Prof. Graham A.W. Rook, BA MB BChir MD

The term "hygiene hypothesis" does not accurately describe why people living in high income countries have diminished exposure to immunoregulation-inducing organisms. This is better described by the "Old Friends" mechanism. Moreover the Old Friends concept explains why these organisms evolved essential immunoregulatory roles.

We co-evolved with various microbiota (gut, lung, skin etc), and also with helminths (some in the gut, but many, such as blood nematodes, that never enter the gut) and ectoparasites. As hunter-gatherers we also had and inputs of microbiota from mud, soil, water, air and animals. This exposure to massive biodiversity, and to organisms that had to be tolerated, (and therefore evolved roles in the induction of immunoregulation) has been lost following urbanisation. But it is major changes in lifestyle rather than hygiene that have removed these organisms from our environments.

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

Rook GAW.
Clin Exp Immunol. 2010 Apr;160(1):70-9.

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].

This paper can be downloaded from here

A Darwinian View of the Hygiene or “Old Friends” Hypothesis.

Rook GAW.
Microbe. 2012;7(4):173-80.

• Microorganisms and macroorganisms such as helminths from mud, animals, and feces play a critical role in driving immunoregulation.
• The term “old friends” is broader than “hygiene” to describe this hypothesis, and it implicates exposures to microbes and other organisms during critical phases of human development.
• Diseases and conditions of the modern era, including multiple sclerosis, type 1 diabetes, and allergies, involve disrupted immunoregulatory circuits, likely reflecting reduced exposures to “old friend” organisms with which humans coevolved.
• Several clinical trials are testing these concepts, determining whether renewed exposures to “old friend” organisms can help to combat these modern-era diseases.

This paper can be downloaded here

The broader implications of the hygiene hypothesis.

Rook GAW.
Immunology. 2009;126:3-11.
Man has moved rapidly from the hunter–gatherer environment to the living conditions of the rich industrialized countries. The hygiene hypoth- esis suggests that the resulting changed and reduced pattern of exposure to microorganisms has led to disordered regulation of the immune sys- tem, and hence to increases in certain inflammatory disorders. The con- cept began with the allergic disorders, but there are now good reasons for extending it to autoimmunity, inflammatory bowel disease, neuroinflam- matory disorders, atherosclerosis, depression associated with raised inflammatory cytokines, and some cancers. This review discusses these possibilities in the context of Darwinian medicine, which uses knowledge of evolution to cast light on human diseases. The Darwinian approach enables one to correctly identify some of the organisms that are impor- tant for the ‘Hygiene’ or ‘Old Friends’ hypothesis, and to point to the potential exploitation of these organisms or their components in novel types of prophylaxis with applications in several branches of medicine.

This paper can be downloaded here

Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders.

Rook GA, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR.
Springer Semin Immunopathol. 2004 Feb;25(3-4):237-55.

** this was the first paper to use the term “Old Friends”

In the rich, developed parts of the world there has been a steady and simultaneous increase in at least three groups of disease: (1) allergies, (2) inflammatory bowel diseases (IBD; e.g. Crohn's disease and ulcerative colitis) and (3) autoimmunity (e.g. type 1 diabetes and multiple sclerosis). Because the medical world is so compartmentalised it was some time before the connection between these increases was noticed and understood. There is now evidence that the simultaneous increase in these diseases of immunodysregulation is at least partly attributable to malfunction of regulatory T cells (Treg). This paper provides an overview of relevant work in each of these fields of medicine (though with emphasis on the allergic disorders), and concludes that the increasing failure of Treg is a consequence of diminished exposure to certain micro-organisms that are "old friends", because of their continuous presence throughout mammalian evolution. These organisms, which include saprophytic mycobacteria, helminths and lactobacilli, are recognised by the innate immune system as harmless, and as adjuvants for Treg induction. Polymorphisms of components of the innate immune system such as TLR2 and NOD2 appear to define subsets of the population that will develop immunoregulatory disorders when living in the modern environment. A further role of the "old friends" and of the Treg that they induce might be to maintain the levels of regulatory IL-10 secreting macrophages and antigen-presenting cells, which are depleted in asthma and Crohn's disease. These concepts are leading to novel therapies based on harmless organisms or their components. Phase I/II clinical trials have yielded some statistically significant results, and phase II trials are in progress.

You may have access to this paper here

Other relevant papers that may be accessible via PUBMED:-

Give us this day our daily germs.
Rook GAW, Stanford JL.
Immunol Today. 1998;19:113-6.