Program Loss Fat

I am in the midst of a new academic year of talks. Last week I went to the Brigham and Women's Hospital behavioral neurology interest group talk, and last Thursday to Boston University Medical Center Psychiatry Grand Rounds.  I do like these academic talks, though naturally the audience is much more skeptical than the Ancestral Health Symposium and PaleoFx folks. Skepticism is good. Keeps me on my toes. At the Brigham Behavioral Neurology group, I had immediate questions involving how long our ancestors lived, how old was the individual who owned the beautiful choppers in the ancient Maori skull when he/she died, and what exactly were the questions asked by Staffan Lindeberg and company to determine that the Kitavan elders didn't seem to have symptoms of dementia.

All important questions! I didn't have answers to as many as I wanted to� but I think I held my own. I do try to make the point that my blog is not about answers, but rather about asking these questions for research in a meaningful way. If the government food plate leads us to "whole grain" sugary honey nut "O" cereal as a big healthy part of our diet, and beautiful nutrient-rich egg yolks are deadly, maybe we should step back and think about that for a moment.

Grand Rounds at Boston Medical Center went well. I thought the talk was received with interest, and I certainly thank Dr. Searl and Dr. Chapman for inviting me to speak. I hope that someone thinks about a research idea�I'm particularly hopeful that we will get more research about fructose malabsorption and depression. We'll see.

Recently I've been hard at work reading an amazing textbook about the immune system and evolution recommended to me by Kurt Harris.

The textbook has quite a bit to say about mental illness, a whole chapter (pages 189-220), which is quite amazing, as most anthropology and hygiene hypothesis tends to avoid mental illness. So much easier to focus on diabetes and obesity and autoimmune disease. All easily marked and tallied. Not so mental illness, defined by the recipe book of symptoms we call the DSMIVTR.

Well. Stress-related psychiatric disorders (which is nearly all of them, when I think about it), particularly depressive and anxiety disorders, are associated with markers of inflammation, particularly raised levels of proinflammatory cytokines.  Some of the proinflammatory cytokines (most famously interferon alpha, used to treat hepatitis C) can induce depression in folks with no previous symptoms. Thus it is reasonable to assume that immune dysregulation, that is our immune system a bit out of whack, like an army milling about without clear leadership, could be part of mental illness.

Like autoimmune disease and allergic disorders (athma, hay fever, type I diabetes, multiple sclerosis, and inflammatory bowel diseases such as ulcerative colitis) have been increasing preciptiously in the developed world in recent decades. The "old friends hypothesis" suggests that we are, in effect, missing a major regulator of our immune system that we co-evolved with for thousands upon thousands of generations. That is, three classes of organisms who have lived within us or passed through us, all of our ancestors, until very recently. They are the pseudocommensals, the commensals, and the parasitic worms. (More about the old friends hypothesis in this article.)

The down and dirty of it is that we have several arms of our immune system, kind of like infantry and navy and military intelligence. There are various forms of T helper cells (Th1 and Th2) that secrete inflammatory cytokines to tell which arms of our immune system to come forth and attack.  What will tell the Th1 and Th2 cells to back off is a third variety of T cell, called Tregs (short for regulatory T cells). Infection with our "old friends" (such as pinworms, or tapeworms, or the pseudocommensals like soil mycobacteria) seems to cause continuous activation of the Tregs, keeping the Th1 and Th2 cells in check. In effect, these "old friends" organisms have always been there, and have become a part of our immune system. It is no wonder that we have problems when we no longer have the old friends at our disposal.*

Both Th1 and Th2-regulated inflammation have been associated with anxiety and depression. The "pro-inflammatory cytokines" IL-1, IL-2, IL-6, IL-12, TNFalpha, and interferon alpha and gamma. On the Th1 side, IL-6 and IL-1 levels are related to symptoms of depression in cancer patients and others. Downstream agents, such as C reactive protein, cerulosplasmin, and lower levels of zinc and albumin are also associated with depression symptoms. There are also increased levels of neutrophils and complement proteins** seen in acute exacerbations of bipolar disorder and major depressive disorder. Seems that people with increased levels of background inflammation are more susceptible to interferon and IL-2 administration causing depressive symptoms as well.

When we go over to the Th2 side of things (Th2 excess seems to be associated with allergies and hay fever and ulcerative colitis, whereas Th1 excess is associated with other autoimmune diseases such as type I diabetes and crohns), the evidence for specific cytokines is not as clear. However, people with allergies are known to have a greater incidence of depression. 50% of asthma sufferers seem to have clinically significant depression, and allergies are associated with an increased risk of suicide.  Asthma is also clearly associated with anxiety (in studies, and also any experienced clinician can tell you� trouble breathing causes great anxiety and worries about future attacks). However, that association begs an important question�is it the immune dysregulation causing both anxiety and asthma, or the asthma symptoms particularly prone to causing anxiety? Until we have a better handle on the Th2 cytokines such as Il-4 (experimental tests are problematic) we may not know.

So, there is an enzyme called IDO, which can act on tryptophan leading to a depletion of serotonin. Inflammation seems to activate IDO, whereas antidepressants (such as SSRIs) seem to deactivate it, which may be the secret to how they might work. In pregnancy, there is a bias toward Th2 and regulatory T cells (thought to prevent immune attack on the growing fetus. Mothers-to-be are in a somewhat immune compromised state, particularly in the third trimester, which can actually decrease the incidence of some autoimmune symptoms during pregnancy). After pregnancy, however, there seem to be a Th1 "bounce back" that can lead to exacerbation of inflammatory disorders and depression. There is increased metabolism of tryptophan and increases in Th1-related cytokines.

The Dead Weather: I Can't Hear You (starts with an ad that can be skipped after a few seconds) 

What about the gut and depression? Are raised levels of immune cytokines seen in depression caused by "leaky gut"? Levels of antibodies directed against several gut bacterial species are elevated in people with depression, suggesting leakiness. Leakiness is associated with increased bacterial endotoxin crossing the gut barrier, leading to increases in proinflammatory cytokines, which could plausibly cause depression symptoms. Gut epithelial barrier permeability is highly dependent upon the enteric immune system, and parasites and healthy, normal commensal organisms may help regulate and protect normal gut integrity. It's not a coincidence that Chron's and ulcerative colitis are associated with higher levels of affective disorders. 

Depression is also very common in folks with vascular disease (those at high risk for heart attacks and thrombotic strokes). Metabolic syndrome, associated with athersclerosis and heart disease, is also associated with depressive symptoms. Brain-derived neurotrophic factor (a nerve fertilizer of sorts) seems to be diminished in depression and in vascular disease. Levels of BDNF are low before treatment, and seem to rise in response to succesful treatment. Autoimmune diseases such as MS are also noted for low levels of BDNF. 

There are a lot of intriguing connections between whole-body immune pathology and depression and anxiety symptoms. Gut and immune dysregulation may be keys to these disorders. It will take more time and more asking the correct questions to find out whether these issues are of fundamental importance or not. Psychiatrists might want to read up on the immune system, however, as a part of continuing medical education.

*there are clear benefits to a hygenic water supply (unless you like cholera for breakfast), not eating dirt, and not having unchecked parasitic infections. Don't go drink untreated pondwater after reading this post. But my guess is that better study of these organisms will lead to safe and ingenious ways to emulate the old friends with much less risk than drinking untreated water and living with hookworms.

** a thorough grounding in immunology is beyond the scope of my post. However, these wikepedia articles can give you a good start.