Back in December of 2010, an amazing paper was published in the Archives of General Psychiatry.  I encourage everyone with access to get your paws on it: Inflammation, Sanitation, and Consternation: Loss of Contact With Coevolved, Tolerogenic Microoganisms and the Pathophysiology and Treatment of Major Depression.  

When I first heard about the paper, however, I was ready to be annoyed.  See, there's this "hygiene hypothesis" of allergies and illnesses of all kinds, which basically boils down to "all your autoimmune problems and asthma are caused by the fact that your mother is a germophobic helicopter parent."  And hey, I have kids, and I worked downstairs from the Shigella lab in college - you don't mess with the dangerous microbes, or they will surely mess with you.    I don't apologize for protecting my kids from Salmonella or E. coli by washing my hands and kitchen work surfaces, hygiene hypothesis or not… 

Well, as it turns out, like most things, the hygiene hypothesis has a bit more subtlety than is played out by the mainstream media.  And it serves us well to listen up and learn a bit about our microbial friends, and not be quite so defensive.

On the defensive side, there are a lot of versions of the hygiene hypothesis (basically the idea that our modern environments are too clean) that make it sound as if your mom is a crazy germophobe and that's why you have asthma. Which ultimately doesn't make sense, because that remote control your kid is chewing on has about a billion microbes on it, and no matter how much your mom cleans, you are going to be exposed to a zillion microorganisms.  Also, you will often hear that "children just aren't exposed to childhood infections anymore" as we have vaccines and smaller family sizes and antibacterial soap.   But the typical childhood infections such as chicken pox, whooping cough, diphtheria, etc. are all as modern as eating grains, and were established in humans as we developed higher population densities and domesticated animals, so lack of exposure to those bugs wouldn't necessarily mess with our evolved immune system.  Add to that bit that there is some (association) evidence that exposure to common viruses increases inflammation and may increase our risk for depression, suggesting that many germs are, indeed, BAD.  That particular version of the hygiene hypothesis is dealt a death blow by the fact that inner city kids rife with childhood infections have the highest rates of asthma, much higher than isolated rural kids living out in the country with all the ragweed (1)

But, in the end, I set aside my preconceptions and took a look at the paper, and thank goodness I did, because it is epic, amazing, and brilliant. All psychiatrists, psychologists, and other doctors download it now if you have access and have a look. It even includes the Dobzhansky quote "nothing in biology makes sense except in the light of evolution."  The accurate version of the hygiene hypothesis makes a distinction between the germs we are exposed to all the time in the modern world and different sorts of bacteria and parasites we were exposed to much more often in a less sanitized time. 

So here we go. I've made a point before that depression is a result of inflammation. Specifically, depression is associated with higher serum levels of IL-6, NFkappabeta, TNF alpha, and a host of other pro-inflammatory cytokines. Medically healthy individuals with depression and a history of early life stress mount a larger inflammatory response to laboratory psychosocial stressors than do nondepressed controls. The prevalence of major depressive disorders is increasing in all age cohorts, but especially in younger people, and countries transitioning to be part of the developed world experience increasing rates of depression along the way. One would hypothesize, then, that something environmental in the modern world makes us vulnerable to depression (and other inflammatory diseases of civilization, such as MS, inflammatory bowel disease, type I diabetes, asthma, etc.)

"Overwhelming data demonstrate the prevalence of helper T cell type I...mediated autoimmune and inflammatory bowel and Th2 mediated allergic/asthmatic conditions have increased dramatically in the developed world during the 20th century, with increases in immune-mediated disease incidence in the developing world during the same period closely paralleling the adoption of first world lifestyles."Asthma, hay fever, type I diabetes, inflammatory bowel disease, and multiple sclerosis have all increased 2-3 fold in the developed world in the last 60 years. Many of these conditions are highly comorbid with major depressive disorder.

I've focused on a pro-inflammatory diet as a hypothetical cause for increasing depression (along with obesity and the other diseases of civilization). The vast majority of the depression literature, I would say, has focused on the pro-inflammatory aspects of a stressful modern life (which I contend isn't necessarily more stressful than life was 60 years ago, or 800 years ago, during the Bubonic Plague, for example). This paper focuses on "the loss of a microbial modulated immunoregulation" of our Th1 and Th2 immune cells.

Quick immune system review - childhood viral infections tend to mobilize type I T helper cells. Since Th1 cells seem to balance and modulate the Th2 cells, one might expect that a lack of Th1 activation due to a sanitized environment would lead to naughty Th2 cells running rampant, causing asthma and allergy and the like. That makes sense, except naughty Th1 cells seem to cause other autoimmune issues, like Crohn's disease, and the incidence of Crohn's disease has increased steadily along with asthma and allergy. In fact, "most follow up studies have failed to show an association between childhood infection and increased autoimmune and/or atopic conditions in the modern world while continuing, in general, to find correlations between a first-world lifestyle and increases in these conditions."

But humans have been living with some microorganism and parasites for much longer than the childhood infectious diseases of the last 10,000 years of agriculture. These ubiquitous organisms seemed to keep Th1 and Th2 cells busy without causing problems, in other words, the "old friends" germs "induced and maintained an adaptive level of immune suppression." Or:

"the mammalian genome does not encode for all functions required for immunological development, but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health."

What are these organisms? First off are the pseudocommensals, saprophytic mycobacteria that are found in mud and untreated water and on unwashed food. They don't colonize the body, apparently, but were known to pass through it in large quantities historically:

A bunch of commensal species are known to inhabit our gut, among them Bacteroides, Lactobacilli, and Bifidobacteria. And finally, the helminths (internal parasites, such as tapeworms and hookworms) are the third member of the triad of "old friends."

There is a whole body of literature dedicated to animal studies showing how exposure to these "old friends" reduces autoimmine, inflammatory conditions, and even cancer. A sugar molecule from Bacteroides species protects against colitis and distorted immune system development in germ-free mice. Prebiotics known to increase Bifidobacteria in the rodent gut reduce serum concentrations of cytokines such as TNF alpha and IL-6.

"Metabolic products from gut microbiota reduce inflammation in animal models of a variety of human autoimmune and allergic disorders, as well as in [test tube] preparations of human [immune cells]."

The health of the human gut microbiome has been shown to impact varied physiologic processes such as pain sensitivity, sleep, and metabolism (all of which are abnormal, by the way, in major depressive disorder.) A parasitic worm, Schistosoma mansoni, can make a friendly phospholipid for us, phosphotidylserine. Exposure to a pseudocommensal organism, M vaccae, reduced serum TNF alpha concentrations over a three month period compared to placebo (in humans and human monocyte cell lines). Recall that TNF-alpha is increased in depression, and antidepressants reduce TNF-alpha - it does make one wonder if these "old friends" have antidepressant effects.

Without constant exposure to these immune modulating "old friends," it is plausible that modern humans are at risk for mounting inappropriate inflammatory responses, leading to many of those undesirable diseases of modern civilization, including depression. I wonder if using inappropriate food, such as vast quantities of fructose, could destabilize the gut microbes and be part of the inflammatory process. One could further postulate that exposing depressed individuals to "old friends" could act as a treatment.

Gut-depression links are already well known - psychological stress in humans is associated with reduced fecal Lactobacilli, and individuals with major depressive disorders had some fragments of gut bacteria inappropriately floating around in their blood, suggesting the presence of leaky guts. One small study showed that giving people a prebiotic that favors Bifidobacteria reduced anxiety in patients with irritable bowel (2), and another 2 month placebo-controlled study showed that lactobacillus treatment reduced anxiety (but not depression) in people with chronic fatigue (3). Probiotic treatment did not reduce depressive symptoms in chronic fatigue patients in another small study, but it did improve some cognitive symptoms that are common in major depressive disorder (4). M vaccae was administered to patients with renal cell cancer, reducing serum IL-2 and some depression symptoms (5), and in another larger study, killed M vaccae reduced depression and anxiety symptoms in lung cancer patients receiving chemotherapy (6).

There is a long way to go before we start feeding people dirt and worms as an evidenced-based strategy for treating depression.  And there are clear advantages to sanitation!  But...the ideas are intriguing, based in common sense, and scientifically sound. People with the "short" genetic form of the serotonin receptor, for example, are known to be more vulnerable to major depressive disorder, and they are also more vulnerable to known forms of depression caused by inflammation, such as depression caused by interferon alpha treatment. These findings link genetic vulnerability to environmental inflammatory factors to depressive symptoms. Priming the body with known anti-inflammatory modulators should help depression. Even if it might not seem that...tasty.

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