Hygiene hypothesis: the dangers of not facing any danger.

By Inés Ochoa Arizu

After the Industrial Revolution in the nineteenth century, there was increased urbanization and progressive implementation of public health measures by western countries. Decontamination of the water supply, pasteurization and sterilization of food products, intensified disinfection of bodies and homes, vaccination or use of antibiotics and other medications all contribute to limiting the number of infections. But at the same time, a persistent rise in the incidence of allergic and autoimmune diseases such as asthma, type 1 diabetes or multiple sclerosis have been observed in developed countries¹ whereas in countries with poor health standards, the prevalence of allergic diseases remains low.²

The Hygiene Hypothesis, also called the “Old Friends Hypothesis”, suggests that due to new hygienic habits, certain microorganisms, which we have co-evolved over thousands of years and learned to tolerate, are being depleted of the urban environment. The depletion of these organisms interferes with the normal education of the immune system thus causing its dysregulation and further resulting in an overresponse to innocuous stimuli.³

But how do we know the rise of these autoimmune diseases and allergies is not due to genetic or even environmental factors such as contamination or the lack of sun?

We know that vitamin D production is linked to sun exposure and its role in immunoregulation has been proven in several studies.^4,5 We could assume that the deficit of vitamin D could be the cause of the rise of these allergies and autoimmunity. However, in Victorian England, it was normal for young girls to avoid the sunlight to comply with the canons of beauty of the time, nevertheless, autoimmunity appears to have been rare.³ Moreover, Karelia, a Russian republic, and Finland, both have the same ethnic group and climate but they present different socio-economic situations and extremely different rates of autoimmune diseases. Karelia has less diabetes type 1 and allergic asthma than Finland.⁶

In fact, there is a positive correlation between the gross national product (intimately linked with the sanitation and hygiene of a country) and the incidence of diabetes type 1, asthma and multiple sclerosis in Europe.⁷ Some studies have gone far beyond and even link the incidence of atopic dermatitis with family income.⁸

Sceptics could argue that the uneven distribution of autoimmune diseases and allergies in Europe could be due to other factors, such as contamination. Nevertheless, before the fall of the Berlin Wall, East Germany had much more pollution in the air than West Germany, yet significantly fewer cases of asthma.⁹

Studies on immigrants show that coming from countries with low incidence (Pakistan or Bangladesh) to countries of high incidence (the United Kingdom or the United States) increases the family frequency of diabetes and multiple sclerosis hence dismissing the genetic factor as a possible explanation.^{10, 11,12}

Thus, the rise of these allergies and autoimmunity is not due to genetic or environmental factors such as lack of sun exposure or contamination, but can we really link it to the depletion of specific microorganisms or the decrease in the number of infections?

Different studies point to allergic diseases being more common in areas of urbanization¹³ whereas exposure to farms and cowshed early in life seems to prevent atopic diseases such as asthma, hay fever or atopic sensitisation.¹⁴ At the same time, it has been demonstrated that germ-free mice have less development of the immune system and a higher tendency to inflammatory diseases.¹⁵

Focusing on specific species of parasites, the injection of Schistosoma mansoni eggs or even the adult worms in non-obese diabetic (NOD) mice inhibits the development of type 1 diabetes.¹⁶ This could explain why the prevalence of type 1 diabetes has significantly increased in the developed world, but it is uncommon in tropical regions where chronic infections like schistosomiasis and other types of parasitic infections are significant. Helminths and humans have coevolved over centuries and established a relationship of tolerance where once the human gets infected, the worm cannot be removed by the immune system. Henceforth, to avoid pointless immunopathology, the immune system downregulates itself. Helminths stimulate T regulatory cells, elicit interleukin-10 (IL-10) and induce the change of immunity type 1 and 3 (the ones responsible for autoimmunity), to immunity type 2.¹⁷

Another example of immunoregulation induced by microorganisms is the polysaccharide A (PSA) of Bacterioides fragilis, which induces the production and activation of T reg, the release of anti-inflammatory cytokines and restraining type 3 response, also promoting immunologic tolerance.¹⁸

A possible explanation of how the exposition to these parasites may help prevent autoimmunity and allergies is via the toll like receptors (TLRs). The TLRs are receptors that detect molecules from bacteria and other pathogens and activate the immune cells. The constant activation of these TLR receptors due to recurrent infection could result in desensitization. This desensitization could be reversible following cessation of infection. An example of this TLR desensitization or tolerance is the repeated treatment of NOD mice with TLR2 agonists, which inhibited the development of diabetes type 1.¹⁹

Taking everything into account, the last question we could ask ourselves if these organisms are even necessary? At which moment of human evolution did we become dependent on them to regulate our own immune system?

It seems that constant exposure to these infectious pathogens with immunoregulatory functions has positively selected genes that partially compensate for this immunoregulation. As soon as these immunoregulatory parasites are withdrawn from the environment there is an imbalance, and these genetic variants produce excessive inflammation, leading to inflammatory disorders and autoimmunity.²⁰

It is important to point out that the hygiene hypothesis is not opposed to the current improvement and implementation of the hygienic or sanitary measures, as their removal would not only expose us to Old Friends but also to old (and new) enemies. Truly, the hygiene hypothesis opens a door to new treatments against autoimmunity such as introducing low-dose of parasites as immunotherapy or discovering the immunoregulatory molecules that these microorganisms release and using them as drugs.

References:

1. Bach J-F. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med [Internet]. 2002;347(12):911–20.
2. Okada H, Kuhn C, Feillet H, Bach J-F. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clinical & Experimental Immunology. 2010 Mar 11;160(1):1–9.
3. Rook GAW. Hygiene hypothesis and autoimmune diseases. Clinical reviews in allergy & immunology [Internet]. 2012;42(1):5–15.
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16. Zaccone P, Fehérvári Z, Jones Frances M, Sidobre S, Kronenberg M, Dunne David W, et al. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. European Journal of Immunology. 2003 May;33(5):1439–49.
17. Smallwood TB, Giacomin PR, Loukas A, Mulvenna JP, Clark RJ, Miles JJ. Helminth immunomodulation in autoimmune disease. Front Immunol [Internet]. 2017;8:453.
18. Carrow HC, Batachari LE, Chu H. Strain diversity in the microbiome: Lessons from Bacteroides fragilis. Leong JM, editor. PLOS Pathogens. 2020 Dec 10;16(12):e1009056.
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