Saturday, March 26, 2011

Stress and Your Gut (Or At Least A Mouse's Gut)

Several folks (Julianne and Chris Kresser come to mind) tweeted about this new paper last week, and it really is a doozy.  "Exposure to a social stressor alters the structure of the intestinal microbiota:  Implications for stressor-induced immunomodulation."  The associated editorial is worth a read as well, if you have access.  Also, the journal it comes from, "Brain, Behavior, and Immunity" is very cool.  The entire journal is devoted to subjects of interest to any psychiatrist who looks into the inflammation/brain connection.  And if inflammation itself is truly behind the pathophysiology of psychiatric disorders, then somewhere in the archives or future of this publication will be the holy grail linking inflammation via diet and lifestyle to actual brain pathology.

This paper is a nice start.  First some fun facts.  The external surfaces of the body (that includes the gut, by the way, as we are a funny tube within a tube) are populated with microbes.  So populated, in fact, that 90% of the cells that make up the roving bacteria party + human host are the commensal microbiome.  Yup.  90% of you (by cell number) is them.  Most of these colonizers and symbiotes live in the intestine, especially the large intestine.  In the Matrix world of commensal species, the large intestine is Zion.

Here's the crazy thing - we know very little about these species.  Mostly because the vast majority seem to be absolutely dependent upon us (as we turn out to be symbiotically dependent on them).  They can't be cultured without the host in a lab.  They need a living working gut, where they flourish, but are difficult to study.   That means we didn't have the capability even to catalog the species of gut bacteria until we could practically and relatively cheaply sequence DNA in large amounts, so not until the last 7 years or so.

The beasties live in a "largely stable climax community" in our guts as the result of natural selection for species best adapted to our habits and personal nooks and crannies.  Fortunately, the beastie community is pretty resilient, but factors such as a change in diet and antibiotics will obviously transiently affect the population.  In addition, exposure to stress also changes the population of beasties, the details of which were more clearly elucidated by the work in this paper.

The beasties do all sorts of nice things for us, really.  They make vitamin K, several B vitamins, and eat up carcinogens and other nasties.  Their health and composition are definitely related to the pathology of obesity and of diabetes (at least in mice).  And, not surprisingly, these bacteria impact the immune system.

Germ-free animals raised in sterile environments without commensal microbiota have a different sort of intestinal immune system, with a lower amount of intestinal antibodies and fewer immune cells.  Colonizing these sterile mice will result in normalization of the gut immune system.  Alterations in the intestinal microbiota has been linked to asthma in animals and humans, suggesting that the beasties modulate adaptive and innate immunity.

Y'all might remember that some of those cytokines and immune system chemicals that are produced in the process of inflammation are known to be elevated in the case of depressive disorders.  Chemicals with names like IL-6, TNF alpha, and interferon gamma.  IFNgamma is known to actually cause depression.  Who cares?  Well, translocation of gut bacteria through the gut lining into the comparatively sterile body interior results in a systemic increase in IL-6 and the other cytokines.  We talked about that a little bit in relation to depression and chronic fatigue in posts a few weeks ago.  Psychological stress in humans, such as caring for a sick relative or chronic work stress, also is associated with elevated cytokines IL-6 and TNF alpha.  So the question asked by these researchers (and subsequently answered) is - does psychologic stress change the microbiota population, and is that related to a cytokine change within the body?

The experiment itself was complex and consisted of several different arms, and many mice made the ultimate sacrifice (along with their gazillion commensal microbiota).  In short, some mice were mostly left alone, others were given antibiotics and stress, others just exposed to mean "aggressive mice," others were restrained, and others given antibiotics and restrained...

So what happened to the microbiota and the levels of cytokines in these various experiments?  Well, the mice exposed to stress had definite changes in internal beastie populations.  In general,  exposure to stress (the mean mouse, or restraint) led to "a reduction in microbial diversity and richness."   In addition, exposure to the stressor led to a significant increase in IL-6 levels.  Interestingly, the specific genus of the population of microbiota were significantly related to the generation of IL-6.  TNF-alpha and INFgamma were also increased in stressed mice, but not significantly.

In the antibiotic-treated mice (with a pummeled microbiota), the IL-6 did not increase in response to stress.  Antibiotics reduced the amount of bacteria about 100-fold, so while it didn't eliminate the commensal bacteria by any extent, it made a good dent in the population.

Taken together, these results tell us that stress affects our gut bacteria, which affect our immune system and cytokines.  We know those increases are related to changes in psychological states.

The editorial quote of note:

The strength of implementing a truly integrative systems approach when studying stress physiology has never been clearer than in the work by Michael Bailey and his colleagues in this issue of the journal.  These scientists investigated the impact of stressor exposure on multiple physiologic symptoms, including the intestinal microbiota and the immune system.  These data reveal dynamic interaction between these systems when orchestrating the innate immunological stress response. 

So yes, they control your brain.  To some extent.  Best keep the beasties happy.  Kefir and sauerkraut anyone?

14 comments:

  1. Cool stuff. I've only recently discovered that the industrial-ag complex has known for years what the paleo/health community is just now finding out... that gut microbes affect weight. Apparently it's been known for decades in the meat industry that if you feed animals low level antibiotics they put on weight much better. Yeah- all those antibiotics people get worked up about, it's not to keep the animals 'healthy', it's to keep them sick enough to get fat!

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  2. Brilliant summary - we have a thread running over at MDA about the mental health improvements many find becoming Primal (there's another one going at Art De Vany's too), this is yet another potential explanation for the phenomena and I guess for improved immunity generally amongst the Primal bunch. Primal certainly helps the wee beasties :-)

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  3. An interesting post. I like this kind of study. Not the fact that some of our murine friends have gone to the big cornfield in the sky as a result I would add, but studies where behaviour/psychology is shown to potentially impact on our physical functions and being.
    I think there are some interesting aspects to this study (reiterating your caveat focusing on mouse and extrapolating to humans) - not least mention of clostridia spp.
    Clostridia (and other anaerobes) really has a bad reputation in relation to lots of different conditions.
    In autism, clostridial colonisation has been frequently mentioned, e.g.:
    http://www.ncbi.nlm.nih.gov/pubmed/15528506
    and when some pretty strong antimicrobials are used in an attempt to erradicate such species, there is some ('some') short-term potential benefit reported:
    http://www.ncbi.nlm.nih.gov/pubmed/10921511
    I had always thought that the short-term nature of such an antibiotic effect was due to something like a 'homeostasis' of our gut microflora.
    What this murine paper potentially adds to this - if extrapolated, and it is still a big 'if' - is to say that 'stress' exposure (and the reaction to that exposure) may proliferate gut bacterial populations back to anaerobic species; bearing in mind the link between autism and heightened arousal.
    Mmm.. I am very interested.

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  4. Hi Paul - that is interesting - I'm going to have to look at my "Microbiology Made Ridiculously Simple" book from medical school to brush up again on the different species and their characteristics. I wonder if there is a good text about this? Seems to me that if all of the real work has been done since 2007, it would be hard to have a good text. The full text of the Bailey paper is explicit about the different species and the ones associated with the most IL-6. Very intriguing. Also, if you ever have a fecal transplant, make sure it is from a slender, non-asthmatic, happy person!

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  5. Fascinating article. Thanks so much for posting these.

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  6. So many bells went off for me when I read this, especially with my own recent experiences. Thanks so much.

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  7. Thanks Emily.
    With regard to gut bacteria and human health, I can recommend looking at the work of Prof. Jeremy Nicholson and his group based at Imperial College, London. Prof. Nicholson and his very technologically advanced Unit at the Biomolecular Medicine Dept have looked at various conditions (somatic and psychiatric) with regards to gut bacteria. Attached is a link to an article he did for Scientific American a few years back:
    http://www.scientificamerican.com/article.cfm?id=jeremy-nicholsons-gut-instincts
    As for texts on gut bacteria, anything by Prof. Glenn Gibson based at Reading University, UK is highly recommended:
    http://www.reading.ac.uk/food/about/staff/g-r-gibson.aspx
    The fecal transplant... Make mine an enterically coated formulation rather than a naso-gastric tube and enema!

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  8. Wow, Emily, thank you for this incredible post. Really brings to focus the often referred to 'mind/body connection', except it seems it would be more accurate to call it the body/mind connection. One can imagine that perhaps there is an inkling of an explanation for why the placebo effect is so powerful - something is happening that may have an actual physical effect produced by the beasties interaction with our brain.

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  9. Very informative -- thanks! This makes me even more glad that I've taken up fermenting lately. :)

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  10. Emily I am surprised your a bit surpised about this. There is even more compelling data already out there. Elizabeth Blackburn just won a Nobel Prize in medicine for work on telomeres. She also uncovered in 2009 and then again in 2010 a link between Cortisol Norepinephrine and Epinephrine in pregnant mothers who had severe stress and the effect on their telomeres. Every women stressed has documented shortening while the control group did not. A London study follow up was done to make sure there were no confounders and done with identical twins. They confirmed the finding. This clearly proves that the mind body connection is mediated by epigenetic controls. The three stress hormones have immediate and huge epigenetic effects on methylation and histone acetylation. Dr. K

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  11. Hi John - what am I surprised about? I'm not following the context of your comment, though the information is very interesting (and not surprising!) As Nick suggests, there is something very interesting about how everything in depression (except shock therapy) is about 55-60% effective (therapy, meds, take your pick, though the combination is perhaps more effective), placebo 40-50% effective. How much is the beastie effect? Even in the Schizophrenia and Wheat early studies it was suggested that the old neuroleptics helped repair the gut.

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  12. I don't know how to arrange a fecal transplant. Is it as effective as eating Paleo-style for at least a year? My asthma symptoms are gone , I am very happy and balanced, but eczema resurfaces from time to time, weight loss is extremely slow (I don't complain about it, just comment on it as a part of picture). Under-active thyroid due to a wrong autoimmune response also is in a picture (Armour thyroid is taken for that). Is it possible to get the same result with the long-term diet as with a fecal transplant?

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  13. As far as I know, at the moment it is only being used in research in the US. Don't know about elsewhere. And typically it is arranged to have a transplant from a relative or partner.

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  14. As the paradigm of a bacteria-filled gut spreads through allopathic medicine, I hope we see MD's waking up to the ramifications...

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