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The Gut-Brain Connection, Mental Illness, and Disease

Psychobiotics, immunology, and the theory of all chronic disease.

We are never truly alone. On our skin, in our gums, and in our guts live 100 trillion organisms, altogether known as the microbiome. These beasties comprise 90% of the cells of our bodies, though these cells are so tiny in size that it appears our own human cells predominate. It is only recently that we have begun to study these organisms with any depth. Most of them live within the gut, and cannot be cultured, and only with the advent of advanced genetic testing have we been able to have a better understanding of the variety and numbers of microbes we’re dealing with. They are Bacteria, Archaea, and even some eukariotic parasites, protozoans, and fungi.

What do they have to do with psychiatry? It turns out way more than we might have suspected. The gut and brain have a steady ability to communicate via the nervous system, hormones, and the immune system. Some of the microbiome can release neurotransmitters, just like our own neurons do, speaking to the brain in its own language via the vagus nerve.

To have a full understanding of how the whole gut-brain connection works, you need robust knowledge of endocrinology, immunology, pathology, and neurology, which is a bit beyond the scope of a blog article. However, to break it down to simplistic terms, here are the basic links:

1) The body responds to stress (mental or physical) via the hypothalamic-pituitary-adrenal axis. For example, if you are eating lunch and a lion jumps into the middle of your picnic table, your “fight or flight” system is fired into full gear, your heart pounds, your pupils dilate, your hair stands on end, natural steroids and adrenaline flood your system to strengthen your muscles and give you an extra burst of speed. Even your platelets change shape so they are more sticky, leaving you less likely to bleed out if you are attacked. Naturally, our bodies have negative feedback that can tone down the fight or flight response once the danger is past (assuming you survive). Under conditions of chronic stress, however, mental or physical, the feedback tends to get messed up, leading to symptoms of chronic stress (which includes mental issues such as anxiety or clinical depression, but also physical problems such as chronic gut problems, headaches, high blood pressure, etc.). What does all of that have to do with the gut?

2) While the hormonal system that regulates fight-or-flight, rest-and-recovery, and everything in between is easy to conceptualize, the second underlying system, the immune system, is far more complex and works at a cellular level. Our bodies aren’t particularly sophisticated when it comes to facing off against stress. Our stress response doesn’t readily distinguish between mental and physical distress; your heart pounds and you tremble with anxiety when you are in an uncomfortable meeting with your boss, when such a reaction is not helpful in that situation, though it might have helped with the lion. And not only to we respond to the tough day on the job with a hormonal response, but also an immunological one. When our body is under stress, it releases what are called inflammatory cytokines, little chemical messengers that bring a certain part of our immune system into high alert. In a sense, our body reacts to all stress as if it were an infection, and to chronic stress as if it were a chronic infection.* Now the immune system works wonders and inflammation saves your life nearly every day from all the pathogens out there like the flu and strep, but chronic levels of inflammatory response also lead to all sorts of chronic disease, for example depressive disorders, high blood pressure, atherosclerosis, autoimmune diseases such as ulcerative colitis and multiple sclerosis. Immune system activation can also determine whether or not we develop cancer. Where does the gut get involved? Well, it turns out the gut microbiome plays a key role in regulating our immune response. Thus the make-up of our gut microbiome could make the difference as to whether we are sick or well, both mentally and physically.

3) Animal and human studies support the theory that pathogenic bacteria in the gut, such as C. Difficile, or in certain circumstances, H. Pylori, lead to human disease, and not just the obvious direct illnesses, pseudomembranous colitis and ulcers. These bacteria also interact with the immune system in the gut to cause the release of inflammatory cytokines, stress steroids, and a systemic stress response (similar in most ways to the lion attack). Some of the responses of the gut even have an effect on our pain response…yes, people with certain unfavorable gut bacteria might be more sensitive to pain than others. However, other commensal organisms in the gut seem to have the opposite effect, the most studied being certain strains of Bifidobacterium and Lactobacillus. The right sort of commensal bacteria keep the numbers of pathogenic bacteria low, and also interact with the immune system in a way to turn off that chronic stress response. The “right” gut bacteria also interact on a hormonal level, helping to turn off the cortisol and adrenaline response that can cause long-term harm to the body. However, each large group of gut bacteria (and Archaea, which have a big influence on digestion and help us ferment and breakdown otherwise indigestible plant fibers) have many different strains, and each of these strains may have differential effects, some of them synergistic or antagonistic. The scope of complexity of the problem is mind-bending. In general, it is felt that more variety in the gut microbiome is probably better, and studies of hunter-gatherers show us they seem to have both more mass and more variety of gut bacteria than do modern Westernized humans.

What is the direct evidence these gut microbes affect the brain? Most of the evidence is in mice or rats, but scientists have shown that rats raised germ-free have different production of key brain neuron fertilizers that help with neuroregeneration, neuroplasticity, and repair than do rats that are (like most animals) colonized with gut bacteria. This same brain fertilizer, BDNF, is necessary in the human brain as well. BDNF being low in the wrong place at the wrong time is implicated in clinical depression, chronic anxiety syndromes, and other psychiatric disease. Other differences in germ free mice include changes in the shape and expression of certain neurotransmitter receptors, NMDA and 5HT1A. These receptors are also important in the regulation of mood, anxiety, and a malfunctioning NMDA receptor is part of the pathology of psychosis, as seen in schizophrenia or bipolar disorder. Certain strains of probiotics can increase the availability of tryptophan, the key precursor to making serotonin.

There is also evidence stress can affect the microbiome. Mice exposed to early parental loss have an immediate reduction in the amount of lactobacilli in the feces. Some of these microbiota changes are long term, including decreasing some “friendly” bacteria and increasing the relative abundance of pathogenic bacteria such as Clostridium.

To add complexity to the whole question, most of these studies are about certain bacterial species among many thousands of bacteria species, and beyond the commensal bacteria, the human immune system is also profoundly affected by so-called pseudocommensal organisms (such as M vaccae) found in soil and water that don’t stay in our guts, but regularly passed through them in human history as we ate wild foods and drank spring and pond water. In modern times, those who have been vaccinated with Bacille-Calmette-Guerin (BCG) as protection against tuberculosis have, in a sense, been chronically infected with a pseudocommensal somewhat similar to M vaccae. Along with some protection against tuberculosis, those who have received the vaccine are also less likely to develop melanoma (and some other cancers) than those who haven’t, suggesting the effect of the vaccine on the immune system helps T cells of our immune system in cancer surveillance and elimination of neoplastic cells. In addition, those infected with chronic parasites such as hookworms seem to have a much lower incidence of autoimmune disease than do modern, Western, mostly parasite-free humans. Since our immune system co-evolved with these parasites, it would make sense that their absence would have a profound effect on immune regulation, leading to all sorts of consequences, both physical and psychiatric.

How can we affect the gut microbiome and the immune system? Changing the diet will have immediate effects, with folks who eat highly refined diets having a different gut composition than those who eat more whole foods, fruits and vegetables. We can also take probiotics, though the research is preliminary, and probiotics only help temporarily (that is, as long as you take them). Some probiotic formulations now include soil bacteria, giving the benefits (and risks?) of both commensal and pseudocommensal exposure. Strains of bacteria that affect the brain or behavior are called psychobiotics. Fecal transplants will cause a permanent change in the microbiota. BCG and vaccinia injections could be something to look at as well. Also, some studies are being done on infection with hookworm and pig whipworm eggs in autoimmune conditions to replicate exposure to the complex eukariotic parasites.

All in all, the gut is a terrific place to start helping humans be as healthy, resilient, and robust as we have evolved to be.

Sources: Dinan, T., Cryan, J., Regulation of the stress response by the gut microbiota: Implications for psychoneuroimmunology. Psychoneuroimmunology (2012) 37, 1369-1378

Wang, Y. Kasper, LH. The role of micro biome in central nervous system disorders. Brain Behav. Immun. (2014),

Krone, B. et al, Protection against melanoma by vaccination with Bacille-Calmette-Guerin (BCG) and/or vaccinia: an epidemiology-based hypothesis on the nature of a melanoma risk factor and its immunological control. European Journal of Cancer. 41 (2005) 107-107.

*Some very bright people believe that chronic diseases are all caused by chronic infections, and in some cases this may be true, for example, toxoplasma infection is associated with a higher risk of developing schizophrenia, but I think the body’s stress response, once it is out of balance, can explain many chronic illnesses without invoking a chronic infection in every case.

Image credit: wikimedia commons

Image credit: wikimedia commons

Copyright Emily Deans, MD

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