Microbial "Old Friends" and the regulation of inflammation: Relevance to psychiatric disorders

The recent Darwinian reformulation of the “hygiene hypothesis” indicates that micro- and macro-organisms that accompanied mammalian evolution co-evolved crucial roles in setting up regulation of the immune system. The papers listed below outline the evidence that failure of these immunoregulatory pathways in modern westernised populations plays a role, not only in the increases in chronic inflammatory disorders (allergies, autoimmunity and inflammatory bowel disease), but also in specific forms of depression and in reduced stress resilience.

The most recent papers also discuss accumulating evidence that the same mechanisms are relevant to understanding health gradients associated with socio-economic status (SES), such as those uncovered in the Whitehall studies, and differences in rural versus urban populations.

In 2011 Lederbogen et al. (Nature 474:498-501) used functional magnetic resonance imaging (fMRI) to study patterns of CNS activation induced by a standardised laboratory stressor. They compared adults who'd had an urban versus a rural upbringing for the first 15 years of life. The patterns were significantly different and the authors suggested that the difference might be a long-term consequence of greater stressfulness of an urban childhood. We doubted this explanation, because we know that rural versus urban upbringing will change the exposure to the microbiota of the natural environment during the critical period for tuning of immunoregulation, and therefore change regulation of the immune system. But since we know that the immune system and inflammation regulate CNS function, differences in the CNS stress response could be partly secondary to different activation of the immune system by the stressor.

The two papers immediately below show that the activation of the immune system by a stressor, as measured via biomarkers in the peripheral blood, is indeed greater in subjects with an urban upbringing, particularly if brought up without pets (Böbel et al 2018) and that there is a relationship with the content of the salivary microbiome (Langgartner et al 2020). These studies help to validate, in the human context, studies of the gut-brain axis, and emphasise the importance of contact with animals in the context of our evolutionarily determined need for contact with the microbiota of the natural environment.

Association of the Salivary Microbiome With Animal Contact During Early Life and Stress-Induced Immune Activation in Healthy Participants

Langgartner D, Zambrano CA, Heinze JD, Stamper CE, Böbel TS, Hackl SB, Jarczok MN, Rohleder N, Rook GAW, Gündel H, Waller C, Lowry CA, Reber SO
Front Psychiatry (2020) 11:353
doi: 10.3389/fpsyt.2020.00353
This paper can be downloaded here

In an extension of the paper Böbel et al 2018 shown below it was found that urban upbringing with absolutely no animal contact (compared to rural upbringing with animal contact) had long-lasting effects on the composition of the salivary microbiome and potentiated the negative consequences of urban upbringing on stress-induced immune activation.

Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively

Böbel T., Hackl S., Langgartner D., Jarczok M., Rohleder N., Rook G., Lowry C., Gündel H., Waller C., and Reber S.
(2018) Proc Natl Acad Sci USA

This paper can be downloaded here.

Urbanization is on the rise, and environments offering a narrow range of microbial exposures are linked to an increased prevalence of both physical and mental disorders. Human and animal studies suggest that an overreactive immune system not only accompanies stress-associated disorders but might even be causally involved in their pathogenesis. Here, we show in young [mean age, years (SD): rural, 25.1 (0.78); urban, 24.5 (0.88)] healthy human volunteers that urban upbringing in the absence of pets (n = 20), relative to rural upbringing in the presence of farm animals (n = 20), was associated with a more pronounced increase in the number of peripheral blood mononuclear cells (PBMCs) and plasma interleukin 6 (IL-6) concentrations following acute psychosocial stress induced by the Trier social stress test (TSST). Moreover, ex vivo-cultured PBMCs from urban participants raised in the absence of animals secreted more IL-6 in response to the T cell-specific mitogen Con A. In turn, antiinflammatory IL-10 secretion was suppressed following TSST in urban participants raised in the absence of animals, suggesting immunoregulatory deficits, relative to rural participants raised in the presence of animals. Questionnaires, plasma cortisol, and salivary α-amylase, however, indicated the experimental protocol was more stressful and anxiogenic for rural participants raised in the presence of animals. Together, our findings support the hypothesis that urban vs. rural upbringing in the absence or presence of animals, respectively, increases vulnerability to stress-associated physical and mental disorders by compromising adequate resolution of systemic immune activation following social stress and, in turn, aggravating stress-associated systemic immune activation.

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health

Lowry CA, Smith DG, Siebler PH, Schmidt D, Stamper CE, Hassell JE, Jr., Yamashita PS, Fox JH, Reber SO, Brenner LA, Hoisington AJ, Postolache TT, Kinney KA, Marciani D, Hernandez M, Hemmings SM, Malan-Muller S, Wright KP, Knight R, Raison CL, Rook GA.

Curr Envir Health Rpt (2016) 3:270–286

The hygiene or “Old Friends” hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress- related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects’ research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes.

This paper can be downloaded here
OTHER PAPERS: Click on the titles below to reveal the abstract, journal reference and links to the paper
  • Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice
    The paper below (Reber et al 2016) uses a model in which stress causes changes in the gut microbiota, systemic inflammation, colitis, inflammation and microglia activation in the brain, and behavioural changes. Boosting immunoregulation by immunising with an organism known to drive Treg activity (Zouany-Amorim et al 2002) was able to oppose most of these effects of stress. These protective effects were Treg-dependent.
                 Reber et al (2016) Proc Natl Acad Sci U S A 113:E3130
                 Zuany-Amorim et al (2002) Nat. Med. 8:625

    Stacks Image 1914


    The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1–2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.

    This paper can be downloaded here.
  • Hygiene and other early childhood influences on the subsequent function of the immune system.
    Rook GAW, Lowry CA, Raison CL.
    Brain Research (2014)
    The immune system influences brain development and function. Hygiene and other early childhood influences impact the subsequent function of the immune system during adulthood, with consequences for vulnerability to neurodevelopmental and psychiatric disorders. Inflammatory events during pregnancy can act directly to cause developmental problems in the central nervous system (CNS) that have been implicated in schizophrenia and autism. The immune system also acts indirectly by “farming” the intestinal microbiota, which then influences brain development and function via the multiple pathways that constitute the gut-brain axis. The gut microbiota also regulates the immune system. Regulation of the immune system is crucial because inflammatory states in pregnancy need to be limited, and throughout life inflammation needs to be terminated completely when not required; for example, persistently raised levels of background inflammation during adulthood (in the presence or absence of a clinically apparent inflammatory stimulus) correlate with an increased risk of depression. A number of factors in the perinatal period, notably immigration from rural low-income to rich developed settings, caesarean delivery, breastfeeding and antibiotic abuse have profound effects on the microbiota and on immunoregulation during early life that persist into adulthood. Many aspects of the modern western environment deprive the infant of the immunoregulatory organisms with which humans co-evolved, while encouraging exposure to non-immunoregulatory organisms, associated with more recently evolved “crowd” infections. Finally, there are complex interactions between perinatal psychosocial stressors, the microbiota, and the immune system that have significant additional effects on both physical and psychiatric wellbeing in subsequent adulthood.

    This paper can be
    downloaded here
  • Microbial Old Friends, immunoregulation and stress resilience.
    Rook GAW, Lowry CA, Raison CL.
    Evolution, Medicine and Pubic Health. 2013;EMPH (2013)(1):46-64. doi: 10.1093/emph/eot004

    Chronic inflammatory diseases (autoimmunity, allergy and inflammatory bowel diseases) are increasing in prevalence in urban communities in high-income countries. One important factor is reduced exposure to immunoregulation-inducing macro- and microorganisms and microbiota that accompanied mammalian evolution (the hygiene hypothesis or ‘Old Friends’ mechanism). Reduced exposure to these organisms predisposes to poor regulation of inflammation. But inflammation is equally relevant to psychiatric disorders. Inflammatory mediators modulate brain development, cognition and mood, and accompany low socioeconomic status and some cases of depression in developed countries. The risk of all these conditions (chronic inflammatory and psychiatric) is increased in urban versus rural communities, and increased in immigrants, particularly if they move from a low- to a high-income country during infancy, and often the prevalence increases further in second generation immigrants, suggesting that critical exposures modulating disease risk occur during pregnancy and infancy. Diminished exposure to immunoregulation-inducing Old Friends in the perinatal period may enhance the consequences of psychosocial stressors, which induce increased levels of inflammatory mediators, modulate the microbiota and increase the risk for developing all known psychiatric conditions. In later life, the detrimental effects of psychosocial stressors may be exaggerated when the stress occurs against a background of reduced immunoregulation, so that more inflammation (and therefore more psychiatric symptoms) result from any given level of psychosocial stress. This interaction between immunoregulatory deficits and psychosocial stressors may lead to reduced stress resilience in modern urban communities. This concept suggests novel interpretations of recent epidemiology, and novel approaches to the increasing burden of psychiatric disease.

    This paper can be downloaded here
  • Microbial "Old Friends", immunoregulation and psychiatric disorders.
    Rook GAW, Raison CL, Lowry CA.
    In: Heidt PJ, Bienenstock J, Rusch V, editors. The gut microbiome and the nervous system. Herborn: Old Herborn University; 2013. p. 61-90.

    Many diseases are increasing in prevalence in urban communities in developed countries. Immigrants are also at increased disease risk, particularly if they move from a poor to a wealthy country during infancy. Moreover, the prevalence of many of these conditions increases further in second-generation immigrants, suggesting that exposure (or lack of exposure) to critical influences during pregnancy and infancy may play an important role in conferring risk for many chronic diseases common in the modern world. The diversity of diseases involved is remarkable. They include chronic inflammatory disorders (autoimmunity, allergy and inflammatory bowel disease), many cancers, (such as prostate, colorectal and various childhood cancers) and a range of psychiatric disorders including depression, disorders precipitated by psychosocial stressors or low socioeconomic status, and disorders with a developmental component such as schizophrenia and autism. Here we explore important parallels among the increases in these diverse types of disease. We merge the immunological explanation (hygiene, or “Old Friends” hypothesis) with psychosocial explanations, and suggest that there are underlying mechanisms, many involving the gut microbiota, that are relevant to all these disorders and that transcend the boundaries between traditional medical disciplines.

    This paper can be downloaded here
  • Childhood microbial experience, immunoregulation, inflammation and adult susceptibility to psychosocial stressors and depression in rich and poor countries.
    Rook G, Raison CL, Lowry CA.
    Evolution, Medicine and Pubic Health. 2012.

    (This is a commentary on a paper by Thom McDade and colleagues which can be found in the same journal)

    This paper can be downloaded here
  • Can we vaccinate against depression?
    Rook GA, Raison CL, Lowry CA.
    Drug Discov Today. 2012 May;17(9-10):451-8.

    Major depression is common in the context of autoimmune and inflammatory diseases and is frequently associated with persistently raised levels of proinflammatory cytokines and other markers of inflammation, even in the absence of another diagnosable immune pathology to account for these findings. Therefore immunoregulation-inducing vaccines or manipulations of the gut microbiota might prevent or treat depression. These strategies are already undergoing clinical trials for chronic inflammatory disorders, such as allergies, autoimmunity and inflammatory bowel disease. In this article, we summarize data suggesting that this approach might be effective in depression and encourage the initiation of clinical vaccination trials in this disorder.

    This paper may be available for download from here
  • Microbial 'old friends', immunoregulation and socioeconomic status Enter description here.
    Graham A.W. Rook, Charles L. Raison and Christopher A. Lowry (2014)
    Clin Exp Immunol 177:1           DOI: 10.1111/cei.12269

    It has often been thought paradoxical that most of the chronic inflammatory disorders associated with defective immunoregulation (and with the "hygiene hypothesis" or "Old Friends" mechanism) are most common in the poorest parts of modern urban environments. This paper explains why it is to be expected that the Old Friends mechanism will act most strongly on people of low socioeconomic status (low SES).    

Other relevant papers that may be accessible via PUBMED:-

Inflammation, sanitation and consternation: loss of contact with co-evolved, tolerogenic micro-organisms and the pathophysiology and treatment of major depression.
Raison CL, Lowry CA, Rook GAW.
Arch Gen Psychiatry. 2010;67(12):1211-24.

Lymphocytes in neuroprotection, cognition and emotion: Is intolerance really the answer?
Rook GA, Lowry CA, Raison CL.
Brain Behav Immun. 2011 Dec 16;25:591-601.

The hygiene hypothesis and psychiatric disorders.
Rook GAW, Lowry CA.
Trends Immunol. 2008;29:150-8.