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

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.

Fecal microbiota transplantation from individual with bipolar disorder and healthy control elicits distinct behaviors and metabolite profiles in mice

“…Mice receiving FMT from individuals with ADHD exhibited neurological changes and anxiety-related behaviors associated with ADHD [17]. Furthermore, FMT from a human donor with BD to mice affected the expression of TRANK1 [18], a gene whose down-regulation in the brain is associated with BD [19]. FMT also has therapeutic potential.…”

“…Furthermore, FMT from a human donor with BD to mice affected the expression of TRANK1 [18], a gene whose down-regulation in the brain is associated with BD [19].…”

“…One study found that depression-like behavior is transferable from humans to mice via FMT [25], and another showed that mice receiving FMT from individuals with ADHD exhibited neurological changes and anxiety-related behaviors associated with ADHD [12]. Furthermore, gut microbiota transferred from a human with BD to mice was shown to affect the expression of TRANK1 [26], a gene whose down-regulation in the brain is associated with BD neuropathogenesis [27]. FMT also has therapeutic potential.…”

Gut Microbial Dysbiosis and Cognitive Impairment in Bipolar Disorder: Current Evidence

“… Altered gut microbial composition in BD. 1 ( Hu et al, 2019 ); 2 ( Lai J. et al, 2021 ); 3 ( Rong et al, 2019 ); 4 ( Zheng et al, 2020 ); 5 ( Evans et al, 2017 ) …”

“…Consistently, gut-derived LPS-related immune activation has been observed in BD patients ( Rudzki and Szulc, 2018 ). In mice transplanted with intestinal flora from BD patients, elevated levels of inflammatory cytokines and TRANK1 messenger RNA ( TRANK1 is an important risk gene of BD) in the hippocampus and prefrontal cortex may be associated with LPS stimulation of BV-2 microglia ( Lai J. et al, 2021 ). Therefore, LPS leakage due to gut microbial dysbiosis may play an important role in cognitive impairment in BD.…”