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Detection of the role of intestinal flora and tryptophan metabolism involved in antidepressant-like actions of crocetin based on a multi-omics approach.
RATIONALE: Depression is a serious mood disorder, and crocetin has a variety of pharmacological activities, including antidepressant effect. The alterations of intestinal flora have a significant correlation with depression, and crocetin can alter the composition of intestinal flora in mice with depression-like behaviors. OBJECTIVE: This study investigated the underlying antidepressant mechanisms of crocetin through multi-omics coupled with biochemical technique validation. METHODS: Chronic unpredictable stress (CUMS) was used to induce mice model of depression to evaluate the antidepressant effect of crocetin through behavioral tests, and the metagenomic and metabolomic were used to explore the potential mechanisms involved. In order to verify its underlying mechanism, western blot (WB), Elisa, immune histological and HPLC techniques were used to detect the level of inflammatory cytokines and the level of metabolites/proteins related to tryptophan metabolism in crocetin-treated mice. RESULTS: Crocetin ameliorated depression-like behaviors and increased mobility in depressive mice induced by CUMS. Metagenomic results showed that crocetin regulated the structure of intestinal flora, as well as significantly regulated the function gene related to derangements in energy metabolism and amino acid metabolism in mice with depression-like behaviors. Metabolomic results showed that the tryptophan metabolism, arginine metabolism and arachidonic acid metabolism played an essential role in exerting antidepressant-like effect of crocetin. According to multi-omics approaches and validation results, tryptophan metabolism and inflammation were identified and validated as valuable biological processes involved in the antidepressant effects of crocetin. Crocetin regulated the tryptophan metabolism in mice with depression-like behaviors, including increased aryl hydrocarbon receptor (AhR) expression, reduced indoleamine 2,3-dioxygenase 1 (IDO1) and serotonin transporter (SERT) expression in the hippocampus, elevated the content of 5-HT, kynurenic acid in serum and 5-HT, tryptophan in hippocampus. In addition, crocetin also attenuated inflammation in mice with depression-like behaviors, which presented with reducing the production of inflammatory cytokines in serum and colon. Meanwhile, crocetin up-regulated the expression of zonula occludens 1 (ZO-1) and occludin in ileum and colon to repair the intestinal barrier for preventing inflammation transfer. CONCLUSION: Our findings clarify that crocetin exerted antidepressant effects through its anti-inflammation, repairment of intestinal barrier, modulatory on the intestinal flora and metabolic disorders, which further regulated tryptophan metabolism and impacted mitogen-activated protein kinase (MAPK) signaling pathway to enhance neural plasticity, thereby protect neural.
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Migration of CD8 + TSCM cells into intestine via PPBP-CXCR2 axis increases host stress susceptibility by inhibiting gut microbiome-derived homovanillic acid.
Psychosocial stress impacts immune system and brain function, yet mechanisms linking peripheral immune dysregulation to major depressive disorder remain unclear. Here, we demonstrate that a specific subset of T cells, the stem cell-like memory CD8+ T (TSCM) cells, is elevated in patients and stress-susceptible mice. CD8+ TSCM cells from patients display unique transcriptional programs and correlated with depression severity. Adoptive transfer of stress-derived CD8⁺ TSCM cells induced depressive-like behavior and neuroinflammation in recipients, without brain migration. Employing a whole-body immunolabeling technology, we discover CD8+ TSCM cells migrated to intestine via the interaction of pro-platelet basic protein and C-X-C motif chemokine receptor 2. CD8+ TSCM cells decrease the abundance of tyrosine-metabolizing bacteria to reducing homovanillic acid production, triggered neuroinflammation and depressive symptoms. Thus, our findings uncover a complex interplay between CD8+ TSCM cells and gut microbial metabolism, shedding light on potential mechanisms underlying depression and suggesting avenues for therapeutic intervention.
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Potential of dietary polyphenols for protection from age-related decline and neurodegeneration: a role for gut microbiota?
Many epidemiological studies have shown the beneficial effects of a largely plant-based diet, and the strong association between the consumption of a Mediterranean-type diet with healthy aging including a lower risk of cognitive decline. The Mediterranean diet is characterized by a high intake of olive oil, fruits and vegetables and is rich in dietary fiber and polyphenols - both of which have been postulated to act as important mediators of these benefits. Polyphenols are large molecules produced by plants to protect them from environmental threats and injury. When ingested by humans, as little as 5% of these molecules are absorbed in the small intestine with the majority metabolized by the gut microbiota into absorbable simple phenolic compounds. Flavan-3-ols, a type of flavonoid, contained in grapes, berries, pome fruits, tea, and cocoa have been associated with many beneficial effects on several risk factors for cardiovascular disease, cognitive function and brain regions involved in memory formation. Both preclinical and clinical studies suggest that these brain and heart benefits can be attributed to endothelial vascular effects and anti-inflammatory properties among others. More recently the gut microbiota has emerged as a potential modulator of the aging brain and intriguingly polyphenols have been shown to alter microbiota composition and be metabolized by different microbial species. However, there is a need for well controlled studies in large populations to identify predictors of response, particularly given the vast inter-individual variation of human gut microbiota.
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Talking about a microbiome revolution.
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Perturbed gut microbiota is gender-segregated in unipolar and bipolar depression.
OBJECTIVE: This study aimed to explore the gender specificity of gut microbiome in patients with unipolar and bipolar depression disorder by analyzing the data of gut microbiome in this two mental disorders and healthy people. METHODS: A case-control study using 16S ribosomal RNA gene sequencing from fecal samples of MDD (male set, n = 43; female set, n = 77) and BD (male set, n = 82; female set, n = 83) compared with HCs (male set, n = 71; female set, n = 100) was conducted. Linear discriminant analysis was used to identify microbial characteristics. Through cooccurrence analysis, the potential correlations of the differential gut microbiota in different genders was explored. Finally, the gender-specific distinguishing microorganisms were identified as biomaker, and the diagnostic performance was verified by five-fold cross validation. RESULTS: A specific cluster was found enriched only in female MDD set, including 4 Bacteroideae OTUs. Similarly, 3 Lachnospiraceae OTUs was found significantly increased in female BD compared with other groups. In addition, the consistent enrichment of Pseudomonadacea in male and female may be the characteristic disease-related gut microbiota of BD. Besides, the diagnostic potential of gender specific biomarker panel in male (male validation AUC: 0.758-0.874, accurancy: 0.693-0.792; female validation AUC: 0.727-0.883, accurancy: 0.678-0.781) and female (male validation AUC: 0.787-0.883, accurancy: 0.719-0.784; female validation AUC: 0.795-0.898, accurancy: 0.689-0.838) has also been identified and confirmed. CONCLUSIONS: The microbiological changes in both MDD and BD are sex specific, and gender specific biomarker panel has better diagnostic performance, which provide a certain reference in sex difference for future clinical differentiation and microbial intervention.
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[Comparative study on anti-depressant effect of Zhizichi Decoction and its solid fermentation product on CUMS rats].
Chronic unpredicted mild stress(CUMS) combined with isolated feeding was used to induce depressed rat model. The anti-depressant effects of Zhizichi Decoction(ZZCD) and its solid fermented product(ZZC) were analyzed by behavioral test and comparison of pathological tissues of hippocampus and liver, metabolic characteristics of intestinal flora, and relative abundance of species. The results showed that ZZC could increase sucrose preference, shorten the immobility time in the forced swim test and tail suspension test(P<0.05), and repair damaged hippocampus and liver tissues, and the effect was superior to that of ZZCD. The results of Biolog ECO plates showed that the average well color development(AWCD) of intestinal flora in the model group significantly decreased and the metabolic levels of sugar and amino acids were reduced, while the AWCD of the treatment groups increased. The metabolic levels of the two carbon sources were improved in the ZZC group, while only sugar metabolic level was elevated in the ZZCD group. Metagenomic analysis of intestinal flora showed that the ratio of Firmicutes/Bacteroidetes was 3.87 in the control group, 21.77 in the model group, 5.91 in the ZZC group, and 18.48 in the ZZCD group. Lactobacillus increased by 3.28 times, and Prevotella and Bacteroidetes decreased by 75.59% and 76.39%, respectively in the model group as compared with that in the control group. Lactobacillus decreased by 31.13%, and Prevotella and Bacteroidetes increased by more than three times in the ZZC group as compared with that in the model group, while the corresponding changes in the ZZCD group were not significant. ZZC could improve depression-like beha-viors by regulating the structure of intestinal flora and metabolic functions and repairing damaged hippocampus and liver tissues in depressed rats, showing an anti-depressant effect superior to that of ZZCD. This study is expected to provide a basis for the development of new anti-depressant food products.
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[Anti-depressant mechanism of Bupleuri Radix in regulating hippocampal FGFR1-5-HT_(1A)R heterodimer formation via intestinal flora-short-chain fatty acids].
Based on the "gut-brain" axis, this study investigated the molecular mechanism of the antidepressant effect of Bupleuri Radix. The effect of Bupleuri Radix on human intestinal flora cultured in vitro was analyzed by 16S rRNA sequencing. Differential bacteria were identified by real-time quantitative PCR(qPCR). Short-chain fatty acid(SCFA) content was determined by the GC-FID method. A depression-like mouse model was established using the "triple-one" compound stress method. Mice were administered the aqueous extract of Bupleuri Radix by gavage, transplanted with Bacteroides acidifaciens or spore-forming bacteria, or gavaged with SCFAs. Behavioral changes were assessed. SCFA content in feces was measured by GC-FID. Hippocampal(fibroblast growth factor 21, FGF21) protein expression was detected by Western blot. The formation of fibroblast growth factor receptor 1-5-hydroxytryptamine receptor 1A(FGFR1-5-HT_(1A)R) heterodimers was examined using the Duolink PLA method. The results showed that Bupleuri Radix significantly increased the abundance of the three spore-forming bacterial genera Ruminococcus, Dorea, and Blautia(P<0.05), as well as B. acidifaciens(P<0.001). Administration of Bupleuri Radix(P<0.001 or P<0.05) and transplantation of B. acidifaciens(P<0.01) both increased the levels of SCFAs such as acetic acid and butyric acid in bacterial metabolites. Treatment with Bupleuri Radix, transplantation of B. acidifaciens, or high doses of SCFAs significantly improved depression-like behaviors in mice, increased hippocampal FGF21 expression(P<0.05, P<0.01, or P<0.001), and promoted FGFR1-5-HT_(1A)R heterodimer formation(P<0.05 or P<0.01), whereas transplantation of spore-forming bacteria showed no obvious antidepressant effect. In conclusion, the antidepressant effect of Bupleuri Radix is mediated by intestinal bacteria such as B. acidifaciens, which regulate the synthesis and metabolism of SCFAs, thereby modulating hippocampal FGF21 expression and activating FGFR1-5-HT_(1A)R heterodimers.
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Impact of probiotic on anxiety and depression symptoms in pregnant and lactating women and microbiota of infants: A systematic review and meta-analysis.
BACKGROUND: Probiotics are non-invasive therapies composed of live bacteria and yeast. Administration of prebiotics improved the health status of pregnant and lactating women, as well as newborns. This review aimed to appraise the evidence concerning the effectiveness of probiotics on the mental health of pregnant women, lactating mother and the microbiota of the newborn. METHODS: This systematic review and meta-analysis ascertained quantitative studies published in Medline (PubMed), Clinical Key, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and Google scholar. Two authors independently screened and extracted the data from the primary studies that analysed the efficacy of probiotics on the mental health of pregnant and lactating women and the microbiota of the newborn. We adopted Cochrane Collaboration guidelines and reported using the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) statement. The qualities of included trials were assessed by Cochrane collaboration's risk of bias tool (ROB-2). RESULTS: Sixteen trials comprised 946 pregnant women, 524 were lactating mothers, and 1678 were infants. The sample size of primary studies ranged from 36 to 433. Probiotics were administered as interventions, using either a single strain of Bifidobacterium or Lactobacillus or a double-strain combination of Lactobacillus and Bifidobacterium. Probiotics supplementation reduced anxiety in pregnant (n = 676, standardised mean difference (SMD) = 0.01; 95% confidence interval (CI) = -0.28,0.30, P = 0.04, I2 = 70) and lactating women (n = 514, SMD = -0.17; 95% CI = -1.62,1.27, P = 0.98, I2 = 0). Similarly, probiotics decreased depression in pregnant (n = 298, SMD = 0.05; 95% CI = -0.24,0.35, P = 0.20, I2 = 40) and lactating women (n = 518, SMD = -0.10; 95% CI = -1.29,-1.05, P = 0.11, I2 = 60%). Similarly, probiotics supplementation improved the gut microbiota and reduced the duration of crying, abdominal distension, abdominal colic and diarrhoea. CONCLUSION: Non-invasive probiotic therapies are more useful to pregnant and lactating women and newborns. REGISTRATION: The review protocol was registered with PROSPERO (CRD42022372126).
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Host genetics influences the relationship between the gut microbiome and psychiatric disorders.
The gut microbiome is associated with psychiatric disorders; however, the molecular mechanisms mediating this association are poorly understood. The ability of host genetics to modulate the gut microbiome may be an important factor in understanding the association. In this study, we aimed to evaluate the role of genetic variants associated with the gut microbiome in the susceptibility of individuals to four psychiatric disorders: schizophrenia (SCZ), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and major depressive disorder (MDD). A total of 201 host genetic markers associated with microbiome outcomes and reported in available genome-wide association studies (GWAS) were included in the analyses. We searched for these variants in the summary statistics of the largest GWAS on these disorders to date, which were published by the Psychiatric Genomic Consortium, and performed gene-based and gene set association analyses. Two variants were significantly associated with ASD (rs9401458 and rs9401452) and one with MDD (rs75036654). For the gene-based association analysis, eight genes were associated with SCZ (ASIC2, KCND3, ITSN1, SIPA1L3, RBMS3, BANK1, CSMD1, and LHFPL3), one with MDD (ACTL8), two with ADHD (C14orf39 and FBXL17), and one with ASD (PINX). The gene set comprising 83 genes was associated with SCZ (p = 0.047). These findings suggest that genes related to microbiome composition may affect the susceptibility of individuals to psychiatric disorders, mainly schizophrenia. Although less robust, the associations with ASD, ADHD, and MDD cannot be discarded.
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The comprehensive pathophysiological changes in a novel rat model of postinflammatory visceral hypersensitivity.
So far, a comprehensive animal model that can mimic both the central and peripheral pathophysiological changes of irritable bowel syndrome (IBS) is lacking. Here, we developed a novel IBS rat model combining trinitro-benzene-sulfonic acid (TNBS) and chronic unpredictable mild stress (CUMS) (designated as TC-IBS) and compared it with the TNBS-induced and CUMS-induced models. TC-IBS showed a pronounced depression phenotype with increased corticotropin-releasing hormone receptor (CRHR)1 and CRHR2 expression at the frontal cortex and increased serum ACTH concentration. Visceral hypersensitivity (VH), as evidenced by colorectal distention (CRD) test, was highest in TC-IBS, accompanied by increased serum 5-hydroxytryptamine (5-HT) level and colonic 5-HT receptor 3A (5-HT3AR)/5-HT receptor 2B expression, impaired tight junction protein expression including occludin, zonula occludens-1, and phosphorylated myosin light chain. Palonosetron, a second generation of 5-HT3AR antagonist, alleviated VH significantly in TC-IBS. 16S rRNA sequencing showed that TNBS plus CUMS induced a significant disturbance of the gut microbiota. Cytokine profile analysis of TC-IBS model indicated an innate immune activation both in serum and colonic mucosa. Further, fecal microbiota transplantation improved VH and some pathophysiological changes in TC-IBS. In summary, we established a postinflammatory IBS model covering multifactorial pathophysiological changes, which may help to develop therapies that target specific IBS subtype.-Ma, J., Li, J., Qian, M., He, N., Cao, Y., Liu, Y., Wu, K., He, S. The comprehensive pathophysiological changes in a novel rat model of postinflammatory visceral hypersensitivity.