Mol Psychiatry︱Hu Shaohua/Song Xueqin/Nie Chao team made new progress in the study of the brain-gut axis mechanism of bipolar disorder

Written by ︱ Peifen Zhang, edited by Hu Chan Chan ︱ Sizhen Wang Bipolar disorder (BD) is a common, chronic, and high self-harm serious mental illness, affecting 2-3% of the world's population [1].
Episodic depressive and/or (hypo)manic symptoms are the main clinical features, accompanied by significant cognitive and social impairment [2], which brings a heavy disease burden to patients, families and society, but the etiology is complex, and the clinical characteristics of BD are complex.
Diagnosis and treatment face great challenges
.

 In recent years, the relationship between gut microbes and human health and disease has attracted more and more attention.
The bidirectional regulation mechanism of information between the brain and gut microbes, the MGB axis, has become a hot field of neuroscience research
.

Blood, as a transporter of metabolites, may act as a communication bridge between the brain and gut microbes
.

Growing evidence suggests a strong relationship between BD and MGB axis dysfunction, but the exact mechanisms involved are unknown
.

The method of multi-omics combined analysis has opened up a new research model for in-depth understanding of the important role of the MGB axis in the pathophysiological process of BD
.

 On April 20, 2022, Professor Hu Shaohua's team from the First Affiliated Hospital of Zhejiang University School of Medicine, Song Xueqin's team from the First Affiliated Hospital of Zhengzhou University and Nie Chao's team from BGI Shenzhen published the latest research results "Multi-omics" online in Molecular Psychiatry.
Analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression”
.

This study is the first to reveal the "microbiota-gut-brain" axis of gut microbes in the pathogenesis of depression in bipolar disorder through combined analysis of blood metabolomics, fecal metagenomics, and brain network omics.
gut-brain axis, MGB axis) mechanism, suggesting that gut microbiota affects brain function by regulating blood metabolomics
.

Based on the combined analysis of serum untargeted metabolomics, fecal metagenomic sequencing, and resting-state functional magnetic resonance imaging, a total of 109 patients with BD depressive episodes and 40 healthy volunteers were recruited in this study.
Short-chain fatty acid (SCFAs) derivatives, kynurenine (KYN), kynurenic acid (KYNA), gamma-aminobutyric acid (GABA), riboflavin, and folic acid decreased serum metabolite levels, while spermine, gamma - Elevated levels of glutamylcysteine, succinic acid, malic acid and indolepyruvic acid are mainly involved in tryptophan metabolism, arginine and proline metabolism, citric acid cycle, and glutathione in the body Metabolic pathways, including metabolism, fatty acid biosynthesis, pantothenic acid and coenzyme A biosynthesis, and SCFAs metabolism, suggested that serum metabolic levels in BD patients changed significantly (Figure 1)
.

Figure 1 Comparison of serum metabolites between the bipolar disorder (BD) depressive episode patient group and the healthy control (HC) group
.

(a) The explanatory effect of phenotypic indicators on serum metabolites in the BD patient group (R2); (b) There were significant differences in serum metabolite levels between the two groups; (c) The main differential metabolite enrichment pathways between the two groups; (d) ) steroid hormone biosynthesis, tryptophan, arginine and proline metabolism, and citric acid cycle reaction steps
.

(Source: Li ZM, et al.
Mol Psychiatry, 2022) The α-diversity of gut microbes in the BD patient group decreased, while the β-diversity increased, and the structural composition and functional characteristics were also changed, mainly manifested as Streptococcaceae and Bacteroidaceae The abundance levels of Akkermansia muciniphila and Faecalibacterium prausnitzii decreased, and there were also significant intergroup differences in metabolic pathways involving amino acid metabolism and vitamin synthesis, suggesting that BD depressive episodes have gut microbial disturbances (Fig.
2)
.

Figure 2 Comparison of differences in gut microbial diversity, composition, and functional characteristics between patients with bipolar disorder (BD) depressive episodes and healthy controls (HC)
.

(Left ab) Boxplots indicate decreased gut microbial alpha diversity in the BD depressive episode group compared to the HC group
.

(Left c) Gut microbial beta diversity was elevated in the BD depressive episode group compared with the HC group
.

(Left de) The gut microbiota composition (d) and functional characteristics (e) were significantly different between the two groups
.

(Right a) Differential gut microbial composition between the two groups
.

Orange: enriched gut microbes in the BD patient group; blue: enriched gut microbes in the HC group
.

(Right b) Major differences in bacterial species (species level) between the two groups
.

(Source: Li ZM, et al.
Mol Psychiatry, 2022) At the same time, further correlation analysis showed that gut microbes were significantly correlated with serum metabolites, such as Akkermansia muciniphila, Faecalibacterium prausnitzii, etc.
, and B vitamins such as folic acid and riboflavin.
, short-chain fatty acids, KYN and GABA and other "neuro-regulatory substances" metabolic pathways are closely related (Figure 3)
.

Figure 3.
Gut microbes were significantly associated with serum metabolites in patients with bipolar disorder (BD) depressive episodes
.

(a) Number of gut microbes significantly associated with serum metabolites
.

(b) Correlation network of gut microbes and serum metabolites in BD patients
.

Red: serum metabolites, other colors: gut microbes
.

(Source: Li ZM, et al.
Mol Psychiatry, 2022) Moreover, the combined analysis of the three omics also found that the effect of serum metabolites on brain functional activity in BD patients was greater than the effect of gut microbes on brain functional activity, suggesting that serum Metabolites may mediate the regulatory effect of gut microbes on the brain, that is, gut microbes and their metabolites may transmit signals to the central nervous system through the circulatory system, thereby regulating the functional activities of the brain and participating in the pathogenesis of BD depression ( Figure 4)
.

Figure 4.
Association analysis of gut microbes, serum metabolites and brain functional activity between patients with bipolar disorder (BD) depressive episodes and healthy controls (HC)
.

(ab): Covariate analysis (CIA) of serum metabolites, gut microbes and brain functional connections; (cd): Correlation network diagrams of serum metabolites, gut microbes and brain “network” functional connections, respectively
.

(Source: Li ZM, et al.
Mol Psychiatry, 2022) Conclusion and discussion, inspiration and prospect This study is the first to analyze the gut microbes, serum metabolites and resting-state fMRI in patients with bipolar disorder (BD) depressive episodes The method of multi-omics combined analysis of data such as these revealed the close relationship between neuroactive metabolites derived from specific gut microbes and brain functional networks, further promoting the understanding of the mechanism of the "brain-gut" axis during BD depressive episodes.
, which provides new clues for further exploring the pathophysiological mechanism in the occurrence and development of BD, screening reliable biomarkers, constructing drugs with gut microbes as new therapeutic targets, and realizing accurate diagnosis and treatment of clinical BD
.

 However, since the present results were obtained on the basis of observational studies, the causal relationship between changes in gut microbes or serum metabolites and depressive episodes in BD cannot be determined
.

At the same time, the size of the sample, the diagnosis and classification of the disease, etc.
may have an impact on the results
.

In future research, it is necessary to consider the impact of more confounding factors on the results.
Longitudinal intervention studies based on time series, combined with different subtypes of BD and animal models, conduct dynamic studies and causal experimental studies
.

 Link to the original text: https://doi.
org/10.
1038/s41380-022-01569-9 Zhang Peifen (first from left), Hu Shaohua (middle), and Lai Jianbo (first from right)
.

(Photo provided by: Hu Shaohua’s team of Zhejiang University School of Medicine) Dr.
Lai Jianbo and Dr.
Zhang Peifen from the Mental Health Center of the First Hospital of Zhejiang University, and Dr.
Li Zhiming and Dr.
Ding Jiahong of Shenzhen BGI as the co-first authors, Professor Hu Shaohua of the First Hospital of Zhejiang University, Shenzhen Professor Nie Chao from BGI, Professor Song Xueqin from the First Affiliated Hospital of Zhengzhou University, Professor Karsten Kristiansen from Copenhagen University, Denmark, and Professor Susanne Brix from Technical University of Denmark are the co-corresponding authors
.

This research was funded by the National Natural Science Foundation of China, the Key R&D Program of Zhejiang Province, the Ten Thousand People Program of Zhejiang Province, and the Natural Science Foundation of Zhejiang Province.
, This project has also received strong support from the School of Brain Science and Brain Medicine, Zhejiang University! Members of Professor Hu Shaohua's team (photo courtesy of: Zhejiang University School of Medicine Hu Shaohua's team) Brief introduction of the corresponding author (swipe up and down to read) The Department of Mental Health of the First Affiliated Hospital of Zhejiang University School of Medicine was established in 1989.
Provincial and ministerial-level research platforms such as the resource bank co-construction unit, the National Mental and Mental Disease Clinical Medical Research Center Zhejiang Branch, the Zhejiang Provincial Key Laboratory of Mental Disorder Diagnosis and Prevention Technology, and the Zhejiang Engineering Research Center for Mathematical Mental Health, are the leading medical institutions in Zhejiang Province.
Key disciplines, supporting disciplines in Zhejiang Province, the first batch of national clinical pharmacology bases for psychiatry, standardized training bases for residents, the forensic psychiatry appraisal room of the Judicial Appraisal Center of Zhejiang University, and the master and doctoral degree programs in psychiatry and mental health of Zhejiang University
.

In the 2018 Chinese Hospital Science and Technology Value (STEM) list, the psychiatry department of the First Hospital of Zhejiang University ranked 9th in the specialist rankings, and ranked 10th in 2020
.

In Fudan's "Chinese Hospital Rankings", the reputation of our discipline has entered the national nomination, ranking 14th, ranking first in the psychiatry department of general hospitals in East China for 6 consecutive years, and ranking first in all psychiatric medical institutions in Zhejiang Province
.

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Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative.
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Wegbreit E, Cushman G, Puzia M, et al.
Developmental meta-analyses of the functional neural correlates of bipolar disorder.
JAMA psychiatry.
(2014), 71:926-35.
Plate making︱Sizhen Wang End of this article