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?