Functional Relationship Between Gut Microbiota and Anxiety

Abstract

Depression and anxiety are etiologically heterogeneous disorders and their pathophysiology remains largely unknown. Gut microbiota has been shown to modulate brain function, behavior, and immune responses, and it has also been proposed to play a role in the pathophysiology of depression and anxiety. Our study aimed to investigate whether microbiota from patients with Generalized Anxiety Disorder (GAD) can induce anxiety and depressive-like behaviour in germ-free mice and whether this is accompanied by changes in immune markers and brain activity.

Germ-free NIH Swiss mice (n=27) were colonized with microbiota from either a GAD patient (n=13) with severe anxiety and comorbid depression or an age and sex-matched healthy control (HC) (n=14). Six mice from each group were treated with infliximab for three weeks (5mg/kg/week) starting at week 1 post-colonization. Microbiota profiles were assessed via 16S rRNA based Illumina. Three weeks post-colonization, all mice underwent six standard psychometric tests, including the open field, digging, marble-burying, and tail-suspension test. Cecal -defensin-3 and serum kynurenine/tryptophan were measured via ELISA. BDNF expression was assessed by immunofluorescence, and gene expression by using Nanostring gene assay.

Fecal -defensin levels were higher in GAD patients than in healthy controls. Similarly, -defensin levels were higher in GAD-colonized mice than in HC-colonized mice. GAD and HC-colonized mice had a unique and distinct microbiota, similar to that of their respective human donors. GAD-colonized mice exhibited anxiety and depressive-like behavior compared to HC- colonized mice, as assessed by the open field, digging, marble burying and tail suspension tests. BDNF expression was decreased in the hippocampus but increased in the amygdala of GAD-colonized mice. GAD-colonized mice also had a greater kynurenine/tryptophan ratio than HC-colonized mice. GAD and HC infliximab-treated mice showed no differences in behavior, central BDNF expression or kynurenine/tryptophan levels.

Our results suggest that GAD microbiota has the ability to induce anxiety and depressive-like behavior and alter brain BDNF expression in a murine host. These changes are accompanied by the activation of the innate immune system and seem to be TNF- dependent.