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The gut microbiome modulates gut–brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression

Molecular Psychiatry volume 26, pages 2380–2392 (2021)Cite this article

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Abstract

Emerging research demonstrates that microbiota-gut–brain (MGB) axis changes are associated with depression onset, but the mechanisms underlying this observation remain largely unknown. The gut microbiome of nonhuman primates is highly similar to that of humans, and some subordinate monkeys naturally display depressive-like behaviors, making them an ideal model for studying these phenomena. Here, we characterized microbial composition and function, and gut–brain metabolic signatures, in female cynomolgus macaque (Macaca fascicularis) displaying naturally occurring depressive-like behaviors. We found that both microbial and metabolic signatures of depressive-like macaques were significantly different from those of controls. The depressive-like monkeys had characteristic disturbances of the phylum Firmicutes. In addition, the depressive-like macaques were characterized by changes in three microbial and four metabolic weighted gene correlation network analysis (WGCNA) clusters of the MGB axis, which were consistently enriched in fatty acyl, sphingolipid, and glycerophospholipid metabolism. These microbial and metabolic modules were significantly correlated with various depressive-like behaviors, thus reinforcing MGB axis perturbations as potential mediators of depression onset. These differential brain metabolites were mainly mapped into the hippocampal glycerophospholipid metabolism in a region-specific manner. Together, these findings provide new microbial and metabolic frameworks for understanding the MGB axisʼ role in depression, and suggesting that the gut microbiome may participate in the onset of depressive-like behaviors by modulating peripheral and central glycerophospholipid metabolism.

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Fig. 1: Behavioral phenotypes of healthy (HC) versus depressive-like (DL) M. fascicularis.
Fig. 2: Gut microbiome differences in healthy (HC) versus depression-like (DL) M. fascicularis.
Fig. 3: Metagenomic species (MGS) differences in healthy (HC) versus depression-like (DL) M. fascicularis.
Fig. 4: Metagenomic modules correlate with depressive-like (DL) phenotypes in M. fascicularis.
Fig. 5: Metabolomic correlations with behavioral phenotypes in depressive-like (DL) M. fascicularis.
Fig. 6: Disturbance of hippocampal glycerophospholipid metabolism in depressive-like (DL) M. fascicularis.

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Funding

This work was supported by the National Key R&D Program of China (2017YFA0505700, 2016YFC1307200), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320002), Projects of International Cooperation and Exchanges NSFC (81820108015), the Natural Science Foundation Project of China (81971296, 81771490, 81371310, and 81200899), Chongqing Science & Technology Commission (cstc 2019 jcyjjqX0009), and institutional funds from the State University of New York (SUNY) Upstate Medical University. This paper is subject to the SUNY Open Access Policy.

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Author notes

  1. These authors contributed equally: Peng Zheng, Jing Wu

  2. These authors jointly supervised this work: Julio Licinio, Peng Xie

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Peng Zheng, Hanping Zhang, Bangmin Yin, Xunmin Tan, Tingjia Chai, Yu Huang, Yifan Li & Peng Xie

  2. NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, Chongqing Medical University, Chongqing, China

    Peng Zheng, Hanping Zhang, Bangmin Yin, Xunmin Tan, Tingjia Chai, Yu Huang, Yifan Li & Peng Xie

  3. Chongqing Key Laboratory of Neurobiology, Chongqing, China

    Peng Zheng, Hanping Zhang, Bangmin Yin, Xunmin Tan, Tingjia Chai, Yu Huang, Yifan Li & Peng Xie

  4. Department of Psychiatry, College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA

    Peng Zheng, Seth W. Perry, Ma-Li Wong & Julio Licinio

  5. The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing, China

    Jing Wu & Jiajia Duan

  6. Department of Neurology, Yongchuan Hospital University, Chongqing, China

    Weiwei Liang

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Contributions

Designed the experiments: PX and JL. Performed the metagenomic analysis: PZ, JW, HPZ, and YFL. Performed the metabolomic analysis: PZ, JW, YFL, and JJD. Analyzed the metagenomic and metabolomic data: PZ, JW, XMT, TJC, and H.P.Z. Animal behaviors: BMY, WWL, and YH. Drafted the paper: PX and PZ. Revised the paper for intellectual content: PX, JL, SWP, and MLW.

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Correspondence to Julio Licinio or Peng Xie.

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Zheng, P., Wu, J., Zhang, H. et al. The gut microbiome modulates gut–brain axis glycerophospholipid metabolism in a region-specific manner in a nonhuman primate model of depression. Mol Psychiatry 26, 2380–2392 (2021). https://doi.org/10.1038/s41380-020-0744-2

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