National Geographic

From guts to brains – eating probiotic bacteria changes behaviour in mice

From “gut feelings” to “having some guts”, English is full of phrases where our bowels exert an influence upon our behaviour. But these are more than metaphors. There are open lines of communication between brains and bowels and, in mice at least, these channels allow an individual’s gut bacteria to steer their behaviour.

The latest evidence for this “gut-brain axis” comes from Javier Bravo at University College Cork. He fed mice with a probiotic bacterium called Lactobacillus rhamnosus, often found in yoghurts and dairy products. The bacterial menu changed the levels of signalling chemicals in the rodents’ brains, and reduced behaviours associated with stress, anxiety and depression.

Probiotic bacteria – those that benefit their host – are the subject of sweeping, hand-waving health claims. But beneath the breathless marketing hype, there is some intriguing underlying science. For example, some trials have found that probiotics can help to alleviate the mood symptoms that accompany irritable bowel or chronic fatigue syndrome. To that end, Bravo wanted to see if L.rhamnosus could influence the brains of normal, healthy animals.

Bravo found that his mice, after regularly eating Lactobacillus, were more likely to spend time in the exposed parts of a maze (a common test for anxiety symptoms) than those who ate bacteria-free meals. They were also less likely to drift motionlessly when plopped into water (a common test for depressive symptoms). And during stressful situations, they built up lower levels of stress hormones.

The bacteria also boosted the role of GABA, a restraining chemical that downplays the buzzing of excitable neurons. GABA works by docking with receptor proteins, and Bravo found that Lactobacillus increased the numbers of these receptors in parts of the brain associated with learning, memory and emotional control. The GABA system is involved in several stress-related mental conditions. For example, animals with depressive symptoms have lower levels of GABA receptors in the front of their brains, and one group of anti-anxiety drugs works by enhancing the effects of GABA receptors in humans.

It may seem odd that bacteria in an animal’s gut can control what happens in its brain, on the other side of the body. But the two organs have a direct line between them – the long, branching vagus nerve, which transmits information from the gut and other visceral organs to the brain. When Bravo severed the vagus nerve in his mice, Lactobacillus lost all of its influence. It changed neither the rodents’ behaviour nor their GABA receptor levels.

Bravo’s study is the latest in an accumulating body of evidence showing that gut bacteria are little backseat drivers for their hosts. Earlier this year, I wrote about work from Rochellys Diaz Heijtz at the Karolinska Institute, who showed that germ-free mice without any gut bacteria behave differently to mice with a normal complement. They were more active, less anxious and more likely to take risks. And when Heijtz transplanted the gut bugs from normal mice into sterile babies, the recipients behaved in the usual cautious way when they grew up. A few months later, a Canadian team led by Karen-Anne Neufeld found similar results.

These studies showed that gut bacteria can affect the way a mouse’s brain develops at a young age, and Bravo expands upon them in two important ways. First, he showed that inoculations of Lactobacillus can change the behaviour of normal, healthy mice, as opposed to artificially sterile ones. Second, he showed that this works in adults, rather than just in babies.

Premysl Bercik says, “This is a very nice and well done study.” Bercik also works on the “gut-brain axis” and in one of his earlier studies, he showed that antibacterial drugs could alter the behaviour of the same strain of mice that Bravo worked on. Those drugs greatly increased the levels of naturally occurring Lactobacillus in the rodents’ guts, and Bercik suggested that these microbes might have driven the changes in behaviour. Bravo’s new results support that idea.

The fact that doses of gut bacteria can change adult behaviour has important implications. John Cryan, who led the study, says, “It is highly plausible that probiotic agents in the future could be used to treat mood and anxiety disorders.” After all, his study has shown that these bacteria play around with the same brain chemicals in the brain that antidepressants and anti-anxiety drugs do.

This doesn’t mean that eating a lot of yoghurt will sort out a bout of depression. The idea of using gut bacteria to treat disorders isn’t far-fetched; after all, some doctors have already managed to treat people with gut infections by giving them “faecal transplants”. However, when it comes to the brain, the science is still in its early days.

Bravo still doesn’t know how the bacteria use the vagus nerve to influence the brain, only that they do. Nor does he know how long the effects on GABA and behaviour would last, or how the microbes affect other chemical signals within the brain. And critically, all of these experiments have been done in mice. No one knows if the same thing applies to humans.

“We have no reason to expect that the same would not apply to humans,” says Cryan. “However, such clinical studies need to be carried out.” However, he cautions that not all probiotics do the same thing and he warns against overinterpreting the results of the study.

Reference: Bravo, Forsythe, Chew, Escaravage, Savignac, Dinan, Bienenstock & Cryan. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. PNAShttp://dx.doi.org/10.1073/pnas.1102999108

There are 22 Comments. Add Yours.

  1. Georg
    August 29, 2011

    “Probiotic” is an invention of food industry, not some real property!
    This study mayby shows that Lactobacillus rhamnosus has that influence
    on mice, but please why do You aid that “probiotic” nonsense?

  2. Trahelion
    August 29, 2011

    Georg, What do you have to back up your claim? I used to have constant nearly crippling stomach problems until I started taking probiotics.

  3. Ed Yong
    August 29, 2011

    ““Probiotic” is an invention of food industry, not some real property!”

    Absolute bollocks. “Probiotic” simply refers to microbes that improve the health of their hosts. The term is used throughout the paper itself to describe the bacterium in question. One of the keywords is “probiotic”. The term brings up over 8,300 hits in Pubmed.

    There is no question that the term is misused by marketing people around the world as I write in the post but the fact that it’s misused does not mean that it has no use and is “nonsense”. In the same way, people talk a lot of rubbish about antioxidants, but that doesn’t stop antioxidants from being a real thing.

  4. Matt Gruner
    August 29, 2011

    It would be interesting to look at the microbial flora of individuals with unique behavioral control (or lack there of) to see if there is some influence of the nervous system on the microbes. We could compare the microflora of buddist monks to med students for example.

  5. Arwen from the Chameleon’s Tongue
    August 29, 2011

    It’s an interesting to see that gut flora can really influence behaviour, but it would be lovely to know why. What are these bacteria releasing? And could that be a better treatment for depression than the bugs themselves?

  6. corriellen
    August 30, 2011

    George, I understand your displeasure with the supplement and yogurt industry, but the word probiotic is in my microbiolgy and nutrition textbooks.

    Omega-3 cured my lifelong anxiety disorder. I thought it was a coincidence at first. Over the past 8 years, I’ve tried to stop taking it many times. Then a few days later I’m absolutely miserable again. The difference is day and night.

    Thankyou scienctist! You hard work is appreciated! Finally a cure with no side effects. However I think maybe omega-3 is addictive :)

  7. Laura
    August 30, 2011

    @Corriellen, how much did you take each day?

  8. Anne
    August 30, 2011

    While there is some solid reporting here there is one statement that is factually inaccurate.

    Mood symptoms are not part of the CDC diagnostic criteria for chronic fatigue syndrome, although like any other severe disease, depression and anxiety are a normal reaction to having contracted a severe disease that has no cure.

    And like any other disease sometimes the physical symptoms of disease are mistaken for the far less severe and specific criteria for mood disorders further muddling the scientific literature and confounding study results.

    Can microbial flora affect mood disorders? This is a bit obvious, but if the patient does not have a mood disorder, then no it is unlikely to make any difference.

    Sub-grouping patients with and without mood disorders and doing double blind trials would have to be done to create an evidence base.

    And what works in mice does not always work in humans. Mice are simply one way to keep expenses down compared to other animals that more closely mimic human reactions.

    Interesting, but a long way from being proven to make a difference in humans.

  9. badnicolez
    August 30, 2011

    I wonder if gut bacteria differ significantly between obese and normal weight people.

    Probiotics definitely prevent TD. I used to get horribly sick ever time I went to Mexico, now with the help of probiotic supplements and yogurt, no problems.

  10. Ed Yong
    August 30, 2011

    A word to the wise here, in light of Comment #7 and some of the others. As with all of medicine, a personal anecdote does not mean that something definitely prevents or treat something else. That being said, people have their own experiences, and I have no problems with people sharing them. Neither do I have any problem with people discussing the evidence for whether an intervention may or may not work.

    But in light of comment #7, this is not a venue where people are going to be swapping medical advice with each other. If the comment thread progresses in that line, I will close it.

  11. Ed Yong
    August 30, 2011

    Also to answer some other questions:

    @Anne – Nothing in the piece implies that mood symptoms are “part of the CDC diagnostic criteria for chronic fatigue syndrome” but congratulations on debunking what you read into what I said.

    @Badnicolez – Yes, there are some gut bacteria differences between obese and normal-weight people. See one of the later slides in the slideshow at the bottom.

  12. corriellen
    August 30, 2011

    @Laura, like Ed Young says, what works for me doesn’t work for everybody. If you’re on heart medication then you need to ceck with your doctor before taking large doses. I have reccomended Omega-3 to a lot of people but it didn’t work for them. Maybe i have an omega-3 metabolism deficiency or something odd like that. I’ve been considering contacting someone who is researching omega-3′s relationship to anxiety and submitting myself to a study or something. I’d personally like to know why it works for me. I don’t think scientist have been able to pinpoint why, they just know that it does work for some people.

  13. Anne
    August 31, 2011

    @ Ed – You are correct. I missed the word accompanying. My apologies.

    I still think this line of thinking has a ways to go before I would consider it evidence-based. But if scientists don’t pursue ideas then they never know whether they will pan out or lead to other discoveries that could put scientists on the right track.

    Science is definitely a fascinating process. Cool slide show.

  14. Alan C. Logan
    September 3, 2011

    Ed thank you for excellent reporting on an important topic.
    I recall attending an international probiotic conference in Montreal in 2002 and during the lunch breakout I found myself sitting with a group of young microbiologists – when I said that I was interested in the gut-brain connection and mood as influenced by bacteria, they looked at me as if I had landed from Mars…a decade later and it is finally starting to heat up.

    btw, although the contemporary work on gut bacteria and mood/behavior can be traced to Mark Lyte’s landmark paper showing that miniscule levels of C. jejuni causes anxiety (Lyte, et al. Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation. Physiol Behv 1998), if you go back even further it was dermatologists John Stokes and Donald Pillsbury that laid out a nice theory connecting the brain and gut (as well as the skin) in 1930…much of it has been confirmed to one degree or another.
    see the open access paper I recently co-authored with dermatologist Dr Whitney Bowe – Acne vulgaris, probiotics and the gut-brain-skin axis – back to the future? Gut Pathogens 2011
    as Goethe said – everything has been thought of before, but the difficulty is to think of it again…
    and for Anne, a clinical trial of probiotics and major depression is now recruiting @ Mass General (Harvard) – see “Study of Probiotic GanedenBC30 for Irritable Bowel Syndrome and Major Depressive Disorder” at clinicaltrials.gov
    Hopefully Ed will have even more exciting reports in the future…

  15. Anita Mitchell
    September 21, 2011

    Does not the microbe T. gondi (cat feces) change the behavior of infected mice ( i.e., making the mice unafraid of the scent of a cat when they would normally be petrified)?

    This isn’t the first gut microbe or set of microbes that has been found to mediate behavior in infected individuals.

  16. WP Ho @ The Conscious Life
    October 13, 2011

    Thanks for the fascinating report. The thought that bacteria can alter behavior is mind boggling. But, what if bacteria have been influencing our behaviours all along, just that we haven’t make the connection? After all, gut bacteria have been quietly producing neurotransmitters ever since humans walk the face of this planet until scientists discovered it one day.

  17. Elyn
    January 20, 2012

    Not in any way contesting the report – just having a thought about it.

    What affect has the bacteria had from the mouse’s point of view?

    In the world of a mouse, he is now more likely to space out in public, and not react as quickly when startled or uncomfortable. Just because we see beneficial changes from the context of our world, doesn’t mean that this is a positive step for the mouse.

    When you think of pain and body functions as a massive influence on mood, does anyone really understand yet what’s happening in there? Somehow your body is taking physical sensations and converting them into a worldview for your consciousness – somehow they help create your emotions, opinions, and personality.

    Personally, i feel that for as much as we do know, and much more that we are on the cusp of comprehending, consciousness still largely remains in the realm of philosophers.

    Would a wild mouse react the same way to this supplement? Lab mice are very domesticated. I’m curious to see what this does to a more self-sufficient organism. Would they become blissed-out, reckless, space cases, or just a slightly more “centered” omnivore?

    As a final stab in the dark – isn’t it likely that the natural selection is mutual? That the most successful digestive ecosystem of any species or group is the one with hosts that survive. In nature, there’s no intentional selection of foods for the “benefits”… Macaws don’t eat dirt off cliff because they heard about it on Oprah. Over a long period of time, the ones that ate more dirt just managed to stay alive longer and have more sex. Maybe the improvement was just in personality. The tough guys got bigger, or the nicer guys always got laid, or the females formed a supportive social structure. Maybe it was something subtle.

    In that case, would they even want to improve on it?

    Then again, they don’t have McDonalds.

    We’ve changed what we eat and how we live so drastically over the last century, and at such a rapid rate over the last few thousand years, that i’m not surprised the first world especially is plagued with chronic complaints. I think probiotics are a good idea. Their effect sounds mostly positive and it’s not like they’re the only thing influencing our brain function these days.

  18. Susan Durham
    June 26, 2012

    I thought this was crazy, and probably didn’t apply to humans for some reason, until I was on antibiotics for 4 weeks and suddenly out of the blue had the Big Bertha of anxiety attacks! I couldn’t go to court (I’m an attorney) and face the big bad judge. I went to a doc, who did tests, bp pretty normal, ekg good, blood flow 97% for an old bat, pretty damn good. So what was wrong with me? I had forwarded this article to a friend who knows about these things, and he called and reminded me of it when I told him about my horrible attack. So I’m gonna go get some unsweetened yogurt (I’m a no-carb paleo), even while I’m still on antibiotics! Maybe something will get as far as my brain so I can function!

  19. Susan Durham
    June 26, 2012

    After reading a few of the responses, I must put my 2 cents in about CFS. I am a life-long fibromyalgia sufferer (another auto immune disorder). When I started eating paleo, the pain and depression disappeared! After almost 60 years of pain, disability, depression, etc. Same with my daughter. And we lost 25 and 30 pounds respectively. These disorders were not evidenced on skeletons that are over 10,000 years old (when farming was invented). (Uti is 6,000 and has musculo-skeletal evidence of arthritis, and had a grain breakfast before he was killed and frozen)

  20. Susan Durham
    June 26, 2012

    And lastly, you affect the effect.

  21. Amber Shakti
    September 5, 2012

    Ive been using Probiotics for years. I’m not talking about yogurt – I don’t eat yogurt. I use VSL#3, fabulous, and I have changed, significantly. I don’t need a case study to tell me otherwise. I like the author, the scientist – and I agree with the possibility that good bacteria swimming, floating – living whatever they do – help my brain function better. I mean take a look at an image of the central nervous system, the “gut” also known as the second brain – with all of those nerve endings there – well it make sense to me and the large vagus nerve as the major highway to both – well it seems logical to me.

    I love science, but when I hear scientists ignorantly bark about the human experience – because it lacks some 50 year case study – uncontrolled – I get bored quickly. If I notice a difference, that’s all that matters and I am intelligent to make that decision. About mice….I am open to the efforts of science and the use of technology to offer up information that gives me more to think about than an arrogant doctor or scientist. Great work!

  22. Carolyn Shanahan
    October 19, 2012

    I recently got off antibiotics because I had been getting a lot of painful gas and constipation and loose stools. I started taking probiotics (Saccharomyces boulardii), and several days after that, I started to feel happy. There was a marked change in my mood which I could not explain. I also notice that I am feeling much more relaxed. I looked up “probiotics and depression” on the internet, and I was thrilled to find out about the connection between probiotics and mood! This is amazing! I also have almost no abdominal symptoms.

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