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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Updates
In another 2014 review Graham Rook, Charles Raison and Christopher Lowry further develop the hygiene hypothesis or the ‘Old Friends’ mechanism and theory. As per these authors, the gut microbiota is a major mediator of the hygiene hypothesis, which describes the role of organisms with which we co-evolved, and that needed to be tolerated, as crucial inducers of immunoregulation.
They explain how the gut microbiota drives immunoregulation, how faulty immunoregulation and inflammation predispose to psychiatric disease, and how psychological stress drives further inflammation via pathways that involve the gut and microbiota.
A new 2023 review by Graham Rook provides an update and summary of the ‘Old Friends’ hypothesis, which emphasizes the role of exposures to microorganisms with which humans co-evolved as essential drivers of the regulatory and anti-inflammatory arm of the immune system.
Interestingly, as per his brief historical perspective it was noted as early as 1873 that the prevalence of hay fever was increasing amongst wealthy urban populations but not amongst farmers. Increases in allergic disorders accelerated during the 20th century, and this focused attention on T helper 2 (Th2) immune responses. However, it was soon realized that the prevalence of autoimmune disorders and inflammatory bowel diseases (IBD) that involve different effector pathways of the immune system were often rising in parallel at the same time and in the same places. This suggested a broad failure of immunoregulation allowing multiple branches of the immune system to target harmless allergens, autoantigens and gut contents.
A summary of the ‘Old friends’ hypothesis. We co-evolved with the microbiota of mother, family and the natural environment, which are involved in multiple physiological functions and provide essential data and signals that drive development of the effector and regulatory arms of the immune system. Factors that distort these microbiota and/or decrease our exposure to the microbiota-derived signals and metabolites that drive immunoregulation may be contributing to the increase in chronic inflammatory disorders. In some human communities many, but not all, of the factors that distort microbial inputs are associated with low socioeconomic status (SES). (Infections and vaccines that enhance “Trained Immunity” rather than immunoregulation are not shown, but are discussed in the text.)
The ‘Old Friends’ hypothesis emphasizes the role of exposures to microorganisms with which humans co-evolved as essential drivers of the regulatory and anti-inflammatory arm of the immune system. Malfunctioning immunoregulation is likely to be fundamental to all these states, but most phenomena in biology are multifactorial. Things are most likely to happen when there are multiple reasons for them to do so.
Also, the author argues that mother, family and the natural environment (including the animals within it) provide the major microbial exposures that are needed to populate the gut microbiota and set up the immunoregulatory pathways that are defective in rich urban societies. The implication is that this mechanism is fundamental to all the current hypotheses. We now know that humans have indeed co-evolved with the microbiota, some members of which are becoming obligate symbionts.
Infections also impact the immune system but mostly they provide data, specific immunity and non-specific activation of the innate immune system (‘Trained Immunity’) rather than immunoregulation. And, finally, the author suggests that the ‘Old Friends’ hypothesis points to many ways in which we can optimize exposures to the necessary microbial inputs.
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Cover Image: From/via: conservationmagazine; Credit: Cristiana Ceppas