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 (MDD), 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 are
also able to produce, or interact with the host metabolism of neuroactive substances,
including classical neurotransmitters and trace amines, like octopamine, which although
found in trace concentrations in the mammalian brain, can affect CNS function.
Specifically, trace amines can affect catecholamine release, reuptake and biosynthesis,
and modulate dopamine and serotonin metabolism.
We investigated whether microbiota from patients with GAD with no signs of immune activation can alter behaviour in gnotobiotic mice and whether this is accompanied by changes in metabolites within the gastrointestinal tract.
Germ-free NIH Swiss mice (n=35) were colonized with microbiota from either a
GAD patient (n=18) with severe anxiety, comorbid depression, and low serum and fecal
octopamine, or an age and sex-matched healthy control (HC) (n=17). Three weeks post-
colonization, mouse behaviour was assessed by standard psychometric tests. Emotionality
z-scores were calculated to provide a robust integrated behavioural assessment.
Microbiota profiles were assessed by 16S rRNA based Illumina, fecal β-defensin-3 level
was measured by ELISA. After sacrifice, mouse brain BDNF and GDNF expression was assessed by immunofluorescence, and gene expression in the hippocampus, amygdala,
and olfactory bulbs was assessed by Nanostring. Stool and cecum metabolites were
measured in all colonized mice by multisegment injection-capillary electrophoresis-mass
spectrometry (MSI-CE-MS).
There were no differences in fecal β-defensin levels between mice colonized with
GAD microbiota as compared to mice colonized with HC microbiota. However, GAD
mice exhibited greater anxiety and depressive-like behavior compared to HC mice in the
digging 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. Mice colonized with microbiota
from a GAD patient had distinct bacterial profiles from mice colonized with HC
microbiota. Compared to HC mice, GAD mice had lower levels of dopamine, octopamine
and acetylcholine in cecum contents. Furthermore, GAD mice had higher expression of
BDNF in the amygdala, lower expression of BDNF in the hippocampus, and lower
expression of GDNF in the midbrain. GAD mice also had lower expression of CCR2 in
the hippocampus, higher Cnlp/CAMP in the amygdala and olfactory bulb, and higher
Nfkb1 in the olfactory bulb compared to HC mice.
Our results suggest that microbiota from a selected patient with GAD has the
ability to induce anxiety and depressive-like behavior, by mechanisms independent of
immune system, likely by altered production of biogenic amines and neurotransmitters. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25293 |
| Date | January 2020 |
| Creators | Thrasher, Devinne |
| Contributors | Bercik, Premysl, Collins, Stephen, Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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