PMID- 37591459 OWN - NLM STAT- MEDLINE DCOM- 20230929 LR - 20231004 IS - 1872-6240 (Electronic) IS - 0006-8993 (Linking) VI - 1819 DP - 2023 Nov 15 TI - Fndc5/irisin deficiency leads to dysbiosis of gut microbiota contributing to the depressive-like behaviors in mice. PG - 148537 LID - S0006-8993(23)00308-6 [pii] LID - 10.1016/j.brainres.2023.148537 [doi] AB - 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. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Liu, Xing AU - Liu X AD - 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. FAU - Hu, Qinxue AU - Hu Q AD - Department of Critical Care Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China. FAU - Xu, Tianhao AU - Xu T AD - 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. FAU - Yuan, Qiaoli AU - Yuan Q AD - 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. FAU - Hu, Qin AU - Hu Q AD - 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. FAU - Hu, Na AU - Hu N AD - 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. FAU - Sun, Weichao AU - Sun W AD - Department of Orthopedics, Shenzhen Second People's Hospital (First Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong, China. FAU - Bai, Yiping AU - Bai Y AD - 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. FAU - Liu, Li AU - Liu L AD - 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. FAU - Feng, Jianguo AU - Feng J AD - 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. FAU - Yi, Qian AU - Yi Q AD - Department of Physiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan Province 646000, China. Electronic address: yiqian2010@yeah.net. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230815 PL - Netherlands TA - Brain Res JT - Brain research JID - 0045503 RN - 0 (Fibronectins) RN - 0 (RNA, Ribosomal, 16S) RN - 0 (FNDC5 protein, mouse) SB - IM MH - Animals MH - Male MH - Mice MH - Depression/metabolism MH - Dysbiosis MH - Fibronectins MH - *Gastrointestinal Microbiome/genetics MH - Mice, Inbred C57BL MH - RNA, Ribosomal, 16S OTO - NOTNLM OT - Depression OT - Fndc5/irisin OT - Gut microbiota OT - Metabolites OT - mTOR signaling pathway COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/08/18 00:42 MHDA- 2023/09/29 06:44 CRDT- 2023/08/17 19:20 PHST- 2023/04/24 00:00 [received] PHST- 2023/08/11 00:00 [revised] PHST- 2023/08/14 00:00 [accepted] PHST- 2023/09/29 06:44 [medline] PHST- 2023/08/18 00:42 [pubmed] PHST- 2023/08/17 19:20 [entrez] AID - S0006-8993(23)00308-6 [pii] AID - 10.1016/j.brainres.2023.148537 [doi] PST - ppublish SO - Brain Res. 2023 Nov 15;1819:148537. doi: 10.1016/j.brainres.2023.148537. Epub 2023 Aug 15.