September 6, 2011 | 8
I saw this paper going around the internet early last week, and I was immediately very interested. After all, right now probiotic yogurt is the yogurt hotness, right up there with greek yogurt (and when they combine the two, someone is going to be very, very rich). Right now people think probiotic yogurt is good for your stomach, but can it also be good for your brain? I was immediately skeptical. But I read the paper, and the data is pretty convincing and with some interesting implications. But while probiotic yogurt certainly doesn’t seem to be harmful and may have some good stuff going on, I don’t know that I’d rely on it to cure your psychiatric ills just yet. We’ve still got a long way to go.
Bravo et al. “Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve” PNAS, 2011.
Your brain interacts with the body in interesting ways. I mean, we know that the brain influences the body. But it’s only recently that we’ve begun really to explore how the body influences the brain. For example, the relatively new interaction between the gut and the brain just got more complicated, with the introduction of…your bugs. The little bugs that live in your digestive tract. There is some evidence that the microbes in your gut can influence your central nervous system. But so far the evidence has largely been indirect. Right now we know that changing the gut flora of mice can change things like stress responses, but the major question…HOW.
This is important not just because of the idea of bacteria (however indirectly) controlling your brain. There are many gut disorders (the usual example is irritable bowel) which bring along with them the increased likelihood of a psychiatric disorder such as anxiety or depression. Of course, you’re always stuck with the chicken and egg problem: does your irritable bowel CAUSE psychiatric disorders, or are you showing psychiatric disorders just because you’re in a lot of gastrointestinal discomfort all the time.
And here we come to the question of probiotic bacteria. Probiotic bacteria are the good kind, the kind that live in and populate your gut. They don’t appear to do any harm, and some studies have suggested that they may help with symptoms of irritable bowel. These same studies have also looked at the emotional symptoms that tend to run with irritable bowel, like anxiety, etc, and shown that these symptoms also decreased. But again you have to wonder: are the women (irritable bowel studies are usually done in women) showing fewer anxiety symptoms because their anxiety is decreased by direct actions of the probiotic bacteria? Or are their anxiety symptoms decreased because they don’t feel all bloated and farty all the time? In other words, if the probiotic bacteria are affecting the psychiatric symptoms, we need to know HOW. We need a mechanism.
To look at the effects of probiotic bacteria in mice, the authors of this paper looked with the bacterium Lacobacillus rhamnosus, which is currently the bacteria of choice for the Amerifit Brand that produces Culturelle. They took a bunch of normal mice, and gave half of them broth, and half broth with the L rhamnosus in it, for 28 days. They then ran a series of behavioral tests, and also looked at levels of specific receptor subtypes.
For the behavioral tests, they looked at two anxiety related tests, the elevated plus maze, and the open field, and they used the forced swim test, which is used to look at the antidepressant effects of drugs. In the elevated plus maze, you have a big plus mark, big enough for a mouse to run around in, that’s a few feet off the floor. Two of the maze arms have nice high walls, and two are just a platform. The mouse likes dark and enclosed spaces, and prefers to stay in the closed arms. Mice who are especially anxious will spend even more time in the closed arms than those who are not. If you give a mouse drugs to make it LESS anxious, it will spend more time exploring the open arms of the maze. The principle of the open field is similar: mice prefer to stay near the darker edges and not in the open area of the maze, but when feeling less anxious will explore more.
In the forced swim test, you put the mouse or rat in a cylinder of water where it cannot touch the bottom. Rodents are good swimmers, and they’ll swim around until they realize there is no escape. At that point they will start to float. But when you give an animal something that is an antidepressant (like prozac) the animal will swim for longer and float less.
In both the elevated zero maze and the forced swim test, the mice with the L rhamnosus in their systems showed less anxiety and more struggle, respectively. In other tests such as fear conditioning, the mice showed less conditioned fear. They also showed a decreased corticosterone response to stress (corticosterone is the stress hormone in mice). So it looks like mice with the probiotic bacteria in their systems show different behavioral responses to stress and less anxiety-like behavior.
Of course then you want to know WHY. After all the brain and the gut are…some distance apart. So the authors looked in the brain, specifically at GABA receptor subtypes. GABA is the main inhibitory neurotransmitter in the brain, which usually serves to decrease neuronal activity. But, as we much always remind ourselves, a neurotransmitter is ONLY as good as its receptor, the protein complex that received the neurotransmitter and changes shape inside the cell membrane to transmit the message inside the next cell. In the case of GABA, there are two major types of receptors: A and B. GABA A receptors, when hit with a GABA molecule, open an ion channel, changing the internal charge of the neuron. In contrast, GABA B receptors, when hit with a GABA molecule, change shape and activate other molecules inside the neuron, in what is called a second messenger system, which can result in a huge cascade of secondary events inside the cell. And each of these receptor types is made up of little modules, receptor subtypes, which combine together to make a single receptor. Changes in these receptor subtypes can change how the receptor functions. And changes in both of these receptor types have been linked to anxiety (GABA A) and depression (GABA B).
When the authors looked at these receptor subtypes, they found that GABA A receptors AND GABA B receptors both had changes in their subtype levels. While there’s no data on what effects these particular subtype changes have behaviorally, it’s an interesting effect, because it means that the difference in the probiotic bacteria in the GUT is influencing the composition of the GABA receptors in the BRAIN. And how do the gut and the brain primarily communicate? Through the vagus nerve.
The vagus nerve is the 10th cranial nerve, and it conveys sensory information from areas like the gut back to the brain (and vice versa). To see if this was the way the probiotic bactera were having their effects, the authors CUT the vagus nerve, fed the mice some probiotic bacteria (or placebo), and checked again.
You can see that when the vagus nerve was cut (the two sets of bars on the right), the L rhamnosus bacteria had no effect on the forced swim test. They found that the GABA receptor changes were also absent when the vagus nerve was cut. This means that the probiotic bacteria may be having their effects on the brain by altering signaling from the vagus nerve.
So it looks like probiotic bacteria change vagus nerve signaling, and this can change receptor subunits in the brain, and in turn change behavioral reactions in mice. So we should all start eating probiotic yogurt, right??
Not so fast. The study has some promising implications, but there are a lot of things we still don’t know. HOW is the probiotic bacteria changing the vagus nerve signaling? By what bacteria mechanism? What do the changes in GABA subunits mean in terms of function? And yes, this was all done in mice. Healthy normal mice, without depression or anxiety. Forced swim test and elevated plus maze are good indicators, and very promising, but they aren’t proof of antidepressant behavior (for example, does this increase neurogenesis? Does it make mice more resilient to stress? What about other antidepressant-like behaviors?). Finally, is this specific to L. rhamnosus? How much of this bacteria do we even HAVE normally? Do people with, say, irritable bowel have less of it? How does this happen? While I think the probiotic bacteria may be able to tell us some interesting things about the relationship between our guts and our behavior, I’m not sure how all this is going to pan out in humans. And I don’t want people eating the probiotic yogurt (or people MARKETING the probiotic yogurt), and wondering why they are still depressed. This is a step in the right direction, but until we really know the mechanism, though the greek stuff in particular is really REALLY tasty, I wouldn’t be looking to your yogurt to change your life.
Bravo, J., Forsythe, P., Chew, M., Escaravage, E., Savignac, H., Dinan, T., Bienenstock, J., & Cryan, J. (2011). Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1102999108