential antidepressant mechanism of SFN, SLL-III-9, and SLL-III-120 associated with their effects in a chronic unpredictable mild stress (CUMS) mouse model was explored based on the microbiota-gut-brain axis. All three compounds were able to relieve depression-like behaviors in CUMS mice and regulate the composition of the gut bacteria Firmicutes, Actinobacteria, Parabasalia, and Tenericutes at the phylum level and Bacteroidales bacterium, Lachnospiraceae bacterium A4, Muribaculum intestinale, Muribaculaceae bacterium, and Prevotella sp. MGM1 at the species level, possibly altering their function associated with the anti-inflammatory effect. Additionally, SFN and its derivatives upregulated the expression of the tight junction proteins ZO-1, occludin, and claudin and increased the concentration of IL-10, dopamine (DA), 5-hydroxytryptamine (5-HT) and the brain-derived neurotrophic factor (BDNF), while downregulating the expressions of proteins related to the NF-κB/NLRP3 pathway and reducing the concentration of TNF-α. Further in vitro studies revealed significant inhibition of the production of inflammatory factors IL-1β, IL-18, IL-6, and TNF-α in LPS-activated BV2 cells via the NF-κB/NLRP3 pathway when these cells were treated with SFN or its two derivatives. Taken together, the results suggested that SFN and its two derivatives, SLL-III-9 and SLL-III-120, could be considered potential compounds for the development of a promising and safe agent for combating depression.
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Roseburia intestinalis ameliorates adolescent depression via GPR43‑dependent Treg cell expansion and suppression of neuroinflammation.
Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poorly understood. A growing body of evidence highlights the gut microbiota-brain axis as a key modulator of host emotional function, acting through interconnected immune, metabolic, and neural pathways. In the current work, a clinical study involving first-diagnosed adolescent depression patients was conducted and significant reductions in Roseburia intestinalis (R.i.) and its metabolite butyrate were identified. Therefore, we hypothesized that alterations in R.i. and butyrate may be involved in adolescent depression and may serve as novel therapeutic strategy. Intriguingly, transplantation of R.i. obviously retarded the chronic restraint stress (CRS)-induced depression in adolescent mice. Critically, this protective effect was completely abrogated by blocking the G protein-coupled receptor 43 (GPR43). Mechanistically, we delineated a novel “peripheral-central” regulatory cascade: R.i. robustly promoted the expansion of peripheral CD25⁺Foxp3⁺ regulatory T (Treg) cells, alleviating pathological inflammation in both of the colon (peripheral) and brain (central). Reciprocally, depletion of Treg cells completely abolished not only R.i.’s antidepressant effects but also its anti-inflammatory actions in the colon and brain in vivo. The in vitro study revealed that either the R.i. conditioned or heated culture medium obviously alleviated the LPS+corticosterone induced neuroinflammation in microglial cells, shifting reactive state toward a homeostatic state. Collectively, our study for the first time reveals that R.i. ameliorates adolescent depression-like changes through a GPR43-dependent, Treg-mediated mechanism. Given the unmet clinical need for clinical diagnosis and therapy of adolescent depression, the present study provided the potential translational values for the novel treatments, such as transplantation of R.i. or butyrate supplement, which represent promising therapeutic strategies.
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Lactobacillus Regulates the Specificity of Polysaccharides Derived From Pericarpium Citri Reticulatae "Chachiensis" to Alleviate High-Fat Diet-Induced Depression-Like Behavior.
Gut microbiota dysbiosis is closely linked to depression and can be modulated by dietary polysaccharides. This study aimed to characterize three polysaccharide fractions from Pericarpium Citri Reticulatae "Chachiensis" (PCRCP)-PCRCPI, PCRCPII, and PCRCPIII-and evaluate their antidepressant effects in a high-fat diet-induced mouse model. Their average molecular weights were approximately 48.9 kDa (PCRCPI), 13.7 kDa (PCRCPII), and 34.8 kDa (PCRCPIII), with a composition primarily of galacturonic acid, arabinose, galactose, and rhamnose. PCRCPI most effectively mitigated depression-like behaviors, as indicated by improved behavioral performance and neurotransmitter levels and reduced neuronal damage. The antidepressant effect of PCRCPI was contingent upon the gut microbiota, as demonstrated by the fact that fecal microbiota transplantation (FMT) from donors treated with PCRCPI conferred behavioral improvements. Mechanistically, PCRCPI treatment selectively increased the abundance of Lactobacillus species and elevated fecal levels of metabolites associated with retrograde endocannabinoid signaling, particularly 2-arachidonoylglycerol (2-AG). Subsequent colonization experiments with specific Lactobacillus strains, either alone or in combination with PCRCPI, activated hippocampal retrograde endocannabinoid signaling as revealed by transcriptomic analysis, and ameliorated depression-like phenotypes. These findings demonstrate the potential of PCRCPI as a prebiotic for alleviating diet-associated depression, through a novel microbiota-gut-brain axis mechanism targeting the endocannabinoid system.
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Atractylodes macrocephala Koidz. Polysaccharide Alleviates Chemotherapy-Induced Depression-Like Behaviors Through the Gut-Brain Axis.
This study explored the potential therapeutic effect and possible mechanism of Atractylodes macrocephala Koidz. Polysaccharide (AP) on pirarubicin chemotherapy-induced depression (CID) in breast cancer mice. This study utilized a variety of techniques to explore the potential of AP in mitigating behavioral abnormalities and elucidate the role of gut microbiota regulation in its therapeutic effects on chemotherapy in breast cancer mice. These included a chemotherapy mouse model, behavioral assessments, histological analysis using hematoxylin and eosin staining, ultrastructural examination, enzyme-linked immunosorbent assays, 16S rDNA sequencing, metabolomic profiling, Western blot analysis, and a pseudo-germ-free animal model. Oral administration of AP significantly improved depression-like behaviors in breast cancer chemotherapy mice while also reducing neuronal damage and inflammation in the hippocampus. AP prevented ferroptosis of intestinal tissues caused by chemotherapy and had a repairing effect on the intestinal barrier damage of chemotherapy-induced mice. Additionally, AP enhanced gut microbiota composition and altered intestinal metabolites in chemotherapy-treated mice. It notably decreased the abundance of certain microbes, such as Bacteroidaceae, Lachnospiraceae, Oscillospiraceae, and Clostridium, while significantly increasing the abundance of Alistipes. Moreover, AP efficiently modulated intestinal metabolites, including glycocholic acid, L-Phenylalanine, and palmitoylcarnitine. More importantly, depletion of gut microbiota through antibiotics diminished the effectiveness of AP. Our results suggest that AP alleviates depression-like behaviors in chemotherapy-treated mice by regulating the gut microbiota and microbial metabolism, as well as suppressing ferroptosis in intestinal tissues.
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Gut microbiota modulates synaptic plasticity, connectivity, and dopamine transmission in the VTA-mPFC pathway in bipolar depression.
Adequate evidence has shown that gut microbial dysbiosis is an emerging disease phenotype of bipolar disorder (BD), and is closely related to clinical symptoms of this intractable disease. However, how gut microbiota affects the nervous system in BD remains largely unclear. In this study, we constructed a BD depression-like mouse model via fecal microbiota transplantation, and explored the changes of synaptic plasticity and connectivity in the medial prefrontal cortex (mPFC) of BD mice. We found that bipolar depression-like mice presented with a decrease in the density of dendritic spines in medial prefrontal neurons, and "Translation at postsynapse" as a key contributor to the changes in synaptic plasticity. In addition, analysis of synaptic connectivity in the mPFC revealed that compared to control mice, less connections were observed between ventral tegmental area and mPFC glutamate neurons and dopamine response was decreased in BD mice. These findings suggest that gut microbiota from BD depression patients induces the development of bipolar depression possibly by modulating aberrant synaptic connectivity and dopamine transmission in the VTA-mPFC pathway, which sheds light on the microbiota-gut-brain mechanisms underlying BD.
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Long-lasting effects of postweaning sodium butyrate exposure on social behaviors in adult mice.
BACKGROUND: The function of gut microbiota as its role in normal physiology and involvement in brain function has gained a great deal of attention. The potential long-lasting effects of postweaning sodium butyrate (SB) exposure on social behaviors are still unknown; however it acts as one of the metabolites of gut microbiota. METHODS: Male mice (24-day old) were exposed to SB through drinking water for 21 continuous days. A series of behavioral tests, mainly including bedding preference test (BP), sexual preference test (SP), social interaction test (SI), tube dominance test (SDT), forced swimming test (FST), open field test (OFT), novel object recognition task (NOR) were conducted at different time after 21-d SB exposure. Serum Trimethylamine oxide (TMAO) levels were investigated to gain insight into a potential mechanism. RESULTS: Behavioral results indicated that postweaning SB exposure significantly decreased the social dominance status of low-ranked mice and decreased the sexual preference without affecting social interaction. SB exposure also exerted transient anxiolytic-like effects, while having induced a long-lasting depression-like effect without effects on memory formation. Postweaning SB exposure increased serum TMAO levels in mice, especially in lower-ranked mice, but decreased in higher-ranked mice. LIMITATIONS: Lack of understanding of the underlying mechanism. CONCLUSIONS: These findings provide direct evidence, for the first time, that postweaning SB exposure produces long-term effects on social behaviors in adult mice, mainly referring to sexual orientation, social dominance, and depression-like behaviors, which may be related to the serum TMAO levels, highlighting the long-lasting potential effects of gut-brain interaction on social behaviors.
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[Mechanism of Xiangshao Granules in alleviating anxiety and depression in mice based on integrated metabolomics and gut microbiota].
This study aims to investigate the mechanism through which Xiangshao Granules treat anxiety and depression using metabolomics and gut microbiota techniques, combined with animal experiments. Sixty female ICR mice were selected for the experiment and randomly divided into six groups: a control group, a model group, a low-dose Xiangshao Granules group, a medium-dose Xiangshao Granules group, a high-dose Xiangshao Granules group, and an estradiol(positive drug) group. Except for the control group, rats in other groups were induced for anxiety and depression model by ovariectomy(OVX) combined with chronic unpredictable mild stress(CUMS). After successful modeling, the mice received oral administration of Xiangshao Granules or estradiol for three weeks. Anxiety and depression behaviors in mice were evaluated using light-dark box tests, open field tests, and elevated plus-maze tests. The levels of substances closely related to anxiety and depression, such as serotonin(5-HT) and estrogen(E_2), were quantified in plasma and hippocampal tissue using enzyme-linked immunosorbent assay(ELISA). Metabolomics and 16S rDNA amplicon sequencing techniques were employed to analyze the regulatory effects of Xiangshao Granules on plasma metabolites and metabolic pathways in anxiety and depression mice, as well as their impact on the distribution of gut microbiota. Finally, the correlation between plasma metabolites and differential gut microbiota was constructed using the Spearman correlation coefficient method. Behavioral experimental results indicated that, compared to the control group, the model group exhibited significantly decreased dwell time in the light box, reduced total distance in the open field, and diminished dwell time in the open arm. In contrast, high dose of Xiangshao Granules were found to increase the dwell time in the light box and total distance in the open field. ELISA results indicated that the levels of 5-HT, gamma-aminobutyric acid(GABA), E_2 were significantly decreased, luteinizing hormone(LH), adrenocorticotropic hormone(ACTH), and corticosterone(CORT) were significantly elevated in the anxiety and depression mice, and treatment with middle, high dose of Xiangshao Granules reversed the levels of these substances. Additionally, in the anxiety and depression mouse model, the levels of follicle-stimulating hormone(FSH) were significantly increased, whereas middle, high dose of Xiangshao Granules decreased FSH levels. Metabolomics analysis revealed that Xiangshao Granules significantly changed the metabolic profile of the anxiety and depression mice, affecting central carbon metabolism, amino acid biosynthesis, and ABC transporter pathways. The results from 16S rDNA amplicon sequencing showed that Xiangshao Granules improved the relative abundance of genera such as Bacteroidia, Bacilli, Lactobacillales, and Lactobacillus. Spearman correlation analysis indicated a close association between specific differential gut microbiota and plasma differential metabolites. This study suggests that Xiangshao Granules significantly ameliorate anxiety and depression symptoms in mice by altering the levels of substances associated with these conditions, including 5-HT, GABA, E_2, LH, and ACTH. The metabolomics and gut microbiota data suggest that the therapeutic mechanism may be closely related to the regulation of amino acid biosynthesis, central carbon metabolism, and the alteration of key microbial community compositions.