Neurophilosophy

THE human gut contains a diverse community of bacteria which colonize the large intestine in the days following birth and vastly outnumber our own cells. These intestinal microflora constitute a virtual organ within an organ and influence many bodily functions. Among other things, they aid in the uptake and metabolism of nutrients, modulate the inflammatory response to infection, and protect the gut from other, harmful micro-organisms. A new study by researchers at McMaster University in Hamilton, Ontario now suggests that gut bacteria may also influence behaviour and cognitive processes such as memory by exerting an effect on gene activity during brain development.

Jane Foster and her colleagues compared the performance of germ-free mice, which lack gut bacteria, with normal animals on the elevated plus maze, which is used to test anxiety-like behaviours. This consists of a plus-shaped apparatus with two open and two closed arms, with an open roof and raised up off the floor. Ordinarily, mice will avoid open spaces to minimize the risk of being seen by predators, and spend far more time in the closed than in the open arms when placed in the elevated plus maze.

This is exactly what the researchers found when they placed the normal mice into the apparatus. The animals spent far more time in the closed arms of the maze and rarely ventured into the open ones. The germ-free mice, on the other hand, behaved quite differently – they entered the open arms more often, and continued to explore them throughout the duration of the test, spending significantly more time there than in the closed arms.

The researchers then examined the animals’ brains, and found that these differences in behaviour were accompanied by alterations in the expression levels of several genes in the germ-free mice. Brain-derived neurotrophic factor (BDNF) was significantly up-regulated, and the 5HT1A serotonin receptor sub-type down-regulated, in the dentate gyrus of the hippocampus. The gene encoding the NR2B subunit of the NMDA receptor was also down-regulated in the amygdala.   

All three genes have previously been implicated in emotion and anxiety-like behaviours. BDNF is a growth factor that is essential for proper brain development, and a recent study showed that deleting TrkB, the receptor to which it binds, alters the way in which newborn neurons integrate into hippocampal circuitry and increases anxiety-like behaviours in mice. Serotonin receptors, which are distributed widely throughout the brain, are well known to be involved in mood, and compounds that activate the 5HT1A subtype also produce anxiety-like behaviours.

The finding that the NR2B subunit of the NMDA receptor down-regulated in the amygdala is particularly interesting. NMDA receptors are composed of multiple subunits, but those made up of only NR2B subunits are known to be critical for the development and function of the amygdala, which has a well established role in fear and other emotions, and for learning and memory. Drugs that block these receptors have been shown to block the formation of fearful memories and to reduce the anxiety associated with alcohol withdrawal in rodents. 

The idea of cross-talk between the brain and the gut is not new. For example, irritable bowel syndrome (IBS) is associated with psychiatric illness, and also involves changes in the composition of the bacterial population in the gut. But this is the first study to show that the absence of gut bacteria is associated with altered behaviour. Bacteria colonize the gut in the days following birth, during a sensitive period of brain development, and apparently influence behaviour by inducing changes in the expression of certain genes.

Exactly how gut bacteria might exert such influences is unclear, but they may do so via the autonomic branch of the peripheral nervous system, which controls functions such as digestion, breathing and heart rate. A better understanding of cross-talk within this so-called ‘brain-gut axis’ could lead to new approaches for dealing with the psychiatric symptoms that sometimes accompany gastrointestinal disorders such as IBS, and may also show that gut bacteria affect function of the mature brain.


Neufeld, K., et al. (2011). Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23 DOI: 10.1111/j.1365-2982.2010.01620.x

Comments

  1. #1 Interest
    March 25, 2011

    Wouldn’t taking antibiotics really damage our cognitive performance then?

  2. #2 Marco
    March 25, 2011

    For a wild animal, the tradeoff between hiding for safety and venturing out to find food is an important decision, made all day, every day. But where to set the balance? The brain must be highly attuned to the needs of the body so as to take as much risk as necessary and no more.

    Information from the digestive system is greatly important in this decision. Our eyes know how much we’ve eaten, but only the gut knows how much energy and nutrition (plus toxins etc) is in progress of being digested. It only makes sense that the gut would have wide influence over emotions as the motivator to action.

    The question seems to be whether the gut bacteria are doing something directly to influence gene expression, or if the body is merely becoming aware (through emotions) of the eating habits of the bacteria. Are they parasites that require the animal to take more risk and find more food to replace the stolen calories? Or do they help to digest food more effectively, providing a net positive effect?

    Sounds like the bacteria are causing, in effect, higher serotonin levels, which means a higher feeling of satiety and satisfaction. The brain in learning from the gut that because bacteria are helping to digest food, the animal can spend more time hiding, taking less risk in open spaces, because its food requirements are lower.

  3. #3 Ildy Flores
    March 25, 2011

    @Interest & Marco:
    The mice were kept germ-free from birth. If anything, I would think the effects are developmental. For antibiotics to damage your cognition in the same way, you’d have to be on them in the womb and out.

    I also don’t think lower serotonin receptor expression in the hippocampus means that the mice are producing more serotonin…and even if they are I don’t think serotonin in the hippocampus has much to do with satiety. If it were changing receptor levels in the hypothalamus, say, that might be more likely.

    Still a very interesting study. Order germ-free rats, study behavior, do in situ, publish. Why can’t they all be that easy?

  4. #4 CVD
    March 25, 2011

    One of our sons has autism & gut issues. We see changes in his behavior when we give him various probiotics; sometimes the changes are quite dramatic, such as a burst of clarity or head-turningly “normal” sounding comments. We work with a specialty doctor who prescribes probiotics for our son, but his primary care doctor has never recommended them. What is the state of the art research on probiotic use/cognitive measures?

  5. #5 morgan
    March 26, 2011

    As a psychotherapist, I do not prescribe anything. But on my website, I share my personal experience of having anxiety, depression, angina, panic attacks, insomnia, tinnitus, fuzzy thinking, etc. dissipate after a year-long course of probiotics to rebalance gut flora that had been disseminated after a decade of use anti-biotics prescribed for chronic sinus infection.

    I also was not breast fed as a baby, which means I did not get the good bugs my gut needed for my nervous system to develop in the best possible way. After the probiotic regimen, I no longer get sinus infections. Go figure…

    PS Please don’t use the derogatory word “germs.” Ninety nine percent of life on earth is invisible to the naked eye…

  6. #6 Sue
    March 26, 2011

    Fascinating….so, what probiotics may be better than others? I had an infection that turned severe and along with the antibiotics I was prescribed, I researched and took, on my own, a probiotic that I truly believed cured the problem. But, where do I find out more information on probiotics? Thanks in advance.

  7. #7 tee
    March 26, 2011

    The X gene that has developed over eons developed in the midst of and working with bacteria, since the scardy cat mice always hid in filthy dark dirty places. This mutual relationship was changed when the germs where taken away and the X gene thus could not function. Thus, the original brave mouse is reborn.

  8. #8 altın çilek
    March 26, 2011

    The question seems to be whether the gut bacteria are doing something directly to influence gene expression, or if the body is merely becoming aware (through emotions) of the eating habits of the bacteria. Are they parasites that require the animal to take more risk and find more food to replace the stolen calories? Or do they help to digest food more effectively, providing a net positive effect?

  9. #9 Uncle B
    March 26, 2011

    Russians, in Siberia, tried to raise silver fox for their valuable furs. much to their chagrin, they found that the Silver fox, in captivity, turned into multi-colored domestic-like puppy dogs.What did they feed them? Did it matter? Look closely at the American Negro. Compare him to his African counter-part. Did food make the difference? in only two hundred years? Check out the physical size of Asians as opposed to the physical size of Americans – big difference, especially Indians to Americans! Food again? you are what you eat? Can the horrendous American diet be equated to the falling I.Q.’s, poorer school scores, lower ratings for American schools, internationally, as most sorrowfully admitted by President Obama himself as 39th in the world? Are Americans complacent due to the variety of foods they prefer? Japanese, who eat primarily fish from the ocean, do they display national characteristics? Is this a branch of so called ‘evolution’ the current band-aid for our ignorance of things yet to be discovered? Can we move forward, believing full-heartedly the ‘evolution’ cover-all? Is this ‘evolution’ the blinkers that prevent our progress? must we teach intellectually limiting crap like this as fact in our schools? What does China teach? Same mind trap games? We must look beyond the pat answers of the 18th century to grow.

  10. #10 Erwin Alber
    March 26, 2011

    Thanks for the interesting article!

    Unless I missed it, the article doesn’t say how the researchers obtained germ-free animals. I must say that I am surprised that it doesn’t mention the importance of allowing the baby or animal to suckle as soon as possible hopefully within minutes)after it has been born. This first milk, called colostrum, is essential for populating the gut with the optimal intestinal flora.

  11. #11 Mo
    March 26, 2011

    @Erwin: Here’s a protocol for the production of germ-free mice.

  12. #12 Brock Stolley
    March 27, 2011

    I am a brain cancer survivor who had his right frontal lobe removed and then later developed ‘brain radiation syndrome’ due to the high levels of radiation I received in post-op treatment. I eat probiotic yogurt regularly and have regularly noted a ‘feel good’ reaction along with apparent increased mental clarity and capacity to work on my Sanskrit studies for longer periods of time. This fascinating article seems to lend some credence and explanation for my perceived benefits of eating probiotic yogurt, It’s not just for simple digestive health and gastrointestinal function!

  13. #13 Alan Williamson
    March 27, 2011

    Recently, they has been research in Autism and abnormal gut flora. I have IBS so I need to take probiotics every day.

  14. #14 Nancy
    March 28, 2011

    I had a brain aneursym a couple of years ago and just last week my sis had a double one in her brain too. Doesn’t the blood break some of the dendrites that flashes the synapes to each other get destroyed and grow over? Or does our brain simply re-route the pathway of our thoughts? And my main question is, does food have a big influence over that kind of trauma? And always? Or only when ur a baby? The brain is very complicated, is it not? I have learned a couple of things about consciousnes thru these experiences…

  15. #15 Sojo
    March 28, 2011

    Is it possible that the tendency for the “brave” mice to be in the open(i.e.possibly feeling driven to forage)is due to a drive to continue food intake in search(unconsciously) of the missing gut flora?

  16. #16 Kerry Maxwell
    March 28, 2011

    Interesting that this article seems to universally elicit probiotic anecdotes. It is my understanding that the article addresses gut bacteria’s effect on very early brain development in mice, and has virtually nothing to do with adult human use of probiotics. And CVD, as the parent of two autistic adult children, I have become quite suspicious of “State of the Art” research, preferring good old-fashioned scientific research, the vast majority of which has shown no link between “gut issues” and autism. A good source of info for autism related science is the blog Left Brain / Right Brain.

  17. #17 sinz54
    March 29, 2011

    The state of the art in probiotics is deliberately infecting oneself with parasitic intestinal worms, called helminths. Such therapy is reportedly successful in stabilizing the human immune system in such autoimmune disorders as Crohn’s disease. Of course, it’s a good idea to choose a species of worms that cannot multiply in the human gut, so that the infection will clear spontaneously after a few weeks. Trichuris suis (porcine whipworms) is often used for this purpose.

    The FDA has granted Trichuris suis the status of an investigational new drug, pending further research.

  18. #18 mrG
    April 21, 2011

    as father of 6, I can attest to observing behavioural changes in children given antibiotics; my guess had been a mild sort of allergic reaction (knowing how some people can react strongly to certain antibiotics) but perhaps there is more to this connection. Also, since we now know the function of the so-called ‘appendix’, I wonder if anyone has noted seemingly persistent behavioural changes following an appendectomy.

  19. #19 herky stubby
    May 11, 2011

    There are really some people who needs to intake their prescribe medicines everyday. Its not an option, but a thing to do.

  20. #20 Greatlakesian
    June 13, 2011

    I wonder if this is the same place/researcher that argued earthy bacteria (Mycobacterium vaccae) with depression in mice. Is anyone familiar with the study I’m referring to? I couldn’t find the original source for it but read it in various news articles.

  21. #21 Nicolas
    August 14, 2011

    Esto no en absoluto lo que me es necesario. Hay otras variantes?
    http://www.webddlworld.com/
    Nicolas

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