Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway

Abstract

IntroductionDepression 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.MethodsMale 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.ResultsWe 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.DiscussionIn 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.

Adverse childhood experience and depression: the role of gut microbiota

“…In a rodent study, adult rats with MS exhibited disturbance in gut microbiota, a decrease in the level of BDNF, and depressive-like behavior ( 89 ). Likewise, Male Sig-1R knockout (KO) mice showed a highly similar depressive-like phenotype ( 90 ).Li et al. further provided a possible causal relationship between the dysbiosis in gut microbes and the changes in BDNF by processing Fecal microbiota transplantation (FMT) experiments.…”

“…further provided a possible causal relationship between the dysbiosis in gut microbes and the changes in BDNF by processing Fecal microbiota transplantation (FMT) experiments. Compared to the WT-FWT group, the WT-FKO group had a significantly lower level of BDNF and also the display of depressive-like behavior ( 90 ), which indicates that specific microbial taxa changes may mediate the decline in BDNF and thereby promote residual depression-like behaviors. However, the results of clinical studies investigating the relationship between ACEs and BDNF are quite heterogeneous.…”

Current landscape of fecal microbiota transplantation in treating depression

“…Its role in influencing neuronal survival and function has attracted considerable attention as a potential therapeutic target for central nervous system diseases (74). Li et al discovered that Sig-1R KO mice exhibited depression-like behavior and gut microbiota disorder, while the depressive behavior was improved after the removal of gut microbiota through ABX treatment (75). After FMT of the Sig-1R KO group into recipient mice, the mice exhibited depression-like behavior, along with a significant decrease in the diversity and abundance of the gut microbiota, specifically Alistipes, Alloprevotella, and Lleibacterium.…”

The Interaction between CD4+ T Cells and BDNF in Depression and Its Potential Implications for Therapy

“…Indirect interactions could encompass interactions between BDNF and the gut-brain axis, primarily influenced by the interaction of CD4+ T cells with the microbiota and the release of cytokines that might impact BDNF levels [78]. In the case of anti-inflammatory cytokines like IL-4, they have been associated with stimulating astrocytic BDNF production, shifting microglial immune responses toward a neuroprotective M2 phenotype, and increasing hippocampal neurogenesis 7 [79][80] [48].…”