Microbial 'Old Friends', immunoregulation and stress resilience

Abstract

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.

Keywords: chronic inflammatory disorders; depression; immunoregulation; microbial ‘Old Friends’; stress resilience.

Figure 1.

Microbial immunomodulation. Microbes from the environment, and from the various microbiota, modulate the immune system. Some of this is due to direct effects of defined microbial products on elements of the immune system. But modulation of the immune system also secondarily alters the host–microbiota relationship and leads to changes in the composition of the microbiota, and so to further changes in immunoregulation (shown as indirect pathways)

Figure 2.

Immunoregulation and the inflammatory response to psychosocial stressors. Stress drives release of proinflammatory mediators via pathways that involve the immune system and the gut. The inflammatory response to a given level of a stressor is modulated and eventually terminated by immunoregulatory mechanisms. If immunoregulation is defective, as can occur when there has been inadequate exposure to immunoregulation-inducing Old Friends, then a given level of stressor will result in greater and more prolonged inflammatory response

Figure 3.

Perinatal influences on adult immunoregulation. Multiple factors in the perinatal period influence the developing brain, immune system, microbiota and HPA axis. Withdrawal of immunoregulation-inducing Old Friends and exposure to perinatal psychosocial stressors can result in immunoregulatory defects that are apparent in the adult. Such adults have increased risk of chronic inflammatory disorders, and increased inflammatory responses to psychosocial stressors, resulting in susceptibility to depression and probably to detrimental effects of low SES due to low stress resilience