Gut bacteria steer the development of the young brain

By Ed Yong | January 31, 2011 3:00 pm

This isn’t something a mother wants to hear: when you gave birth to your child, you laced it with millions of unseen forces that are shaping the way it thinks and behaves. Under their influence, your baby’s nerves will grow and connect in ways that will affect everything from how anxious to how coordinated it is. Thanks to your very first birthday present, your infant’s brain is being shaped by its gut. Or, more accurately, what’s inside its gut.

The bowels of every baby are filled with trillions of bacteria that outnumber the cells of our own body by ten to one. This “microbiome” acts like on of our own organs, harvesting energy from our food and blocking the growth of harmful bacteria. It’s also a gift from our mothers. In the womb, we’re largely sterile. It’s only when we pass through the vagina that we’re seeded with our first set of bacteria. This community of passengers changes as we grow up, shifting in membership as we move from milk to solid food.

But the bacterial passengers of HMS Baby don’t just react as their vehicle develops; they help to steer it too. By studying mice, Rochellys Diaz Heijtz from the Karolinska Institute has found that a mammal’s gut bacteria can affect the way its brain develops as it grows up. They could even influence how it behaves as an adult.

Heijtz worked with two strains of mice – one that was completely free of germs, and another that had an intact microbiome but no disease-causing bacteria. The two strains behaved differently. The germ-free mice were more active, and spent more time scurrying around their enclosures. They were also less anxious and more likely to take risks, such as spending long periods of time in bright light or open spaces.

Could it really be that gut bacteria were behind these differences? Heijtz proved as much by transplanting the microbiome of the disease-free mice into the bowels of the germ-free ones. Sure enough, when the inoculated babies grew up, they behaved in the “normal” cautious way, just like the disease-free ones. This only worked if Hejitz did the transplants on baby mice. If she gave sterile adults a shot of gut bacteria, their behaviour didn’t change.

These differences aren’t just skin-deep. The absence of the gut bacteria also triggered a slew of changes in the rodents’ brains. Heijtz compared her germ-free and disease-free mice and found that over a hundred genes were twice as active in the brains of one strain compared to the other. Some of these genes are involved in providing cells with energy, others in chemical communications across the brain, and yet others in strengthening the connections between nerve cells.

How do these bacteria, lurking within the bowels, affect the fate of the brain, half a body away? For a start, they have a direct phone – the vagus nerve. This long branching nerve transmits information about what happens in the gut (and other organs) to the brain. But the bacteria could also route their calls via hormones. By definition, these are chemicals that can affect parts of the body over long distances. By changing hormone levels, the microbiome can ensure that what happens in the gut doesn’t stay in the gut.

For example, a Japanese team found that gut bacteria can change levels of stress hormones in the body. And an American group found that germ-free mice have almost three times more serotonin in their blood than normal ones. Heijtz herself found that chemicals like noradernaline and dopamine came and went at a faster pace in her germ-free mice. All of these chemicals could affect the way the young brain develops.

Heijtz’s mice tell us that there’s an important window in early life when the microbiome can affect the way its host develops. And this could very well depend on the bacteria that you start with. For example, babies end up with a less diverse set of skin and gut bacteria if they are delivered through Caesarean section than through the vagina. This could affect how susceptible they are to diseases. If Heijtz’s work in mice applies to humans too (and other microbiome studies have found comparable results between the two species), the way a child is born could affect its brain and behaviour.

Hejitz’s work is part of a rapidly growing number of studies, which show the wide-ranging influence of our hitch-hiking trillions. She joins Gil Sharon from Tel Aviv University, who found that the bacteria can change the sexual preferences of fruit flies. And other scientists have put forward specific species of gut bacteria as potential culprits in the development of autism.

These passengers do much more than process our food, and we are much more than just their containers. They’re part of us and our evolutionary history (you can even recap the evolution of apes by looking at the bacteria in our guts). We’re each like a superorganism – a unified alliance between the genes of several different species, only one of which is human.

Reference: Heijtz, Wang, Anuar, Qian, Björkholm, Samuelsson, Hibberd, Forssberg & Petterson. 2011. Normal gut microbiota modulates brain development and behaviour. PNAS http://dx.doi.org/10.1073/pnas.1010529108

Images by Shushruth and Rama

More on the microbiome:

http://commons.wikimedia.org/wiki/File:Mouse_cingulate_cortex_neurons.jpg

An introduction to the microbiome

mouse_neurons_gut_bacteria
apes
bacteria-with-guts
genetic-loans
introduction
our-zeroeth-birthday-present
poliovirus_reovirus
the-bacteria-that-make-you-
the-zoo-on-your-skin
your-are-what-you-eat

Comments (17)

  1. A bit on the side, and without having read more than the abstract of the article on gut bacteria and autism: I’d just like to point out that autists tend to have a pretty restricted diet, something which is bound to have an effect on the gut flora. The question then becomes: Does the gut flora in any way cause autism, or does autism (via a change in the diet) cause a changed gut flora? Correlation is not allways causation ;-)

  2. Hege, I was thinking the exact same thing when I was reading this post. :) Inflexible patterns of behavior are typical of kids with autism, and they often restrict their food selections/methods of preparation (you would be amazed at how limited some kid’s diets are, with the most bizarre combination of items). I know if I eat terribly for a few days, I feel physically horrible. I can only imagine the effects of such limited diets on the entire digestive system long-term.

  3. Assuming the gut bacteria help to break down food and provide nutrients to the mouse, is it possible that the changes in behaviour are a result of a different diet? Given the same amount of food, mice without gut flora might be hungrier than those with a complete microbiome. Maybe they were out in the light looking for something to eat. Suppose that doesn’t explain why injecting gut flora into adult mice didn’t change behaviour though…

    Is there any evidence that C-section kids are more susceptible to diseases or have behavioural differences?

  4. Michelle

    What is the effect of the increase of Caesarian births in this country on brain development? Could the exponential increase in C-sections (for doctors’ convenience) be responsible for the increase in autism?

  5. Jessica McCann

    You bring up an interesting point about early microbial colonization being key – it is starting to look like you have about a 4 week window post birth to get the right bugs in and on you, and then a 5 or so year window to cultivate them properly (drink breast milk, don’t take too many broad spectrum antibiotics, play in the dirt, etc) to get all your systems on the right track. I am a microbiologist in a pediatrics department and work with neonatology fellows trying to help preemies get the right bugs to help their guts mature. We think mostly about how the microbiome influences gut and immune development in our department, will be cool to see if this bacterially controlled mouse brain development research holds up in humans.
    I heart bacteria.

  6. Michelle2

    “It’s only when we pass through the vagina that we’re seeded with our first set of bacteria.”

    Yeah, but that’s on the outside for the most part. When we feed our human infants, we are nursing them 10-12 times a day, every day for at least a year. That day and night supply of gut bacteria has to have a significant impact on their growth and development. I would think that babies could get their most significant supply of gut bacteria (plus a whole lot of other helpful gut stuff) from mother’s milk, and that would include C-section babies.

    I would love to learn whether formula-based gut bacteria differs significantly from that in breast milk. I would be curious to learn what food(s) were the baby mice given in these experiments. Were their mothers allowed to nurse them or were they given a formula? Or a pellet of some kind?

    Also, would be interesting in finding out how antibiotics effect infant gut bacteria. Can the same healthy gut bacteria grow back after antibiotic use, or is it a whole new gut ballgame every time antibiotics are used? Does nursing after use of antibiotics fully restore the gut flora or is it forever changed? Perhaps the use of antibiotics for certain infant illnesses permanently alters the gut flora and subsequently deprives some children of the nutrition they need to develop normally, causing the increase of autism we are seeing today.

    Great article, would love to know more about this subject as it develops. Thank you!

  7. adrian paul blake

    If only some commenters would read the whole article, not just a few words they have unsubstantiated beliefs about. anyway, this really is remarkable. The ceasarian kid vs vagina kid (name needs work) question especially so. I have little brothers who are twins, one of each birth. who wants to help me cut them open?

  8. Judi

    Adrian you need not cut them open to investigate their gut bacteria. Just ask each for a handful of poop, that will give you everything you need to know concerning their gut population.

  9. Judy Converse MPH RD LD

    I work with kids in my pediatric nutrition practice who have problems like asthma, allergies, autism, adhd, growth failure, eosinophilic esophagitis, and so on. Their common denominator: Something disrupted their newborn microflora environments. It happens in many different ways. It can be C-section, premature birth plus NICU time where antibiotics were given, mom breastfeeding while needing antibiotics, mom being treated for Group B strep with antibiotics, and so on. Giving hepatitis B vaccines at birth, which contain yeast protein, add to the confusion for a newborn’s immune system. Some children in my practice disintegrate quickly when left off strong drugs like Flagyl or Diflucan, which keep yeast and other unwanted microbes in check. Their immune systems just don’t seem to have “learned” to do that. And yes – babies fed formula do develop different (less healthy) bowel microflora than babies on breast milk. And.. that mouthful of bacteria baby gets on its way out from the birth canal is the very first imprint the immune system gets. It matters – and I must wonder why our current practice so wantonly tampers with it by vaccinating immediately, using antibiotics without probiotics or antifungal measures, or offering C-sections too freely.

  10. Daniel J. Andrews

    Judy… First vaccines are at 2 months, at least according to Canada’s vaccination schedule.
    http://www.phac-aspc.gc.ca/im/is-cv/#a

    The HepB vaccine is given to infants within 12 hours after birth IF the mother is infected. http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-hepb-eng.php
    Being born with HepB will make any “confusion” from a yeast protein the least of the issues (do you have a reliable source talking about this confusion, btw?).

    problems like asthma, allergies, autism, adhd, growth failure, eosinophilic esophagitis, and so on. Their common denominator: Something disrupted their newborn microflora environments. It happens in many different ways. It can be C-section, premature birth plus NICU time where antibiotics were given, mom breastfeeding while needing antibiotics, mom being treated for Group B strep with antibiotics, and so on.

    Do you have a link to a medical academy site or peer-reviewed literature for those problems being caused by disruption of microflora environments? Anecdotal evidence is a start, but there are numerous biases that render anecdotes highly unreliable.

    Did you know that children with asthma, allergies, autism, adhd, growth failure etc have all drunk juice? That 98 percent of people in jail have eaten bread? Ban juice, ban bread. I suspect you’re making the same mistake in your quote above, just like the doctor, who seeing sick people in his office, determined that the root cause of all their ailments was masturbation (and then wrote a book about it).

    You have some valid points (e.g. offering C-sections too freely–this has been discussed in peer-review, btw), but by conflating them with fallacies and biases (correlation vs causation, sample bias, selective recall bias, etc), people may dismiss your valid points along with your evidence-free points. On science blogs, websites, you need to back up statements with reliable sources.

    Also would like to see a link that demonstrates that babies fed on formula have less healthy bowel microflora. How do you determine what is healthy or not healthy as opposed to just “different”?

  11. Paul S

    Judi and adrian paul blake,

    Judi, agreed that a handful of poop would be sufficient to study the brothers’ gut microbiomes, but adrian paul blake is correct that it may be necessary to cut open his brothers’ heads to study their brain neuroanatomy and neurophysiology, though some non-invasive studies of their brains may be possible.

  12. Helen Love

    Daniel, Judy is right. Just look on pubmed, there is plenty of research showing the difference in flora of breastfed and formula fed babies. pubmed dot com. I don’t think that comments are the place for references. My son was vacinated for Hep B in the NICU as a 2 month premature fetus, he had not even made it to his due date. How sick is that? After weeks of IV antibiotics. He was allergic to my breastmilk. Now he has autism, epilepsy, ADHD and eosinophilic esophagitis. Chronic diarrhea until I put him on probiotics. No one in my family has autism or epilepsy or eosinophilic esophagitis. The rest of us adults have allergies. We weren’t vaccinated for as many diseases as he was. We got the infections and didn’t take antibiotics. We had worms as kids. I imagine if we went through what my son did, we would also be mentally challenged, seizing and allergic to many foods. My son is 5 and canot have a conversation, he just repeats meaningless phrases over and over. It is time people find out about the things that are causing problems for our kids so we can prevent these kind of problems. I know I don’t want your tax money spent on putting my kid in an institution.

  13. susan

    Daniel, I’m glad to hear Canada waits 2 months for the Hep B vaccine. Consider yourself lucky. Here in Florida it is given on the first or second day of life – before you leave the hospital. And to clarify, I am not Hep B positive and he was not at risk for it in any way. That is just the schedule in our fine state.
    My son has developmental issues and I’ve always questioned the Hep B vaccine’s impact on his gut.

  14. Sorry to come late to the party, but after reading this paper, I’m a bit skeptical. Don’t get me wrong, I love the emerging field of gut-microbe-related stuff, but I think this paper is reaching a bit.

    First off – none of the results they see are all that striking. Sure, they’re statistically significant, but many of the changes they claim are only off by a few percent. We know there are some dramatic differences between germ-free and regular mice, these just aren’t that impressive.

    Second, Hege’s point (#1) is well taken, and not just for the autism paper. Germ-free mice are known to have poor nutrition, and don’t get up to a healthy weight. I would actually be surprised if there were NO effect on neurological development based on nutrition alone. To say that the bugs are directly causing these changes is unsupported by the evidence.

    Finally, speaking as a biochemist, the western blots in figure 6 are terrible.

  15. To kevin Bonham, I totally disagree. There is a huge amount of human based studies showing that you are way behind the eight ball on this subject.

    @ Captain Skellett: There is a huge amount of medical literature showing that babies born by caesarian have different gut flora – not just short term, but long term. PMID 18716189 is one of many.

    When a baby descends through the vagina it is not just seeded on the outside of the body. Hundreds of different bacteria, viruses, fungi – commensal flora, move speedily into the nose and mouth, and by the time the baby is born, they are well on the way down into the lungs and gut.

    Caesarian babies are first colonised by the hands of the doctors, nurses and devices put down the mouth, throat and lungs. They are also far more likely to then be routinely hit with broad spectrum antibiotics (standard “best” practice with no scientific evidence to back it) as will be the mother. PMID 19187750.

    Caesarian delivery is association with celiac Disease: PMID 20478942. Caesarian delivery results in epigenetic modulation at birth, not seen with vaginal deliveries: PMID 19638013. Caesarian babies are more likely to have allergic rhinitis and allergy sensitization: PMID 18571710, Caesarian deliver is associated with an increased risk of type 1 childhood onset diabetes: PMID: 18292986, and are at risk of increased sensitization to food allergens: PMID 19076564. Mothers who have caesarians are far more likely to seek and request medical intervention for herself, the child and the family, than mothers who have vaginal deliveries: PMID12801309.

    Caesarian delivery affects the immune system adversely and caesarian/formula fed babies have cumulative issues in this regard: PMID 10361245.

    The changes in Instinal flora of caesariean babies at birth, are PERMANENTLY different to vaginally born babies: PMID 9890463. What needs to be understood from the medical literature are: First, that the colonisation as the cervix dilates, bacteria etc move up to the baby, and the baby moves down the vagina, cannot be replicated any other way. These bacteria are ingested into the baby and form the fundamental innoculum of the gut flora, and are crucial. (If a mother has been treated with repeated antibiotics that will also affect the composition of her vaginal flora and adversely impact on the baby. At the same time, vaginal deliveries cause a catecholamine surge, which kick-starts the baby’s immune system. Ideally, from there, the baby goes to the breast where a clear fluid which is pre-colostrum, contains a surfactant which helps the primary innoculum to adhere and colonise the gut. This process is reinforced in the period before colostrum. Colostrum then comes in behind the catecholamine surge, and along with antigens and other immune components, starts orchestrating the development of the baby’s immune system.

    @ Michelle, yes, the gut flora of formula fed babies are very different from breastfed babies not just in bacterial composion but also in ph. Breast fed babies have a gut composition and ph which discourages the colonisation of yeast, and bacteria like E coli or other bacteria which excrete endo or exotoxin. The bacteria in the gut, modulated by breastmilk, are crucial for the optimal working of the baby’s immune system – and account for about 70% of the activity of the baby’s immune system. There are a lot of medical studies on this. If you look, you will find them. However, formula fed babies suffer from a confounders breast-fed babies don’t. Formula fed babies have five times higher the level of acute infections. So if a baby is a caesarian/formula baby, and the mother seeks earlier intervention, then serial antibiotics are a very real napalming threat to that baby’s gut flora. This results in excess illness as this 2010 study states: “If 90% of US families could comply with medical recommendations to breastfeed exclusively for 6 months, the United States would save $13 billion per year and prevent an excess 911 deaths, nearly all of which would be in infants ($10.5 billion and 741 deaths at 80% compliance),” PMID: 20368314.

    That doesn’t include deaths in later years for formula fed babies which could have been avoided by breastfeeding. Better explanations need to be provided to parents that breastmilk isn’t just food. Breastmilk orchestrates the developlment of the baby’s immune system; PMID 19292608, 15603202, 18716187, 17211132, helps lay down much stronger bones PMID 15155868

    Vaginal birth /breastfeeding, are the key epigenetic orchestrators of a healthy immune system PMID 16306121, and both intellectual and emotional brain development for the baby. PMID:20035247. “A shorter duration of breastfeeding may be a predictor of adverse mental health outcomes throughout the developmental trajectory of childhood and early adolescence.” PMID: 20004910. Less than six months breastfeeding was associated with poorer behaviour and higher mental health scores… a shorter duration of breastfeeding is consistently associated with increased risks for mental health problems of clinical significance throughout childhood and into adolescence” (This particular article also listed a variety of other positive indications of breastfeeding). PMID 20004910.

    Caesarians are absolutely life-saving for babies under circumstances where without abdominal removal the baby would die.

    What needs to happen now, is for scientists to stop talking about mice studies, take the human studies seriously and to see how they can work out a system whereby emergency caesarian babies are innoculated somehow with commensal flora as soon as possible. Elective caesarian parents should be informed of the known research, and short and long term outcomes of caesarians on their babies health.

    Parents need to be told the real facts about breastmilk, instead of being deceived into believing that formula offers choice, flexibility of care, and no advantages over breastmilk. If more mothers understood the life-long superior health outcomes of breastfeeding on the health of their children, paediatricians might be pressured into putting a lot more effort into giving mothers the information and support they need to successfully breastfeed, instead of the current half-hearted lip service followed by formula samples.

  16. John

    It might appear that it’s not the (non-existent?) mercury preservatives in vaccines that cause problems, but the vaccines themselves?

  17. Daniel J. Andrews

    Ed…any updates on this topic? The Nature of Things with David Suzuki had an episode on gut bacteria and a possible link to autism. Do you have any more information on this?

    And since I’m here (I’d forgotten I’d commented here before)….

    …John, of all the possible causes of autism, it has been fairly conclusively demonstrated it is NOT the scheduled vaccines.

    Helen…comments *are* the places for references. These are science-blogs, evidence-based blogs. You comment on something that is new, interesting, ground-breaking or goes against standard thinking to date, you need to post a reference so readers can tell if what you are saying should be taken seriously (e.g. reliable source cited, well done study, authors’ conclusions haven’t been misrepresented, etc). For example, since you suggested checking PubMed, see here regarding formula vs breast-feeding.

    ncbi.nlm.nih.gov/pubmed/22140499

    Some differences but formula seems good–notice though that this is a formula with an innovative mixture of oligosaccharides, which have been added to many formulas to help mimic the effects of breast milk. Pubmed has many articles on this so if anyone makes a claim that breast-feeding is better than formula and results in healthier gut flora, they need to indicate what formulas they are talking about (the ones from the 60s, 70s, 2000s?)–if they fail to indicate the differences that may mean they don’t know there are differences and may mean they haven’t actually done any research on reliable sites, so their opinion may be based on very old research.

    So when someone, like Judy, says formula-fed children develop less healthy bowel flora, but doesn’t indicate what formula types she is talking about, that sends up a red-flag. There were several other red flag statements, none of which mean she’s wrong but which do mean a closer look is warranted–and a closer looks reveals that while there are differences in gut flora between two groups, they are not labelled as healthy vs unhealthy (when it comes to oligosaccharide mixes). These differences in the long-run may indeed be unhealthy so not disagreeing there–I just want to see evidence that this is the case, and hence the need to post some references.

    Another reason to post references is to educate. So, for John and others who may think vaccines are responsible, see….

    antiantivax.flurf.net/

    Be sure to follow his references to ensure he’s obtaining his information from reliable sources.

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