BACKGROUND TO THIS PAGE
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 ParticipantsLanggartner 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
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, respectivelyBöbel 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 115:5259
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 HealthLowry 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
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.