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Extracellular Matrix and Oxidative Phosphorylation: Important Role in the Regulation of Hypothalamic Function by Gut Microbiota - PubMed

  • ️Wed Jan 01 2020

Extracellular Matrix and Oxidative Phosphorylation: Important Role in the Regulation of Hypothalamic Function by Gut Microbiota

Xunzhong Qi et al. Front Genet. 2020.

Abstract

Background: In previous studies, our team examined the gut microbiota of healthy individuals and depressed patients using fecal microbiota transplantation of germ-free (GF) mice. Our results showed that depression-like and anxiety-like behavioral phenotypes of host mice were increased, but the molecular mechanism by which gut microbiota regulate host behavioral phenotypes is still unclear.

Methods: To investigate the molecular mechanism by which gut microbiota regulate host brain function, adult GF mice were colonized with fecal samples derived from healthy control (HC) individuals or patients with major depressive disorder (MDD). Transcriptomic profiling of hypothalamus samples was performed to detect differentially expressed genes (DEGs). qRT-PCR was used for validation experiments.

Results: Colonization germ-free (CGF) mice had 243 DEGs compared with GF mice. The most enriched KEGG pathways associated with upregulated genes were "protein digestion and absorption," "extracellular matrix (ECM)-receptor interaction," and "focal adhesion." MDD mice had 642 DEGs compared with HC mice. The most enriched KEGG pathways associated with upregulated genes in MDD mice were also "protein digestion and absorption," "ECM-receptor interaction," and "focal adhesion." Meanwhile, the most enriched KEGG pathway associated with downregulated genes in these mice was "oxidative phosphorylation," and genes related to this pathway were found to be highly correlated in PPI network analysis.

Conclusion: In summary, our findings suggested that regulation of ECM is a key mechanism shared by different gut microbiota and that inhibition of energy metabolism in the hypothalamus by gut microbiota derived from MDD patients is a potential mechanism of behavioral regulation and depression.

Keywords: extracellular matrix; gut microbiota; hypothalamus; major depressive disorder; oxidative phosphorylation.

Copyright © 2020 Qi, Zhong, Xu, Zeng, Chen, Zang, Zeng, Bai, Zhou, Wei and Xie.

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Figures

FIGURE 1
FIGURE 1

Gut microbiota promote the expression of extracellular matrix-related genes in the hypothalamus. (A) Histogram representing KEGG enrichment analysis of expressed genes upregulated in colonized germ-free (CGF) versus uncolonized germ-free (GF) mice. ***FDR < 0.001, **FDR < 0.01; (B) Chord diagram representing KEGG enrichment analysis of up-regulated genes in CGF versus GF mice. CGupC, Genes upregulated in CGF mice compared with GF mice; CGupG, Genes downregulated in CGF mice compared with GF mice.

FIGURE 2
FIGURE 2

Protein–protein interaction network construction and module analysis of genes differentially expressed between colonized germ-free (CGF) and uncolonized germ-free (GF) mice.

FIGURE 3
FIGURE 3

Gut microbiota derived from patients with major depressive disorder (MDD) promoted the expression of extracellular matrix-related genes in the hypothalamus. (A) Histogram representing KEGG enrichment analysis of expressed genes upregulated in MDD versus HC. ***FDR < 0.001, *FDR < 0.05; (B) Chord diagram representing KEGG enrichment analysis of genes upregulated in MDD versus HC. MHupM: Genes upregulated in MDD mice compared with HC mice.

FIGURE 4
FIGURE 4

Protein–protein interaction network construction and module analysis of genes differentially expressed between patients with major depressive disorder (MDD) and healthy controls (HC). (A) Extracellular matrix; (B) Oxidative phosphorylation; (C) Ribosome; (D) Neuroactive ligand-receptor interaction; (E) Spliceosome.

FIGURE 5
FIGURE 5

(A) Venn diagram of 52 overlapping differentially expressed genes (DEGs) from CG and MH; (B) Histogram representing KEGG enrichment analysis of overlapping DEGs. ***FDR < 0.001, **FDR < 0.01, *FDR < 0.05. (C) Gut microbiota promoted the expression of extracellular matrix (ECM)-related genes in the hypothalamus (n = 5); (D) Gut microbiota derived from patients with major depressive disorder promoted the expression of ECM-related genes in the hypothalamus (n = 5). **P < 0.01, *P < 0.05 (assessed by Student’s t-test); CG, DEGs between CGF mice and GF mice; MH, DEGs between MDD mice and HC mice; CG∩MH, Overlapping DEGs from CG and MH.

FIGURE 6
FIGURE 6

(A) Histogram representing KEGG enrichment analysis of genes downregulated in mice colonized with gut microbiota from patients with major depressive disorder (MDD) versus from healthy controls (HC). ***FDR < 0.001, **FDR < 0.01, *FDR < 0.05; (B) Gut microbiota derived from MDD patients reduce the expression of genes related to oxidative phosphorylation in the hypothalamus (n = 5). **P < 0.01, *P < 0.05 (assessed by Student’s t-test).

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