Fndc5/irisin deficiency leads to dysbiosis of gut microbiota contributing to the depressive-like behaviors in mice

Xing Liu; Qinxue Hu; Tianhao Xu; Qiaoli Yuan; Qin Hu; Na Hu; Weichao Sun; Yiping Bai; Li Liu; Jianguo Feng; Qian Yi

doi:10.1016/j.brainres.2023.148537

Fndc5/irisin deficiency leads to dysbiosis of gut microbiota contributing to the depressive-like behaviors in mice

Brain Res. 2023 Nov 15:1819:148537. doi: 10.1016/j.brainres.2023.148537. Epub 2023 Aug 15.

Authors

Xing Liu¹, Qinxue Hu², Tianhao Xu³, Qiaoli Yuan³, Qin Hu³, Na Hu³, Weichao Sun⁴, Yiping Bai³, Li Liu³, Jianguo Feng⁵, Qian Yi⁶

Affiliations

¹ Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Department of Anesthesiology, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Department of Anesthesiology, The Third Central Clinical College of Tianjin Medical University, Tianjin, China.
² Department of Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China.
³ Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Department of Anesthesiology, Southwest Medical University, Luzhou, Sichuan Province 646000, China.
⁴ Department of Orthopedics, Shenzhen Second People's Hospital (First Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong, China.
⁵ Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Department of Anesthesiology, Southwest Medical University, Luzhou, Sichuan Province 646000, China. Electronic address: fengjianguo@swmu.edu.cn.
⁶ Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province 646000, China. Electronic address: yiqian2010@yeah.net.

PMID: 37591459
DOI: 10.1016/j.brainres.2023.148537

Abstract

Background: Depression is one of the most common mental diseases and the leading cause of disability worldwide. A dysfunctional gut microbiota-brain axis is one of the main pathological bases of depression. Irisin, an exercise-related myokine, reduces depression-like behaviors and may guide the relief of depressive symptoms by exercise. However, its underlying mechanism remains unclear.

Methods: Fibronectin type III domain containing 5 (Fndc5)/Irisin was knocked out in male wide-type C57BL/6N mice using CRISPR-cas9. The depression and anxiety symptoms were examined in irisin knockout and control mice with or without chronic unpredictable mild stress by sucrose preference test (SPT), forced swimming test (FST), and tail suspension test (TST). Fecal microbiota was assessed by 16S rRNA sequencing and microbiota-related metabolites using liquid chromatography with tandem mass spectrometry. Differential metabolites were analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

Results: The knockout mice showed anxiety- and depression-like behaviors and altered diversity and richness of gut microbiota. At the phylum level, these mice had decreased Firmicutes and increased Bacteroidota populations, while at the genus level, they exhibited a low relative abundance of Lactobacillus and Bifidobacterium. Moreover, knocking out of Irisin gene in these mice significantly reduced N-desmethyl-mifepristone (RU 42633) and elevated (-)-stercobilin levels. The KEGG results showed that the microbiota-related metabolites affected by irisin mainly clustered into arginine and proline metabolism and affected the mechanistic target of rapamycin kinase (mTOR) signaling pathway.

Conclusion: Our findings show that Fndc5/irisin deficiency causes depression in mice by inducing dysbiosis of gut microbiota and changes in microbiota-related metabolites.

Keywords: Depression; Fndc5/irisin; Gut microbiota; Metabolites; mTOR signaling pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Depression / metabolism
Dysbiosis
Fibronectins
Gastrointestinal Microbiome* / genetics
Male
Mice
Mice, Inbred C57BL
RNA, Ribosomal, 16S

Substances

Fibronectins
RNA, Ribosomal, 16S
FNDC5 protein, mouse