Could We See a Stress Vaccine in Our Lifetime?

Depression is the leading cause of disability worldwide, and is a major contributor to the overall global burden of disease. ⁽¹⁾ Together with other stress-related disorders, including anxiety disorders and trauma- and stressor-related disorders, such as post-traumatic stress disorder (PTSD), stress-related psychiatric disorders are a significant global health problem. Stress-related psychiatric disorders may be more prevalent in urban relative to rural settings. The prevalence rates for psychiatric disorders, including mood disorders and anxiety disorders, were found to be higher in urban areas compared with rural areas.⁽²⁾

Although there are many potential explanations for these differences, one hypothesis is that as humans have moved from a hunter-gatherer or agricultural existence to urban environments, they have lost contact with microorganisms with which humans co-evolved that served to prevent inappropriate inflammation.⁽³⁾ This, in turn, may have predisposed those living in urban environments to chronic low-grade inflammation, which is considered a risk factor for stress-related psychiatric disorders.^(4-7) Furthermore, those living in urban environments, relative to those growing up on farms, may respond to psychosocial stressors with exaggerated stress-induced inflammation,⁽⁸⁾ compounding any effects of persistent chronic low-grade inflammation.

Evidence suggests that exaggerated or inappropriate peripheral inflammation increases the risk of stress-related psychiatric disorders. ^(4-6) A number of factors predispose individuals towards peripheral proinflammatory immune responses, and of these, alterations in the microbiome have received a great deal of recent attention.^(9-11) Throughout human evolution, humans have coevolved with diverse microorganisms, including prokaryotes, eukaryotes, and viruses, which together constitute the human microbiome. ⁽¹²⁾ Interestingly, the interactions among these microorganisms, cells, and organs of the human immune system have shaped how these human cells and organs respond.

Specific microorganisms have been shown to prime immunoregulatory circuits, as well as to suppress pathological inflammation. ⁽¹³⁾ Microorganisms that have evolved to prime immunoregulatory circuits include: (i) the commensal microbiota, which have been altered by the Western lifestyle, including a diet that is commonly low in microbiota-accessible carbohydrates^(14;15); (ii), pathogens associated with the “old infections” that were present throughout the hunter-gatherer period of human evolution ⁽¹⁶⁾; and (iii) organisms from the natural environment, including environmental saprophytes, with which humans were inevitably in daily contact (and so had to be tolerated by the immune system).

However, it is thought that the microbiome of humans has shifted radically as a result of living a modern urban lifestyle (i.e., the hygiene hypothesis), with entire classes of microorganisms now either absent or much reduced (i.e., the “disappearing microbes hypothesis” ⁽¹⁷⁾, “microbial biodiversity hypothesis, ⁽¹⁸⁾ or “Old Friends” hypothesis ⁽¹³⁾). It has been argued that this change in the constitution of the microbiome alters the manner in which the peripheral immune system responds to challenge, resulting in a shift towards imbalanced immunoregulation, indicated by deficits in development of regulatory T cells (Treg) that produce anti-inflammatory responses. ⁽¹³⁾ This reasoning has led to efforts to develop strategies for prevention or treatment of psychiatric disorders by restoring some of the lost “Old Friends” through microbial-based interventions, thereby shifting immune signaling toward immunoregulation. ⁽¹⁹⁾

We have found that immunization with a heat-killed preparation of one of these “Old Friends”, Mycobacterium vaccae, a soil-derived bacterium, promotes stress resilience in animal models. Immunization with M. vaccae prevents a number of negative outcomes of chronic psychosocial stress in mice. This includes prevention of:

1) stress-induced colitis, or inflammation of the colon
2) stress-induced exaggeration of proinflammatory cytokines (immune signaling molecules) from stimulated immune cells
3) chemically-induced colitis in a model of inflammatory bowel disease
4) stress-induced exaggeration of anxiety. ⁽²⁰⁾

In other studies, immunization with M. vaccae, when given either before or after fear conditioning, enhanced extinction of learned fear. ⁽²¹⁾ In addition, immunization with M. vaccae induces an anti-inflammatory milieu in the brain, specifically in the hippocampus, a region that is known to be important for learning and memory, and control of anxiety and fear. ⁽²²⁾ Again, this effect is associated with prevention of stress-induced exaggeration of anxiety. ⁽²²⁾

Until recently, it was not known what, specifically, about M. vaccae allowed it to confer such potent anti-inflammatory effects and promote stress resilience. It turns out, this soil-derived bacterium (as well as other types of mycobacteria) produce a novel fat, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, the free fatty acid form of which, 10(Z)-hexadecenoic acid, has potent anti-inflammatory effects in immune cells. We showed that 10(Z)-hexadecenoic acid suppresses inflammatory responses in macrophages (a type of immune cell that is critical for our innate immune response). Furthermore, it does so by, in a way, hijacking the immune cell’s own molecular machinery, binding to a receptor called peroxisome proliferator-activated receptor alpha (PPARα). This leads to a cascade of effects on intracellular signaling, resulting in a highly orchestrated anti-inflammatory response.

Why a fat molecule from a soil-derived bacterium would act in such a specific manner to reduce inflammation in mammalian immune cells remains a mystery. However, this is likely to be one of many molecules from soil-derived bacteria that have potential to reduce inflammation in mammalian hosts, including humans. Increased exposure to soil-derived bacteria may be one of the mechanisms through which “nature prescriptions” lead to improved health outcomes. Future studies should be able to further clarify mechanisms through which soil-derived bacteria like M. vaccae promote stress resilience, and lead to improved health outcomes.

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