The changing microbial environment and chronic inflammatory disorders

Abstract

: There is much to be gained from examining human diseases within the expanding framework of Darwinian medicine. This is particularly true of those conditions that change in frequency as populations develop from the human "environment of evolutionary adaptedness" to the living conditions of the rich industrialized countries. This development entails major changes in lifestyle, leading to reductions in contact with environmental microorganisms and helminths that have evolved a physiologic role as drivers of immunoregulatory circuits. It is suggested that a deficit in immunoregulation in rich countries is contributing not only to increases in the incidence of allergic disorders but also to increases in other chronic inflammatory conditions that are exacerbated by a failure to terminate inappropriate inflammatory reponses. These include autoimmunity, neuroinflammatory disorders, atherosclerosis, depression associated with raised inflammatory cytokines, and some cancers.

Figure 1

Organisms such as helminths and environmental saprophytes, which are part of mammalian evolutionary history ("old friends") and must be tolerated, are detected by pattern recognition receptors such as Toll-like receptor 2 (TLR2) and CARD15 (caspase recruitment domain family, member 15) on dendritic cells (DCs). The DCs mature into regulatory DCs that drive regulatory T cell (Treg) responses to the antigens of these organisms. The continuing presence of these antigens in the gut flora, in food, or resident as parasites such as microfilariae leads to continuous background release of regulatory cytokines from these Tregs, exerting bystander suppression of other responses, as shown in the upper arm of the figure. Meanwhile, the increased numbers of regulatory DCs lead to increased processing by such DCs of self-antigens, gut content antigens, and allergens, as shown in the lower arm of the figure. Therefore, the numbers of Tregs specifically triggered by these antigens is also increased, downregulating autoimmunity, inflammatory bowel disease, and allergies, respectively. CTLA-4 = cytotoxic T-lymphocyte antigen 4; IL-10 = interleukin-10; TGF-β = transforming growth factor β.

Figure 2

Human physiology was shaped by the hunter-gatherer way of life, which is regarded as the human "environment of evolutionary adaptedness," although there have been further adaptations during the approximately 10,000 years (≈500 generations) since the introduction of farming and livestock. Most human evolution has been cultural and technological rather than genetic, and a gene-environment misfit may be occurring. Harmless organisms that were abundant in food and water (such as environmental actinomycetes) and helminths that had to be tolerated developed a role in the induction of immunoregulatory circuits. Without these, there may be a failure to terminate inappropriate inflammatory responses, leading to an increased susceptibility to chronic inflammatory disorders, the precise nature of which depends on the genetics and history of the individual. DCreg = dendritic regulatory cells; Th = T helper; Treg = regulatory T cells.