Changes in Gut Microbiota Lead to Depressive Behavior Through the Vagus Nerve in Mice
Post by Megan McCullough
The takeaway
Chronic stress induces changes in the gut microbiome that leads to deficits in hippocampal neurogenesis (i.e. the growth of new neurons) and increases in depression-related behaviors. The vagus nerve plays a key role in mediating these gut associated effects on the brain.
What's the science?
Beyond being a major risk factor for depression, chronic stress has been shown to disrupt the gut microbiome. Previous research has shown that an imbalance in the gut microbiome can affect hippocampal neurogenesis and induce behaviors associated with depression, although the exact mechanisms of this relationship are unclear. One proposed explanation for the relationship between the gut and the brain is the vagus nerve - known to facilitate bidirectional communication between the two. This week in Molecular Psychiatry, Siopi and colleagues examined the effects of gut microbiome changes on brain and behavior by transferring fecal microbiota from stressed mice into healthy mice and evaluating the effect on neurogenesis and neurotransmission. The authors then removed the vagus nerve in mice to study its impact on the relationship between gut microbiome and the brain.
How did they do it?
First, the authors exposed a group of male mice to unpredictable mild stressors such as cage shaking and cage tilting over a period of 8 weeks. After this period, fecal samples were harvested from the group of stressed mice and transferred into the gut microbiomes of mice that did not undergo these stress procedures. The authors then verified that this inoculation of stress-triggered gut microbiota activated the vagus nerve by looking at neuronal activity in the region of the brain where the vagus nerve projects.
Next, the authors studied whether vagus nerve activation affected neuronal activity in the hippocampus. This brain region is pertinent to depression research because it is involved in memory, learning, and emotional processing, and is also a site for neurogenesis. To examine the effects of vagus nerve activation on hippocampal neurons, the authors measured the levels of c-Fos proteins, a protein expressed when neurons fire action potentials. The authors then examined the behavioral effects of receiving a stressed gut microbiome. Behavioral tests to measure depression related behaviors such as the sucrose preference and novelty suppressed feeding tests were administered on the mice.
Finally, the authors tested the hypothesis that the vagus nerve mediates the effects of a stressed gut on neurogenesis and depression-related behaviors. To assess this, a group of both control mice and mice with a stressed gut microbiome underwent a procedure damaging the vagus nerve. Neuronal activity and behavior were then measured in this group of mice and compared to the groups of mice that did not have the vagotomy.
What did they find?
The authors found that transferring the gut microbiota from stressed mice into healthy mice activated the vagus nerve; there were significant c-Fos immunoreactivity patterns sustained for up to at least 24 hours after the fecal transplant. This vagus nerve activation affected neuronal activity in the hippocampus; there were also increases of c-Fos immunoreactivity in the dentate gyrus of the mice. Furthermore, the authors found a decrease in the expression of enzymes that synthesize serotonin and dopamine and decreases in the production of new neurons in the hippocampus. This suggests that changes in the gut microbiome due to stress have an impact on the neurogenesis and neuronal activity in the hippocampus. These changes in the brain translated to changes in behavior; mice with stressed gut bacteria displayed more depression-like behaviors than control mice.
When the authors studied a group of mice that underwent a vagotomy (damage to the vagal nerve), they found that these mice did not display the same depression-like behaviors nor have the same changes in brain chemistry as did mice with an intact vagus nerve. Damage to the vagus nerve was a protective factor against the neurological effects of changes in gut microbiota due to stress.
What's the impact?
This study is the first to investigate the role of the vagus nerve in mediating the effects of changes in gut microbiota due to chronic stress on neurogenesis and behaviors in adult mice. The authors found that chronic stress changes gut microbiota and activates the vagus nerve, leading to deficits in serotonin and dopamine neurotransmission that leads to decreases in neurogenesis and increases in depression related behaviors. These changes in the brain require an intact vagus nerve which illustrates the key role that the vagus nerve has in brain-gut communication. This research provides an opportunity for new therapies for treatment resistant depression.