Buspirone alleviates anxiety, depression, and colitis; and modulates gut microbiota in mice

Dong-Hyun Kim,Min-Kyung Joo,Jeon-Kyung Kim,Sang-Kap Han

doi:10.1038/s41598-021-85681-w

Abstract

Gut microbiota regulate the neurodevelopmental processes and brain functions through the regulation of the microbiota–gut interaction and gut–brain communication. Buspirone, an agonist for serotonin 5-HT1A receptors, is used for the treatment of anxiety/depression. Therefore, to understand the gut microbiota-mediated mechanism of buspirone on anxiety/depression, we examined its effect on the immobilization stress (IS) or Escherichia coli K1 (EC)-induced anxiety/depression in mice. Oral or intraperitoneal administration of buspirone significantly suppressed stressor-induced anxiety/depression-like behaviors in the elevated plus maze, light/dark transition, tail suspension, and forced swimming tasks. Their treatments also reduced TNF-α expression and NF-κB+/Iba1+ cell population in the hippocampus and myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon. Buspirone treatments partially restored IS- or EC-induced gut microbiota perturbation such as β-diversity to those of normal control mice: they reduced the IS- or EC-induced gut Proteobacteria population. In particular, the anxiolytic activity of buspirone was positively correlated with the populations of Bacteroides and PAC001066_g in EC- or IS-exposed mice, while the populations of Lachnospiraceae, KE159660_g, LLKB_g, Helicobacter, and PAC001228_g were negatively correlated. The anti-depressant effect of buspirone was positively correlated with the Roseburia population. The fecal microbiota transplantations from buspirone-treated mice with IS-induced anxiety/depression or normal control mice suppressed IS-induced anxiety/depression-like behaviors and reduced hippocampal NF-κB+/Iba1+ and colonic NF-κB+/CD11c+ cell populations in the transplanted mice. Furthermore, they modified IS-induced perturbation of gut microbiota composition, particularly Proteobacteria, in the transplanted mice. In conclusion, buspirone alleviates IS as well as EC-induced anxiety/depression and colitis. It also suppresses associated neuroinflammation and modulates gut microbiota. Future studies can help to explain the relationship, if any, in the central and peripheral effects of buspirone.

Highlights

Anxiety/depression, the most prevalent mental disorder, are raised by exposure to stressors such as immobilization, social defeat, forced swimming, and pathogen infection[1,2]
Exposure to immobilization stress (IS) increased the anxiety-/depression-like behaviors: it decreased the time spent in the open arm (OT) in the elevated plus maze (EPM) task and time spent in the light box (TL) in the light/dark transition (LDT) task and increased immobility times in the tail suspension test (TST) and forced swimming test (FST) (Fig. 1A–D)
Exposure to stressors including immobilization, antibiotics, or pathogen infection causes anxiety-like behaviors in rodents and induced the expression of proinflammatory cytokines tumor necrosis factor (TNF)-α, IL-1β, and IL-6 in the hippocampus and colon, resulting in the occurrence of anxiety/depression and colitis[4,18,19]

Summary

Introduction

Anxiety/depression, the most prevalent mental disorder, are raised by exposure to stressors such as immobilization, social defeat, forced swimming, and pathogen infection[1,2]. Patients with anxiety disorder progress to the depressive disorder that is a common illness worldwide[2] Exposure to stressors such as immobilization stress (IS) and social defeat stimulates the secretion of adrenaline and glucocorticoids in the adrenal gland via the hypothalamic–pituitary–adrenal (HPA) axis and tumor necrosis factor (TNF)-α and interleukin (IL)-6 in immune cells, leading to the outbreak of anxiety/depression and gut inflammation[3,4]. Anti-inflammatory therapy in patients with inflammatory bowel disease (IBD) alleviates psychiatric disorder[11,12] Many medications, such as benzodiazepines and selective serotonin reuptake inhibitors, (SSRIs) are used for the treatment of anxiety/depression[13,14]. To clarify the action mechanism of buspirone, we examined the gut microbiota-mediated effects of buspirone on HPA axis-triggering IS- or MGB-triggering Escherichia coli K1 stress (EC)-induced anxiety/ depression, colitis, and gut microbiota perturbation in mice

Methods

Results

Conclusion