Abstract
The present study aimed to understand the crosstalk between anxiety and gut microbiota. Exposure of mice to immobilization stress (IS) led to anxiety-like behaviors, increased corticosterone and tumor necrosis factor-α levels in the blood, increased nuclear factor (NF)-κB activation and microglia/monocyte populations in the hippocampus, and suppressed brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Furthermore, IS exposure increased NF-κB activation and monocyte population in the colon and increased Proteobacteria and Escherichia coli populations in the gut microbiota and fecal and blood lipopolysaccharide (LPS) levels while decreasing the lactobacilli population. Oral administration of the fecal microbiota of mice treated with IS (FIS) or E. coli led to the increased NF-κB activation and monocyte population in the colon. These treatments increased blood corticosterone and LPS levels and anxiety-like behaviors, decreased BDNF expression, and induced NF-κB activation and microglia/monocyte populations in the hippocampus. Intraperitoneal injection of LPS purified from E. coli also led to anxiety and colitis in mice. Oral administration of commensal lactobacilli, particularly Lactobacillus johnsonii, attenuated IS- or E. coli-induced colitis and anxiety-like behaviors and biomarkers. These findings suggest that exposure to stressors can increase Proteobacteria populations and fecal LPS levels and cause gastrointestinal inflammation, resulting in the deterioration of anxiety through NF-κB activation. However, the amelioration of gastrointestinal inflammation by treatment with probiotics including L. johnsonii can alleviate anxiety.
Highlights
Anxiety disorders are the most prevalent mental disorders, affecting up to 10% of the world’s population[1,2,3]
In order to understand the interaction between anxiety disorders and gut microbiota disturbance, we instituted immobilization stress (IS) once daily for 10 days and assessed anxiety-like behaviors in the elevated plus maze (EPM), marble-burying (MB), and light/dark transition (LDT) tasks (Fig. 1a–d)
Exposure of mice to IS for 10 days led to gradually less time spent in the open arms (OT) and open arm entries (OE) in EPM task; it significantly decreased OT and OE by 74.5% [F(1,14) = 30.193, p < 0.001] and 47.4% [F(1,14) = 22.877, p < 0.001], respectively, of that spent by mice not treated with IS
Summary
Anxiety disorders are the most prevalent mental disorders, affecting up to 10% of the world’s population[1,2,3]. Gut microbes play a role in host physiology through their contribution to nutrient and xenobiotic metabolites (e.g., vitamins, polysaccharide metabolites, and drug metabolites), microbial byproducts (e.g., short chain fatty acids and lipopolysaccharide [LPS]), immune cytokines (e.g., interleukin [IL]-6 and tumor necrosis factor [TNF]-α), neuroendocrine hormones (cortisol), and neurotransmitters (e.g., norepinephrine, dopamine, and gamma-aminobutyric acid)[16,17,18,19]. These influence the gut barrier, inflammatory response, and metabolic homeostatic control in different tissues[18,20]. To understand whether stress-induced gut microbiota could raise anxiety and what kinds of gut bacteria could alleviate or deteriorate anxiety, we investigated the gut microbiota composition in immobilization stress (IS)-treated mice, isolated commensal bacteria in the feces, and assessed their anxiety-like or anxiolytic effects in mice
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