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Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression

Molecular Psychiatry volume 27, pages 4123–4135 (2022)Cite this article

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Abstract

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.

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Fig. 1: Altered metabolites in serum of BD patients compared to healthy controls.
Fig. 2: Gut microbiota species associated with BD compared to controls.
Fig. 3: Relationships between specific gut microbial functions and the concentration of BD-related serum metabolites.
Fig. 4: Alterations in the gut microbial composition in patients with BD contribute to the loss in the biosynthesis of neuroactive metabolites.
Fig. 5: Characteristics of brain functional connectivity in BD patients.
Fig. 6: Gut microbiota and serum metabolome of bipolar disorder correlate with brain functional connectivity.

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Data availability

Metagenomic and neuroimaging data have been deposited into the CNGB Sequence Archive (CNSA; https://db.cngb.org/cnsa/) [85] of China National GeneBank DataBase (CNGBdb) [86] with accession number CNP0002003. The datasets generated by this study are available from the corresponding authors upon request.

Code availability

All codes used for data analysis including serum metabolome, gut microbiome and rs-fMRI are available on https://github.com/lizhiming11/BD_project.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant numbers: 81971271 and 81971253), the Zhejiang Provincial Key Research and Development Programme (Grant number: 2021C03107), the Leading Talent of Scientific and Technological Innovation - 'Ten Thousand Talents Programme' of Zhejiang Province (Grant number: 2021R52016), the Zhejiang Provincial Natural Science Foundation (Grant number: LQ20H090013), the Programme from the Health and Family Planning Commission of Zhejiang Province (Grant number: 2020KY548) and Zhong yuan Technological Innovation leading Talents (Grant number: 204200510019).

Author information

Author notes

  1. These authors contributed equally: Zhiming Li, Jianbo Lai, Peifen Zhang and Jiahong Ding.

Authors and Affiliations

  1. Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Zhiming Li, Jianbo Lai, Peifen Zhang, Jiajun Jiang, Huimin Huang, Caixi Xi, Lingling Wu, Xingle Gao, Yaoyang Fu, Danhua Zhang, Yiqing Chen, Yiyi Zhu, Shaojia Lu, Jing Lu, Dandan Wang, Hetong Zhou, Manli Huang & Shaohua Hu

  2. The Key Laboratory of Mental Disorder’s Management in Zhejiang Province, Hangzhou, 310003, China

    Jianbo Lai, Shaojia Lu, Jing Lu, Dandan Wang, Hetong Zhou, Manli Huang & Shaohua Hu

  3. Brain Research Institute of Zhejiang University, Hangzhou, 310003, China

    Jianbo Lai, Shaojia Lu, Jing Lu, Dandan Wang, Hetong Zhou, Manli Huang & Shaohua Hu

  4. Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, 310003, China

    Jianbo Lai, Shaojia Lu, Jing Lu, Dandan Wang, Hetong Zhou, Manli Huang & Shaohua Hu

  5. Wenzhou Medical University, Wenzhou, 325035, China

    Huimin Huang & Yiyi Zhu

  6. BGI-Shenzhen, Shenzhen, 518083, China

    Zhiming Li, Jiahong Ding, Chuanfa Liu, Hefu Zhen, Yuzhe Sun, Lifang Wang, Yan Li, Zhuye Jie, Huanming Yang, Wenwei Zhang, Karsten Kristiansen & Chao Nie

  7. China National GeneBank, BGI-Shenzhen, Shenzhen, 518120, China

    Zhiming Li, Jiahong Ding, Chuanfa Liu, Hefu Zhen, Yuzhe Sun, Lifang Wang, Yan Li, Zhuye Jie, Huanming Yang, Wenwei Zhang & Chao Nie

  8. Shenzhen Key Laboratory of Neurogenomics, BGI-Shenzhen, Shenzhen, 518083, China

    Zhiming Li, Jiahong Ding, Hefu Zhen, Yuzhe Sun, Lifang Wang, Yan Li, Wenwei Zhang & Chao Nie

  9. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China

    Chuanfa Liu

  10. Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083, China

    Shenghui Li

  11. Department of Psychiatry, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Xiuxia Yuan, Xue Li, Lijuan Pang & Xueqin Song

  12. Biological Psychiatry International Joint Laboratory of Henan, Zhengzhou University, Zhengzhou, 450052, China

    Xiuxia Yuan, Xue Li, Lijuan Pang & Xueqin Song

  13. Department of Biotechnology and Biomedicine, Technical University of Denmark, DK-2800 Kgs, Lyngby, Denmark

    Susanne Brix

  14. Qingdao-Europe Advanced Institute for Life Sciences, Qingdao, Shandong, 266555, China

    Susanne Brix & Karsten Kristiansen

  15. Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, DK-2100, København, Denmark

    Karsten Kristiansen

  16. Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, and MOE Frontier Science Center for Brain Science and Brain-machine Integration, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Shaohua Hu

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  1. Zhiming Li
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  2. Jianbo Lai
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  27. Lijuan Pang
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Contributions

S.H., X.S. and J.L. designed the study; Participants were recruited by J.L., P.Z., J.J., H.H., C.X., L.W., X.G., Y.F., D.Z., Y.C., Y.Z., X.Y., X.L. and L.P.; J.L. and P.Z. coordinated the data processing and availability; Data analysis was performed as follows: serum metabolome analysis (Z.L.), gut microbiota analysis (Z.L.) and neuroimaging analysis (J.D.); C.L., S.L., J.L., D.W., H.Z., M.H., H.Z., Y.S., L.W., Y.L., Z.J., S.L., W.Z. and H.Y. facilitated scientific discussion and gave suggestions; S.H., C.N., X.S. and K.K. supervised these activities; Z.L., J.D. and J.L. wrote the paper, which was revised by S.B., K.K. and S.H.; and all authors read and approved the manuscript.

Corresponding authors

Correspondence to Susanne Brix, Karsten Kristiansen, Xueqin Song, Chao Nie or Shaohua Hu.

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Li, Z., Lai, J., Zhang, P. et al. Multi-omics analyses of serum metabolome, gut microbiome and brain function reveal dysregulated microbiota-gut-brain axis in bipolar depression. Mol Psychiatry 27, 4123–4135 (2022). https://doi.org/10.1038/s41380-022-01569-9

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  • DOI: https://doi.org/10.1038/s41380-022-01569-9

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