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Aims: We aimed to investigate whether peripheral T-cell subsets could be a biomarker to distinguish major depressive disorder (MDD) and bipolar disorder (BD)., Methods: Medical records of hospitalized patients in the Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2015 to September 2020 with a discharge diagnosis of MDD or BD were reviewed. Patients who underwent peripheral blood examination of T-cell subtype proportions, including CD3+, CD4+, CD8+ T-cell, and natural killer (NK) cells, were enrolled. The Chi-square test, t-test, or one-way analysis of variance were used to analyze group differences. Demographic profiles and T-cell data were used to construct a random forest classifier-based diagnostic model., Results: Totally, 98 cases of BD mania, 459 cases of BD depression (BD-D), and 458 cases of MDD were included. There were significant differences in the proportions of CD3+, CD4+, CD8+ T-cell, and NK cells among the three groups. Compared with MDD, the BD-D group showed higher CD8+ but lower CD4+ T-cell and a significantly lower ratio of CD4+ and CD8+ proportions. The random forest model achieved an area under the curve of 0.77 (95% confidence interval: 0.71-0.83) to distinguish BD-D from MDD patients., Conclusion: These findings imply that BD and MDD patients may harbor different T-cell inflammatory patterns, which could be a potential diagnostic biomarker for mood disorders., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Preliminary studies have indicated metabolic dysfunction and gut dysbiosis in patients with bipolar disorder (BD). In this study, we aimed to clarify the impact of the gut microbial composition and function on metabolic dysfunction in BD patients with an acute depressive episode., Methods: Fresh fecal samples were provided from 58 patients with BD depression, including 29 with normal weight (NW) and 29 with overweight/obesity (OW), and 31 healthy controls (HCs). The hypervariable region of 16 S rRNA gene (V3-V4) sequencing was performed using IonS5TMXL platform to evaluate the bacterial communities. Differences of microbial community and correlation to clinical parameters across different groups were analyzed., Results: Compared to NW and HCs, the OW group showed a decreased tendency in alpha diversity index. Beta diversity was markedly different among these groups (PERMANOVA: R 2  = 0.034, p = 0.01) and was higher in patients versus HCs. A total number of 24 taxa displayed significantly different abundance among OW, NW, and HCs. At the family level, the abundance of three taxa was remarkably increased in NW, one in OW, and one in HCs. At the genus level, five taxa were enriched in OW, eight in NW, and two in HCs. The relative abundance of the genera Megamonas was positively associated with BMI, while Eggerthella was negatively correlated with BMI. Functional prediction analysis revealed the metabolism of cofactors and vitamins and amino acid were highly enriched in OW compared to HCs. In addition, microbial functions involved in "lipid metabolism" were depleted while the "fructose and mannose metabolism" was enriched in OW compared to NW group., Conclusions: Specific bacterial taxa involved in pathways regulating the lipid, energy, and amino acid metabolisms may underlie the weight concerns in depressed BD patients. Potential targeting gut microbial therapy is provided for overweight/obesity patients with BD, which still need further studies in the future., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The intricate processes of microbiota-gut-brain communication in modulating human cognition and emotion, especially in the context of mood disorders, have remained elusive. Here we performed faecal metagenomic, serum metabolomics and neuroimaging studies on a cohort of 109 unmedicated patients with depressed bipolar disorder (BD) patients and 40 healthy controls (HCs) to characterise the microbial-gut-brain axis in BD. Across over 12,000 measured metabolic features, we observed a large discrepancy (73.54%) in the serum metabolome between BD patients and HCs, spotting differentially abundant microbial-derived neuroactive metabolites including multiple B-vitamins, kynurenic acid, gamma-aminobutyric acid and short-chain fatty acids. These metabolites could be linked to the abundance of gut microbiota presented with corresponding biosynthetic potentials, including Akkermansia muciniphila, Citrobacter spp. (Citrobacter freundii and Citrobacter werkmanii), Phascolarctobacterium spp., Yersinia spp. (Yersinia frederiksenii and Yersinia aleksiciae), Enterobacter spp. (Enterobacter cloacae and Enterobacter kobei) and Flavobacterium spp. Based on functional neuroimaging, BD-related neuroactive microbes and metabolites were discovered as potential markers associated with BD-typical features of functional connectivity of brain networks, hinting at aberrant cognitive function, emotion regulation, and interoception. Our study combines gut microbiota and neuroactive metabolites with brain functional connectivity, thereby revealing potential signalling pathways from the microbiota to the gut and the brain, which may have a role in the pathophysiology of BD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Tetratricopeptide repeat and ankyrin repeat containing 1 ( TRANK1 ) is a robust risk gene of bipolar disorder (BD). However, little is known on the role of TRANK1 in the pathogenesis of BD and whether the gut microbiota is capable of regulating TRANK1 expression. In this study, we first investigated the serum mRNA level of TRANK1 in medication-free patients with a depressive episode of BD, then a mice model was constructed by fecal microbiota transplantation (FMT) to explore the effects of gut microbiota on brain TRANK1 expression and neuroinflammation, which was further verified by in vitro Lipopolysaccharide (LPS) treatment in BV-2 microglial cells and neurons. 22 patients with a depressive episode and 28 healthy individuals were recruited. Serum level of TRANK1 mRNA was higher in depressed patients than that of healthy controls. Mice harboring 'BD microbiota' following FMT presented depression-like phenotype. mRNA levels of inflammatory cytokines and TRANK1 were elevated in mice hippocampus and prefrontal cortex. In vitro , LPS treatment activated the secretion of pro-inflammatory factors in BV-2 cells, which was capable of upregulating the neuronal expression of TRANK1 mRNA. Moreover, primary cortical neurons transfected with plasmid Cytomegalovirus DNA (pcDNA3.1(+)) vector encoding human TRANK1 showed decreased dendritic spine density. Together, these findings add new evidence to the microbiota-gut-brain regulation in BD, indicating that microbiota is possibly involved in the neuropathogenesis of BD by modulating the expression of TRANK1 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lai, Zhang, Jiang, Mou, Li, Xi, Wu, Gao, Zhang, Chen, Huang, Li, Cai, Li, Zheng and Hu.)

Bipolar disorder (BD) is a common psychiatric illness with high prevalence and disease burden. Accumulating susceptibility genes for BD have been identified in recent years. However, the exact functions of these genes remain largely unknown. Despite its high heritability, gene and environment interaction is commonly accepted as the major contributing factor to BD pathogenesis. Intestine microbiota is increasingly recognized as a critical environmental factor for human health and diseases via the microbiota-gut-brain axis. BD individuals showed altered diversity and compositions in the commensal microbiota. In addition to pro-inflammatory factors, such as interleukin-6 and tumour necrosis factor-α, type 1 interferon signalling pathway is also modulated by specific intestinal bacterial strains. Disruption of the microbiota-gut-brain axis contributes to peripheral and central nervous system inflammation, which accounts for the BD aetiology. Administration of type 1 interferon can induce the expression of TRANK1, which is associated with elevated circulating biomarkers of the impaired blood-brain barrier in BD patients. In this review, we focus on the influence of intestine microbiota on the expression of bipolar gene TRANK1 and propose that intestine microbiota-dependent type 1 interferon signalling is sufficient to induce the over-expression of TRANK1, consequently causing the compromise of BBB integrity and facilitating the entrance of inflammatory mediators into the brain. Activated neuroinflammation eventually contributes to the occurrence and development of BD. This review provides a new perspective on how gut microbiota participate in the pathogenesis of BD. Future studies are needed to validate these assumptions and develop new treatment targets for BD., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Effective pharmacotherapy of bipolar depression with mixed features defined by DSM-5 remains unclear in clinical treatment guidelines. Quetiapine (QTP) and valproate have potential treatment utility but are often inadequate as monotherapy. Meanwhile, the efficacy of combination therapies of QTP plus valproate or lithium have yet to be verified. Hence, we conducted a randomized controlled pilot study to evaluate the efficacy of QTP monotherapy in patients with bipolar depression with mixed features defined by DSM-5 and compared the combination therapy of QTP plus valproate (QTP + V) versus QTP plus lithium (QTP + L) for those patients who responded insufficiently to QTP monotherapy. Data was analyzed according to the intent-to-treat population. Generalized linear mixed model was performed by using "nlme" package in R software. A total 56 patients were enrolled, among which, 35 patients responded to QTP alone, and 11 and 10 patients were randomly assigned to QTP + V and QTP + L group, respectively. Nearly 60% enrolled patients responded to QTP monotherapy at the first two weeks treatment. No statistically significant difference in efficacy between QTP + V and QTP + L was observed. In conclusion, QTP monotherapy appeared to be efficacious in patients with bipolar depression with mixed features, and for those who responded insufficiently to QTP, combining with either valproate or lithium appeared to have positive effects. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is one of the major psychiatric disorders that is characterized by recurrent episodes of depression and mania (or hypomania), leading to seriously adverse outcomes with unclear pathogenesis. There is an underlying relationship between bacterial communities residing in the gut and brain function, which together form the gut-brain axis (GBA). Recent studies have shown that changes in the gut microbiota have been observed in a large number of BD patients, so the axis may play a role in the pathogenesis of BD. This review summarizes briefly the relationship between the GBA and brain function, the composition and changes of gut microbiota in patients with BD, and further explores the potential role of GBA-related pathway in the pathogenesis of BD as well as the limitations in this field at present in order to provide new ideas for the future etiology research and drug development. [ABSTRACT FROM AUTHOR]

Trillions of microorganisms inhabiting in the human gut play an essential role in maintaining physical and mental health. The connections between gut microbiome and neuropsychiatric diseases have been recently identified. The pathogenesis of bipolar disorder, a spectrum of diseases manifesting with mood and energy fluctuations, also seems to be involved in the bidirectional modulation of the microbiome‐gut‐brain (MGB) axis. In this review, we briefly introduce the concept of MGB axis, and then focus on the previous findings in human studies associated with bipolar disorder. These studies provided preliminary evidences on the gut microbial alterations in bipolar disorder. Limitations in these studies and future directions in this research field, such as fecal microbiome transplantation and microbiome‐targeted therapy, were discussed. A research framework linking gut microbiome to determinants and health‐related outcomes in BD was also proposed. Better characterizing and understanding of gut microbial biosignatures in bipolar patients contribute to clarify the etiology of this intractable disease and pave the new way for treatment innovation. [ABSTRACT FROM AUTHOR]