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Charismatic Microfauna

February 11, 2012

As promised, I present you with Installment #1 in a trio of articles discussing the contribution of microbes to our overall health. In a 2011 paper published in Proceedings of the National Academy of Sciences in 2011, Javier Bravo and co-authors described the beneficial effects of feeding bacteria to mice.  These weren’t just any bacteria, though. These were probiotics, or helpful bacteria, of the species Lactobacillus rhamnosus. Probiotics are often touted to improve intestinal health with euphemisms about “regularity,” but Bravo and colleagues didn’t dally with improved intestinal function. Their paper was truly remarkable because, in mice, probiotics reduced indicators of anxiety and depression. Yes, folks, you heard it right – mood-altering bacteria!

At this point, you probably have a lot of questions. What, exactly, are probiotics? How do scientists measure anxiety in a mouse, for crying out loud? Are microbes the next Xanax? Read on…

What are probiotics, anyway?

Literally, “probiotic” means “for life”. According to the World Health Organization, probiotics are bacterial cultures that confer a health benefit. Probiotic supplements consist of millions of bacterial cells, conveniently packaged in food or pill form. The ick factor of intentionally consuming millions of bacteria might be off-putting, but there are already billions of bacteria in your intestine that help you digest food.  Probiotic supplements are intended to be reinforcements for those good bacteria, or replace the bad bacteria that aren’t digesting your food properly.

So, OK, bacteria help digest food. Why should anyone expect that they would affect the brain, let alone someone’s mood? First off, there are no bacteria in the brain, except maybe in zombie brains. Presumably, Bravo and coauthors began ruminating (pun intended) about the role of intestinal bacteria on brain functionality and mood after learning of reports that probiotics alleviate mood problems in humans with bowel disorders. Is it possible that the bacterial populations in the intestine are acting a world away to affect brain function? Let’s explore!

How can we tell whether a mouse is anxious or depressed?

What is an anxious mouse? Is it pulling out its fur or spazzing out?  Animals can experience anxiety – possibly similar to our own – in stressful situations that might arise in nature (for example, because of a fear of heights). Specifically, Bravo et al. used these 3 tests of anxiety and depressive behavior:

  •  “Elevated plus maze” is a very simple, 4-armed maze. A mouse is placed at the center of all 4 arms and is allowed to explore the maze. Two arms are enclosed and dark (habitat that mice prefer); the other two arms are open and elevated. The conclusion in the psychological community is that a mouse that enters the open arms more frequently over a certain period of time is less anxious than one that does not.
  • Fear conditioning is similar to what you probably learned about in high school psychology class; mice are subjected to a musical tone and receive an electrical shock at the same time. Once they learn to associate the tone with a shock, they will stand still (in anticipation of the shock) when they hear the tone, even when no shock occurs. Anxiety interferes with learning, so improved learning in a fear conditioning test is usually considered to be indicative of decreased anxiety.
  • The forced swim test serves two purposes: first, it is a strenuous, stressful situation that can be used to examine what happens to a mouse after significant stress. Second, it can be used to assess depressive behaviors; a refusal to swim is considered depressed behavior.

What did the authors find?

First, probiotic-fed mice in the elevated plus maze entered open arms significantly more often: more than twice as frequently, in fact! This suggests that probiotic bacteria help reduce a normal fear – or anxiety – of heights and open spaces in mice.

Second, control and probiotic-fed mice learned and forgot the fear of shock equally quickly, but probiotic-fed mice were more likely to freeze in anticipation of the shock when they heard the musical tone. This finding begs the question: did the administration of bacteria only improve memory, or did it increase anxiety, knowing that a shock was impending?

Third, the forced swim test illustrated an anti-depressive effect of probiotic feeding because probiotic-fed mice swam more than control mice.  Furthermore, the stress-induced levels of corticosterone, an important stress hormone, were significantly lower in probiotic-fed mice, indicating that they perceived the physical stress to be less dangerous. Given that other studies have shown antidepressants to prevent increases in stress hormones, probiotics appear to cause reductions in both anxiety and depression.

Finally, the authors also measured neurotransmitters in the brain. These neurotransmitters, called “GABA,” are well-known to influence anxiety; the expression of more of them is associated with reduced anxiety. Sure enough, Bravo et al. found that probiotic-fed mice had higher expression of the neurotransmitter in parts of the brain responsible for anxiety (the frontal cortex). GABA levels also work in the opposite way to affect learning and memory in other parts of the brain (less = better learning). Probiotic-fed mice had less GABA in the parts of the brain responsible for learning and memory, corroborating the improved memory of probiotic mice in the fear conditioning experiment.

How can all of this happen?!

The vagus nerve, a large nerve that runs all the way from the brain to the intestines, is what communicates information about intestinal status to the brain. Therefore, the authors suspected the vagus nerve was the middle man communicating with the brain. So, they severed the nerve and repeated their behavioral tests. They found that all of the probiotic reductions in anxiety and depression were reversed when the vagus nerve connection was lost. This finding indicates that the vagus nerve is responsible for relaying signals from the gut, ultimately affecting what determines mood in the brain!

Closing thoughts

A reduction in anxiety, like that seen in the elevated maze, could be considered the same as an increase in boldness. Although a reduction of clinical anxiety in humans can result in major improvements in quality of life, how safe is it to increase boldness? In this study, mice were less anxious about a situation about which they arguably should be fairly anxious – the elevated maze. Will therapies that decrease anxiety result in more reckless behavior or an uptick in Camaro sales?

What are the broader impacts of these findings? Should we all start taking probiotics? Stay tuned for the next installment on how your diet affects your intestinal flora. Spoiler alert: if you eat lots of McDonalds, the answer might be yes…

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