Li Jia-Hao, Liu Jia-Li, Li Xiu-Wen, Liu Yi, Yang Jian-Zheng, Chen Li-Jian, Zhang Kai-Kai, Xie Xiao-Li, Wang Qi
Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China.
Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), Guangzhou, Guangdong, China.
Front Microbiol. 2023 Apr 6;14:1143648. doi: 10.3389/fmicb.2023.1143648. eCollection 2023.
Depression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression.
Male Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq.
We found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway.
In our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.
抑郁症是一种常见的精神障碍，全球约有3.5亿人受其影响。关于这种复杂疾病的分子机制，仍有许多未知之处。西格玛-1受体（Sig-1R）在中枢神经系统中高表达。越来越多的证据表明Sig-1R与抑郁症之间存在密切关联。最近，研究表明肠道微生物群可能在抑郁症的发生发展中起关键作用。
本研究使用雄性Sig-1R基因敲除（Sig-1R KO）小鼠和野生型（WT）小鼠。所有转基因小鼠均为纯C57BL/6J背景。小鼠连续一周每天灌胃万古霉素（100 mg/kg）、硫酸新霉素（200 mg/kg）、甲硝唑（200 mg/kg）和氨苄青霉素（200 mg/kg）以耗尽肠道微生物群。进行粪便微生物群移植（FMT）以评估肠道微生物群的影响。通过悬尾试验（TST）、强迫游泳试验（FST）和蔗糖偏好试验（SPT）评估抑郁样行为。通过16s rRNA分析肠道微生物群，并通过RNA测序评估海马转录组变化。
我们发现Sig-1R基因敲除可诱导小鼠出现抑郁样行为，包括FST和TST中不动时间显著减少以及不动潜伏期增加，而抗生素治疗清除肠道微生物群后这种情况得到逆转。Sig-1R基因敲除显著改变了肠道微生物群的组成。在属水平上，Alistipes、Alloprevotella和Lleibacterium的丰度显著降低。通过FMT实验可以重现Sig-1R基因敲除小鼠的肠道微生物群功能障碍和抑郁样表型。此外，海马RNA测序确定了多个与抑郁症相关的KEGG途径。我们还发现Sig-1R KO组中cAMP/CREB/BDNF信号通路受到抑制，同时包括CTNF、TGF-α和NGF在内的神经营养因子表达降低。来自Sig-1R KO小鼠的粪便细菌移植也抑制了cAMP/CREB/BDNF信号通路。
在我们的研究中，我们发现肠-脑轴可能是Sig-1R调节抑郁样行为的潜在机制。我们的研究为Sig-1R调节抑郁症的机制提供了新的见解，并进一步支持了肠-脑轴的概念。
