Immunoregulating Microbes – Stress Resilience
In the March 2013 issue of Evolution, Medicine, and Public Health, Graham Rook et al. review a multitude of epidemiological data to highlight links between sanitation, psychiatric disorders and stress resilience.
At the core of this concept is the Hygiene Hypothesis and “Old Friends” mechanism, which suggest that increased sanitation accounts for increases in inflammatory disorders, specifically because decreasing exposure to the microbes, chronic infections, or helminths with which we co-evolved leads to unchecked inflammation.
The Old Friends mechanism states that mammals co-evolved with an array of organisms that, because they needed to be tolerated, took on a role as inducers of immunoregulatory circuits. Such organisms include various microbiotas and commensals (gut, skin, lung, etc.); chronic infections picked up at birth; helminths that persist for life and environmental organisms from animals, mud and untreated water with which we were in daily contact in the environments in which humans evolved and lived until recently.
In the past, and currently in developing countries, humans were more frequently exposed to animals, mud, untreated water, and feces. When ingested, the helminths and pseudocommensal bacteria contained therein alter the microbiota, expand regulatory T cell populations, and modulate dendritic cells, leading to net immunoregulation.
Contact with the immunoregulatory ‘Old Friends’ rapidly diminishes when industrialization occurs, and individuals start to inhabit a plastic and concrete environment, to consume washed food and chlorine-treated water, and to minimize their contact with mud, animals and faeces. This withdrawal of the organisms that drive immunoregulatory circuits results in defective immunoregulation that, depending on the genetic background of any given individual, can manifest as a variety of chronic inflammatory disorders, including allergies, IBD and autoimmunity.
The evidence:
- The chronic inflammatory disorders all show evidence of failed immunoregulation.
- ‘Old Friends’ (such as helminths, non-pathogenic environmental bacteria [pseudocommensals] or certain gut commensals and probiotics) have been shown to drive immunoregulation, and to block or treat models of ‘all’ of these chronic inflammatory conditions.
- Some Old Friends, or molecules that they secrete, can be shown to specifically expand populations of regulatory T cells (Treg), or to cause dendritic cells to switch to regulatory phenotypes that preferentially drive immunoregulation.
- When MS patients become infected with helminths, the disease stops progressing and circulating myelin-recognizing regulatory T cells (Treg) appear in the peripheral blood, indicating that the helminths act as Treg adjuvants.
The Old Friends mechanism implies that inflammation is better regulated in low-income than in high–income urbanized countries. At first sight this seems paradoxical, because the high prevalence of infections in low-income countries might be expected to cause high levels of inflammation. However, recent work by McDade et al. discussed previously in this journal has largely resolved this paradox.
The results reveal that in a low-income country where there is still abundant exposure to the immunoregulation-inducing ‘Old Friends’, immunoregulation is efficient, and the inflammatory response is vigorous during an infection, but it is terminated when no longer needed, with the result that ‘resting’ C-reactive protein (CRP) is close to zero. This longitudinal study illuminated the previous finding that ‘high’ levels of microbial exposure in the perinatal period and in infancy correlated with ‘low’ levels of ‘resting’ CRP in adulthood. In contrast, in the USA and other high-income countries, there is often constant low-grade inflammation which tends to be stable across individuals, manifested as chronically raised CRP or interleukin (IL)-6.
A feature shared by most of the disorders discussed here is a higher prevalence in urban than in rural communities. This has been explored in some detail in relation to the allergic disorders. Contact with the farming environment, whether postnatal or prenatal, protects against allergic disorders, whereas the prevalence of these conditions increases with increasing urbanization.
Various studies have shown elevated proinflammatory cytokines in depression, as well as exaggerated cytokine response to social stressors. Both of these are more prominent in higher income countries and in urban as compared to rural areas. In addition, when comparing immigrants from a lower to higher income country with their birth population, the immigrants have higher rates of both various chronic inflammatory diseases and psychiatric disorders.
The findings summarized by Rook et al. suggest that defective immunoregulation secondary to diminished “Old Friends” exposure impairs stress resilience, thus leading to a vicious cycle of depression, psychosocial stress, and unmitigated inflammation. Rook et al. furthermore suggest specific research questions that have yet to be investigated to further clarify these complex interrelationships.
Source: Evolution, Medicine, and Public Health. 2013; 1:46-64.
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Cover Image: From/via: conservationmagazine; Credit: Cristiana Ceppas
