Stress and Our Missing Old Friends

Yesterday I devoted several hours to reading a fascinating article on the connection between stress and the microbiome.[i]  The conclusion:  the lack of exposure to our “old friends” (those commensal organisms with which humans co-evolved) has caused immune dysregulation, leading to a greater susceptibility to the adverse effects of stress…and that stress, in turn, has caused alterations to the biome and immune system.

The paper was extensiveso I will just hit on some of the major highlights.  (And even just highlights means this is going to be a loooong post, so brace yourself!)

1. Many illnesses, both physical (somatic) and mental, are the result of chronic, low-grade inflammation.  That inflammation, in turn, is the result of a “…compromised regulatory T (Treg) cell compartment, a failure of immunoregulation might be involved in promoting an over-reacting of the inflammatory stress response and, thus, predisposing an individual to the development of certain stress-related somatic and mental disorders.”  The regulatory (T regulatory cells, typically abbreviated as Treg) part of the immune system- that is responsible for turning off inflammation when it’s no longer needed to fight pathogens – is deficient.  Levels of the necessary regulatory cytokines are too low, resulting in a continual (and incredibly destructive) inflammatory process.
2. Chronic stress is known to be a major risk factor for an enormous array of diseases: cardiovascular disease, fibromyalgia, bronchial asthma, atopic dermatitis (eczema), arthritis, inflammatory bowel diseases (IBD), stomach ulcers, diarrhea and digestive problems, chronic pelvic and abdominal pain, infections, headaches, impaired wound healing, cancers, major depressive disorder, PTSD, and chronic fatigue syndrome…and many more.
3. The greater the degree of industrialization in a country, the higher the incidence of stress and inflammation related disorders, including autoimmune diseases like multiple sclerosis, IBD and type 1 diabetes, allergy, atopic dermatitis, asthma, etc.
4. “Mental health” diseases that are known to be associated with increased chronic inflammation include PTSD, generalized anxiety disorder, panic disorder, phobias, depression, burnout, chronic fatigue syndrome. There are likely many more but these are the ones confirmed in the medical literature.
5. I thought this was a pretty interesting point: “From an evolutionary perspective, it makes sense that activation of the innate, rather unspecific and, therefore, fast-acting immune system has been selected to be an inevitable part of the classical stress response.”  The innate immune system – the part we are born with – can act immediately when faced with a threat.  The adaptive immune system, the part responsible for creating antibodies to fight germs, takes a couple of days to kick in.  When you get bruised, for example, the area swells, as that innate immune system rushes (via the blood stream) to the area to fight the damage and invaders.  “Those individuals showing an activated immune status, even before the actual physical injury and pathogenic invasion happens, elicited by perceiving a certain situation psychologically as threatening or dangerous, had an evolutionary benefit and were selected over the past millions of years.”  That is, those early humans whose innate immune systems rapidly primed, ready to kick into action, when the person simply perceived a threat survived better.
6. The article describes numerous studies relating stress to physical and mental illnesses. A quick example:  “…individuals with inflammatory diseases are three to four times more likely to experience depression.”  In one experiment, people were given a low-dose of toxins (not enough to cause physical symptoms) from the pathogenic bacteria, Salmonella.  However, the toxins did cause a rise in inflammatory blood markers…and an increase in anxiety levels and depressed mood.  It also caused a measurable negative effect on verbal and non-verbal memory.  The higher the level of inflammation (measured by blood markers), the greater the mental symptoms.  (These results have been replicated in multiple experiments in both people and animals.)
7. How does all this relate back to the gut microbiome? The bacteria of the gut are responsible for profound manipulation of the immune system. “Microbes in large part mediate their immunomodulatory effects by influencing the activity and maturation of immune cells.”
8. In experiments, when mice raised germ-free are given commensal bacteria, the regulatory system kicks in, boosting levels of regulatory cytokines including one of the key ones, IL-10 (interleukin 10). Even colonizing with just a single strain of a probiotic has this effect.  “…treatment with the probiotic bacterium Bifidobacterium infantis promotes the proliferation of Treg cells in mice and results in an increased production of IL-10 in humans.”  (Not coincidentally, I mention this particular strain in a recent post on depression and the microbiome! )
9. Commensal gut bacteria promote the production of immune cells in the gut lining (epithelium), and their metabolites (like the short chain fatty acids for example) boost Treg cells both directly and indirectly.
10. Gut bacteria are very much responsible for the metabolism of the amino acid tryptophan, the precursor to serotonin. As I’m sure you know, serotonin in the brain positively affects mood, and increasing levels of it is the target of medications like Prozac.  Serotonin too is a huge player in normal immune functioning and actually, most of it is produced in the gut – as the gut comprises about 70% of our immune system.  (Remember that most germs enter through your nose and mouth!)
11. “…alterations of the gut microbial composition can have detrimental effects on host immunity. Besides factors like diet, age, and pharmaceuticals, one highly potent disruptor of the intestinal bacterial community is chronic stress.” So it swings both ways, as you know:  microbiome alterations cause stress.  Stress causes microbiome alterations.
12. As I have talked about many times before, the depletion of the gut microbiota results from our westernized lifestyles, that has greatly reduced our potential exposure to a myriad of microorganisms that were present during our evolution and that “play a role in setting up regulatory immune pathways”: sanitation, drinking water treatment, antibiotics, changes in diet, formula feeding, cc-sections, time spent indoors, etc. are all factors.
13. Treating with anti-inflammatory pharmaceuticals DOES positively affect psychiatric disorders like PTSD. However, because of the complexity of the immune system, it makes more sense to clinically treat by activating “…the body’s own immunoregulatory mechanism, which is able to comprehensively suppress unnecessary inflammation…”  (You’ve heard this sentiment from me many, many times before.  This is why, for example, I talk about using helminths so often.  They are perhaps the most potent stimulator of the Treg system we have!  And our industrialized society has basically removed the possibility of exposure.)
14. The authors of this paper ran a study on young, healthy men raised (during the first 15 years of life) in either a city or a farm. (By the way, if the city residents had a pet growing up they were disqualified, as pets increase microbial exposure and thus, reduce the risk of inflammatory disorders.)  As the researchers predicted, those raised in an urban environment had an increased systemic immune response when exposed to a stressor than did their rural peers.  More than that, the Treg system of the urbanites was suppressed, “…suggesting immunoregulatory deficits relative to rural participants…”  I’m shocked. NOT
15. I think 15 highlights is more than enough so the last one. “In addition to the protective effects of various Old Friends against a plethora of inflammatory somatic disorders, Old Friends have been further shown to positively affect mood, stress coping, and fear extinction, as well as to prevent the negative consequences of chronic psychosocial stress in humans…”

Unfortunately, these authors – like most scientists these days – limit their definition of Old Friends to the bacterial microbiome.  Our Old Friends, though, are far more diverse and include viruses (as I pointed out, for example, here), macrobiotic organisms (like helminths, as I have pointed out many times (for example, here), protozoa (as I talked about here), and so forth.  As in any ecosystem, there is much greater complexity than a single class of organisms and all are inexorably intertwined.  Limiting scientific research to only the bacterial microbiome is like saying you will research a rain forest but only study the mammals…forgetting that the diversity of the mammalian population in the forest is reliant upon all their co-inhibitors, like the insects, the birds, the reptiles, and so forth.

As always, I will continue to hope that at some point, science starts to think about the bigger picture.  The question I constantly ask myself is, can biome restoration really happen if we only attempt it using 1 type of organism?

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[i] Langgartner, D, Lowry, CA, Reber, SO. Old Friends, immunoregulation, and stress resilience.  European Journal of Physiology. 2018.  doi: 10.1007/s00424-018-2228-7