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.

  • (1) World Health Organization. Depression. https://www who int/news-room/fact-sheets/detail/depression [serial online] 2018; Accessed June 18, 2019.
  • (2) Peen J, Schoevers RA, Beekman AT, Dekker J. The current status of urban-rural differences in psychiatric disorders. Acta Psychiatr Scand 2010;121:84-93.
  • (3) Rook GA, Lowry CA. The hygiene hypothesis and psychiatric disorders. Trends Immunol 2008;29:150-158.
  • (4) Miller AH, Raison CL. Are anti-inflammatory therapies viable treatments for psychiatric disorders?: Where the rubber meets the road. JAMA Psychiatry 2015;72:527-528.
  • (5) Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016;16:22-34.
  • (6) Hodes GE, Pfau ML, Leboeuf M et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A 2014;111:16136-16141.
  • (7) Rohleder N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom Med 2014;76:181-189.
  • (8) Bobel TS, Hackl SB, Langgartner D et al. Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively. Proc Natl Acad Sci U S A 2018;115:5259-5264.
  • (9) Lowry CA, Smith DG, Siebler PH et al. The microbiota, immunoregulation, and mental health: Implications for public health. Curr Environ Health Rep 2016;3:270-286.
  • (10) Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701-712.
  • (11) Cryan JF, Dinan TG. More than a gut feeling: the microbiota regulates neurodevelopment and behavior. Neuropsychopharmacology 2015;40:241-242.
  • (12) Logan AC, Jacka FN, Craig JM, Prescott SL. The microbiome and mental health: Looking back, moving forward with lessons from allergic diseases. Clin Psychopharmacol Neurosci 2016;14:131-147.
  • (13) Rook GA, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR. Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders. Springer Semin Immunopathol 2004;25:237-255.
  • (14) Sonnenburg ED, Sonnenburg JL. Starving our microbial self: The deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab 2014;20:779-786.
  • (15) von Hertzen L, Beutler B, Bienenstock J et al. Helsinki alert of biodiversity and health. Ann Med 2015;47:218-225.
  • (16) Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: Ancient history, modern implications. J Clin Invest 2009;119:2475-2487.
  • (17) Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009;7:887-894.
  • (18) von Hertzen L, Hanski I, Haahtela T. Natural immunity. Biodiversity loss and inflammatory diseases are two global megatrends that might be related. EMBO Rep 2011;12:1089-1093.
  • (19) Lowry CA, Smith DG, Siebler PH et al. The microbiota, immunoregulation and mental health: implications for public health. Current Environmental Health Reports 2016;3:270-286.
  • (20) Reber SO, Siebler PH, Donner NC et al. Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci U S A 2016;113:E3130-E3139.
  • (21) Fox JH, Hassell JE, Jr., Siebler PH et al. Preimmunization with a heat-killed preparation of Mycobacterium vaccae enhances fear extinction in the fear-potentiated startle paradigm. Brain Behav Immun 2017;66:70-84.
  • (22) Frank MG, Fonken LK, Dolzani SD et al. Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: Attenuation of stress-induced microglial priming, alarmins and anxiety-like behavior. Brain Behav Immun 2018;73:352-363.

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  • Christopher Lowry, Ph.D.

    Associate Professor, Integrative Physiology, and Faculty Director, Research & Innovation Office

    University of Colorado, Boulder

    Christopher A. Lowry, Ph.D., is an Associate Professor in the Department of Integrative Physiology and Center for Neuroscience at the University of Colorado Boulder, with a secondary appointment in the Department of Physical Medicine and Rehabilitation (PM&R) and Center for Neuroscience at the University of Colorado Anschutz Medical Campus (AMC), a Principal Investigator in the Department of Veterans Affairs Eastern Colorado Health Care System, VA Rocky Mountain Mental Illness Research, Education, & Clinical Center (MIRECC), Denver Veterans Affairs Medical Center (VAMC), and director of the Behavioral Neuroendocrinology Laboratory at CU Boulder. He is Co-Director, with Dr. Lisa Brenner, of the Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE). Dr. Lowry's research program focuses on understanding stress-related physiology and behavior with an emphasis on the role of the microbiome-gut-brain axis in stress resilience, health and disease.