99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the 'hygiene' or 'old friends' hypothesis

Abstract

The current synthesis of the 'hygiene hypothesis' suggests that the recent increase in chronic inflammatory disorders is at least partly attributable to immunodysregulation resulting from lack of exposure to microorganisms that have evolved an essential role in the establishment of the immune system. This document provides a background for discussion of the following propositions. 1. The essential role of these organisms is an example of 'evolved dependence'. 2. The most relevant organisms are those that co-evolved with mammals, and already accompanied early hominids in the Paleolithic. 3. More recently evolved 'childhood infections' are not likely to have evolved this role, and recent epidemiology supports this contention. 4. This mechanism is interacting with other modern environmental changes that also lead to enhanced inflammatory responses [inappropriate diet, obesity, psychological stress, vitamin D deficiency, pollution (dioxins), etc.]. 5. The range of chronic inflammatory disorders that is affected is potentially larger than usually assumed [allergies, autoimmunity, inflammatory bowel disease, but also vascular disease, some cancers, depression/anxiety (when accompanied by raised inflammatory cytokines), and perhaps neurodegenerative disorders and type 2 diabetes].

Fig. 1

An attempt to summarize those aspects of man's microbiological history that might be most relevant to the hygiene hypothesis. Epidemiological data, laboratory and animal models and preliminary clinical trials investigating the hygiene hypothesis implicate several of the organisms (top right of the figure, in bold type) that are thought to have accompanied mammalian and human evolution. This relationship was clearly long enough for the establishment of evolved dependence. Organisms that evolved during the Neolithic are less likely to be relevant in this context, and the first epidemiological transition did not reduce human contact with organisms associated with animals, faeces and mud that had been present during the Paleolithic. Conversely, the second epidemiological transition might have led to a gene–environment misfit, as the ‘old friends’ from the Paleolithic were removed progressively from the modern environment.

Fig. 2

Several aspects of modern life are potentially interacting with the lack of ‘old friends’ at the level of immunoregulation. Obesity is associated with altered gut microbiota and excessive release of proinflammatory cytokines. Stress also alters gut microbiota and drives corticotrophin-releasing hormone (CRH), which increases permeability of the gut mucosa. Increased absorption of lipopolysaccharide (LPS) and other microbial components drives further release of proinflammatory cytokines. Lack of vitamin D exacerbates immunodysregulation, as does the triggering of T helper type 17 (Th17) cells by dioxins. Meanwhile, the changes in the gut are also likely to impact on Th17 development. Raised levels of proinflammatory cytokines trigger depression in some individuals, and this feeds back into the CRH/gut circuits.

Fig. 3

Several chronic inflammatory disorders need to be considered in the light of the hygiene hypothesis, in addition to the traditional trio of allergy, autoimmunity and inflammatory bowel disease. Atherosclerosis and the subtype of depression that is accompanied by raised circulating proinflammatory cytokines are both strong candidates.