A32 THE ROLE OF GUT MICROBIOTA AND TRACE AMINES IN A MURINE MODEL OF GENERALIZED ANXIETY DISORDER

Anxiety disorders are the most prevalent psychiatric conditions within primary care, affecting up to 29% of people across their lifetime. Generalized Anxiety disorder (GAD) is frequently comorbid with major depressive disorder, resulting in greater functional impairment. Gut microbiota have been shown to modulate brain chemistry and function, possibly also playing a role in the genesis of anxiety. Bacteria can produce, or interact with the host metabolism of neuroactive substances, including classical neurotransmitters and trace amines, like octopamine, which despite found in trace concentrations in the mammalian brain, can significantly affect CNS function. Trace amines alter catecholamine release, reuptake and biosynthesis, and modulate dopamine and serotonin metabolism. We investigated whether microbiota from patients with GAD and an absence of immune activation can induce altered behaviour in gnotobiotic mice and whether this is accompanied by changes in trace amines levels. Germ-free NIH Swiss mice (n=34) were colonized with microbiota from either a GAD patient (n=17) with moderate anxiety, comorbid depression, and low serum and fecal octopamine, or an age and sex-matched healthy control (HC) (n=17). Immune activation/inflammation profiles of human donors was assessed from tissue and plasma cytokines, CRP and β-defensin-3 levels. Microbiota profiles were assessed via 16S rRNA based Illumina. Three weeks post-colonization, mouse behaviour was assessed by standard psychometric tests. Emotionality z-scores were calculated to provide a robust integrated behavioural assessment. Fecal b-defensin-3 was measured via ELISA. After sacrifice, brain BDNF and GDNF expression will be assessed by immunofluorescence, and gene expression by qPCR. There were no differences in fecal b-defensin levels between mice with GAD and HC microbiota. However, GAD mice exhibited greater anxiety and depressive-like behavior compared to HC mice in the digging, marble-burying, step-down and tail suspensions tests. Behavioural z-scoring across all six standard psychometric tests showed a significant increase in group emotionality score means of GAD-colonized mice compared to HC-colonized mice (p= 0.02; Figure 1). Our results suggest that GAD microbiota has the ability to induce anxiety and depressive-like behavior, by mechanisms independent of the immune system, likely by altered production of trace amines. This needs to be confirmed however by full metabolomics analysis of stool and tissues samples, which is currently underway. Figure 1 - Individual and Group Emotionality Scores of GAD- and HC-colonized mice. Behavioural z-scoring across all six standardized psychometric tests showed a significant increase in group emotionality score means of GAD-colonized mice compared to HC-colonized mice (p= 0.02) NIH

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