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Is the term “Hygiene hypothesis” now obsolete?

We argue that hygiene is not an important factor in the changes to our microbial exposures, so this misleading term should be replaced by "Old Friends Hypothesis" or the "Biodiversity Hypothesis"
Click here to download a paper reviewing this topic.

The background to the OLD FRIENDS HYPOTHESIS

The human ecosystem
We are not individuals. We are ecosystems with microbial partners (microbiota) that are involved in the development (particularly in early life) and function of essentially every organ, including the brain. In fact we have more microbes in our guts than we have human cells in our bodies, and vastly more microbial DNA and genes than human genes.

Evolution
This situation appeared with the evolution of vertebrates about 500 million years ago, and gives vertebrates enormous adaptability and flexibility because microbial genes can evolve rapidly when we change environment, diet or lifestyle. At the same time vertebrates evolved a more complex immune system that is able to achieve the tricky task of tolerating and “farming” our many hundreds of species of microbial partners (microbiota), while simultaneously protecting us from pathogens.

Failing regulation of our immune systems
However the high-income countries are now experiencing diseases where the immune system is attacking targets that it should not attack, such as our own tissues (multiple sclerosis, Type 1 diabetes), or harmless molecules in the air we breathe (hay fever, allergic asthma), or gut contents (inflammatory bowel diseases).
Our immune systems are also failing to terminate episodes of inflammation that are no longer needed, and persistent inflammation, even if accompanied by no apparent symptoms, predisposes to cardiovascular disease, obesity and depression and some cancers.

So why are our immune systems attacking things they should not attack?
At least part of the answer lies in changes to the composition of the gut microbiota and loss of its biodiversity. This is easily proved by transferring gut microbiota from obese or depressed humans into the guts of animals, which then develop similar symptoms.

Why are these changes occurring?
Lifestyle changes, antibiotics, caesarean births and lack of breast-feeding limit the transmission of maternal microbiota to the next generation. Then, unvarying diets lacking plant-derived fibre and polyphenols aggravate this loss of biodiversity. We also have less contact with the natural environment which is the source of many of the microbial partners that we need.
Without these microbial inputs in early life our immune systems, endocrine systems and metabolic systems do not develop correctly, and can malfunction.

So domestic hygiene is not an important cause of the poor regulation of our immune systems that we see in high-income settings. Other lifestyle changes described in these pages are to blame.


Click here to download a paper reviewing this topic.

Below we list papers on this topic, and on the implications for autoimmunity, and for the increase in cancers associated with inflammation.

LANCET paper on evolution and microbiota.

Rook G, Bäckhed F, Levin BR, McFall-Ngai MJ, McLean AR.
"Evolution, human-microbe interactions, and life history plasticity."
Lancet
. (2017), Jul 29 390(10093):521-530. doi: 10.1016/S0140-6736(17)30566-4.

Abstract. A bacterium was once a component of the ancestor of all eukaryotic cells, and much of the human genome originated in microorganisms. Today, all vertebrates harbour large communities of microorganisms (microbiota), particularly in the gut, and at least 20% of the small molecules in human blood are products of the microbiota. Changing human lifestyles and medical practices are disturbing the content and diversity of the microbiota, while simultaneously reducing our exposures to the so-called old infections and to organisms from the natural environment with which human beings co-evolved. Meanwhile, population growth is increasing the exposure of human beings to novel pathogens, particularly the crowd infections that were not part of our evolutionary history. Thus some microbes have co-evolved with human beings and play crucial roles in our physiology and metabolism, whereas others are entirely intrusive. Human metabolism is therefore a tug-of-war between managing beneficial microbes, excluding detrimental ones, and channelling as much energy as is available into other essential functions (eg, growth, maintenance, reproduction). This tug-of-war shapes the passage of each individual through life history decision nodes (eg, how fast to grow, when to mature, and how long to live).

OTHER PAPERS: Click on the titles below to reveal the abstract, journal reference and links to the paper
  • 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.

    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].

    This paper can be downloaded from here
  • A Darwinian View of the Hygiene or “Old Friends” Hypothesis. Enter description here.
    Rook GAW.
    Microbe. 2012;7(4):173-80.

    Abstract

    • 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.

    Abstract

    Man has moved rapidly from the hunter–gatherer environment to the living conditions of the rich industrialized countries. The hygiene hypothesis suggests that the resulting changed and reduced pattern of exposure to microorganisms has led to disordered regulation of the immune system, and hence to increases in certain inflammatory disorders. The concept began with the allergic disorders, but there are now good reasons for extending it to autoimmunity, inflammatory bowel disease, neuroinflammatory 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 important 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”

    Abstract
    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

  • Hygiene hypothesis and autoimmune diseases.
    Rook G.A.W.
    Clin Rev Allergy Immunol. (2012) 42(1):5-15.

    Abstract
    Throughout the twentieth century, there were striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These included autoimmune disorders such as Type 1 diabetes and multiple sclerosis. Although genetics and specific triggering mechanisms such as molecular mimicry and viruses are likely to be involved, the increases have been so rapid that any explanation that omits environmental change is incomplete. This chapter suggests that a series of environmental factors, most of them microbial, have led to a decrease in the efficiency of our immunoregulatory mechanisms because we are in a state of evolved dependence on organisms with which we co-evolved (and that had to be tolerated) as inducers of immunoregulatory circuits. These organisms ("Old Friends") are depleted from the modern urban environment. Rather than considering fetal programming by maternal microbial exposures, neonatal programming, the hygiene hypothesis, gut microbiota, and diet as separate and competing hypotheses, I attempt here to integrate these ideas under a single umbrella concept that can provide the missing immunoregulatory environmental factor that is needed to explain the recent increases in autoimmune disease.

    This paper can be dowloaded from here
  • Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders.       This was the first paper to use the term “Old Friends”
    Rook GA, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR.
    Springer Semin Immunopathol. 2004 Feb;25(3-4):237-55.
    Abstract
    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
  • Infection, immunoregulation and cancer. (The "Old Friends" hypothesis and cancer)

    Defective immunoregulation and increases in inflammation-associated cancers

    It is often assumed that all immunoregulation and Treg cells in cancer are bad for prognosis. However it is becoming increasingly clear that a failure of immunoregulation can lead to cancer, and can also drive the cancer after it has developed. Inflammation drives mutation and provides angiogenenic factors, and tumour growth factors. The increase in the incidence of some cancers (such as prostate) parallels the increases in other chronic inflammatory disorders. Similarly, colorectal cancer has a clear inflammatory component.

    Infection, immunoregulation and cancer.

    Rook GAW, Dalgleish A.
    Immunological Reviews. (2011) 240:141-59.

    Abstract
    As man has moved rapidly from the hunter–gatherer envi- ronment to the living conditions of the industrialized countries, the incidences of some cancers have increased alarmingly. Recent increases are usually attributed to dietary changes or to altered exposures to putative carcinogens associated with the modern lifestyle. However, the changes in cancer incidence parallel similar increases in non-neoplastic chronic inflammatory disorders (inflammatory bowel disease, allergies, and autoimmunity), and the epidemiology is often strikingly similar. This parallel is worth exploring, because the increases in chronic inflammatory disorders are at least partly explained by immunoregulatory defects resulting from diminished exposure to microorganisms that co-evolved with mammals and developed a role in driving immunoregulatory circuits (the hygiene hypothesis). Dysregulated chronic inflammation can drive oncogenesis and also provides growth and angiogenic factors that enhance the subsequent proliferation and spread of tumor cells. Thus, a modern failure to downregulate inappropriate inflammation could underlie increases in some cancers in parallel with the increases in chronic inflammatory disorders. This possibility is supported by recent work showing that in some circumstances regulatory T cells protect against cancer, rather than aggravating it, as previously assumed. A greater understanding of these interactions might pave the way to improved microbe-based immunotherapies.

    It may be possible to download this paper from here
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    Other authors have expressed very similar views :-

    Microbial deprivation, inflammation and cancer.


    von Hertzen LC, Joensuu H, Haahtela T.
    Cancer Metastasis Rev. (2011) 30(2):211-23.

    This paper can be found on PUBMED here