New Evidence of Gut Microbiota Involvement in the Neuropathogenesis of Bipolar Depression by TRANK1 Modulation: Joint Clinical and Animal Data.

Jianbo Lai,Huijuan Li,Caixi Xi,Peng Zheng,Peifen Zhang,Yiqing Chen,Xin Cai,Tingting Mou,Jiajun Jiang,Danhua Zhang,Ming Li,Huimin Huang,Xingle Gao,Yifan Li,Shaohua Hu,Lingling Wu

doi:10.3389/fimmu.2021.789647

Abstract

Tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1) is a robust risk gene of bipolar disorder (BD). However, little is known on the role of TRANK1 in the pathogenesis of BD and whether the gut microbiota is capable of regulating TRANK1 expression. In this study, we first investigated the serum mRNA level of TRANK1 in medication-free patients with a depressive episode of BD, then a mice model was constructed by fecal microbiota transplantation (FMT) to explore the effects of gut microbiota on brain TRANK1 expression and neuroinflammation, which was further verified by in vitro Lipopolysaccharide (LPS) treatment in BV-2 microglial cells and neurons. 22 patients with a depressive episode and 28 healthy individuals were recruited. Serum level of TRANK1 mRNA was higher in depressed patients than that of healthy controls. Mice harboring ‘BD microbiota’ following FMT presented depression-like phenotype. mRNA levels of inflammatory cytokines and TRANK1 were elevated in mice hippocampus and prefrontal cortex. In vitro, LPS treatment activated the secretion of pro-inflammatory factors in BV-2 cells, which was capable of upregulating the neuronal expression of TRANK1 mRNA. Moreover, primary cortical neurons transfected with plasmid Cytomegalovirus DNA (pcDNA3.1(+)) vector encoding human TRANK1 showed decreased dendritic spine density. Together, these findings add new evidence to the microbiota-gut-brain regulation in BD, indicating that microbiota is possibly involved in the neuropathogenesis of BD by modulating the expression of TRANK1.

Highlights

Bipolar disorder (BD) is a recurrent, debilitating mood disorder with a high heritability [1]
Compared to HCs, patients with BD depression showed an elevated level of tetratricopeptide repeat and ankyrin repeat containing 1 (TRANK1) mRNA in peripheral blood (P = 0.002, Figure 1)
An upregulated circulating TRANK1 expression was firstly reported in patients with BD depression

Summary

INTRODUCTION

Bipolar disorder (BD) is a recurrent, debilitating mood disorder with a high heritability [1]. We have systematically discussed a hypothesis that gut microbe-derived LPS could influence the host TRNAK1 expression in BD [14] These preliminary findings indicate the involvement of the microbiota-gut-brain regulation in BD. A most recently published study provided robust evidence that microbial biomolecules from the intestinal tract could be transferred to brain and other organs via outer membrane vesicles [23]. Based on these findings, we speculate that the regulatory role of gut microbiota on host genes in BD may link to a complicated neuroinflammatory mechanism. This study helps to reveal that gut microbiota may participate in the BD pathogenesis by interacting with a robust BD risk gene

METHODS

Participants

RESULTS

DISCUSSION

ETHICS STATEMENT