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 a specific form 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.
A particularly clear and readable review of this complex interdisciplinary area has been published by A. Miller and C. Raison in Jan 2016 in Nature Reviews Immunology. This paper is open source and can be downloaded here.
A new paper suggesting links between microbial exposures, immunoregulation, and resilience to psychosocial stressors.
Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectivelywww.pnas.org/cgi/doi/10.1073/pnas.1719866115
Proc Natl Acad Sci USA 115:5259
Böbel T., Hackl S., Langgartner D., Jarczok M., Rohleder N., Rook G., Lowry C., Gündel H., Waller C., and Reber S.
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.