Velina Kozareva ’16, THURJ Staff

With hand-sanitizing stations at nearly every corner of Harvard’s dining halls and the overall ubiquity of cleaning products in Western society, it can be hard to imagine a more “germophobic” culture than our current one. Yet what if our intense focus on cleanliness is actually harming us more than helping us, by increasing our susceptibility to chronic immunoregulatory disorders? This idea, often referred to as the “hygiene hypothesis,” has steadily grown in popularity over the past few decades, although it remains controversial among researchers and medical professionals.

According to the hygiene hypothesis, a lack of exposure to microorganisms during the early years of development can actually increase an individual’s likelihood of developing an immunoregulatory disorder, such as an allergy or eczema, later in life (1). The idea was first posited in 1989 by researcher Dr. David Strachan, who noticed a negative correlation between the number of children in a family and the incidence of hay fever among the siblings (2). He suggested that because having fewer siblings would limit microbial exposure during early childhood, this could lead to the development of hay fever.

Since Strachan’s initial proposition, there have been numerous epidemiological studies which seem to confirm that cases of atopic, or allergy-related, disorders have become more frequent in developed countries (1) (3). In the United States, the prevalence of asthma has increased by 1% just in the past 10 years, following an even sharper increase in prevalence in the past five decades (4). Similarly, a cohort study in Britain revealed an increase in hayfever incidence from 12% in 1958 to 23.3% in 1970 (3). Even now, there is a significant disparity between developed and developing countries in atopic disease rates; the World Health Organization reported in 2012 that 2% of adults in Ethiopia exhibit clinical asthma, as compared to 18.2% of adults in the United Kingdom (5). Assuming that developed countries are “cleaner” and have lower rates of infectious disease than their underdeveloped counterparts, these results certainly make the hygiene hypothesis sound plausible.

However, the exact biological explanation for this epidemiological evidence is not as clear. Initially, many researchers believed that the increase in immunoregulatory disorders was caused by an imbalance in TH1 and TH2 immune-mediated responses (6). Infectious pathogens in the body tend to trigger TH1 immune responses, which reduce unnecessary TH2 responses, the cause of most allergic reactions. Thus, as exposure to infectious pathogens decreased for many people, their immune systems overcompensated by producing unnecessary TH2 responses, leading them to develop allergic conditions (6). Yet, this theory does not explain the parallel rise in autoimmune disorders such as multiple sclerosis and inflammatory bowel disease, which are TH1-mediated.

In attempt to better understand this phenomenon, scientists have introduced two extensions to the hygiene hypothesis – the “Old Friends” hypothesis proposed by Graham Rook in 2003, and the “microbial diversity” hypothesis proposed by Paolo Matricardi in 2010 (1). The Old Friends hypothesis claims that it is not decreased exposure to common childhood pathogens, but rather decreased exposure to traditionally “pseudo-commensal” microorganisms which has caused an increase in autoimmune conditions. Rook characterizes “pseudo-commensals” as harmless or non-fatally parasitic microbes which coexisted with humans during the early stages of our evolution, when our immune systems were developing (1) (6). In fact, these microbes, the aforementioned “old friends,” were so commonplace that the human immune system grew completely accustomed to them, eventually requiring their presence for immune cell maturation and proper immune response.

Evidence for Rook’s hypothesis has come in several surprising studies, which show that patients suffering from autoimmune disorders like multiple sclerosis actually experience an improvement in symptoms after infection with certain parasites (6). In fact, one type of immunotherapy currently available is inoculation with helminthes –parasitic worms— including hookworms and human whipworms. Infestation with such worms has already been linked to reduced progression of multiple sclerosis and autoimmune liver disease, and researchers are currently studying the efficacy of these treatments in patients with inflammatory bowel disease (IBD), asthma, eczema, Crohn’s disease, and several other autoimmune disorders (1) (6).

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But how can parasitic worms possibly be beneficial? Rook suggests that these worms, which were likely much more prevalent during humans’ early evolution, help to modulate the immune system by stimulating activation and maturation of regulatory T cells and dendritic cells (6). These cells are responsible for suppressing inappropriate inflammatory response, such as that associated with many autoimmune disorders. Recent studies which lend support to this idea indicate that the presence of helminthes and other pathogens actually correlates positively with the production of anti-inflammatory cytokines (6) (7).

While scientists have yet to determine the precise mechanism underlying these pathogens’ helpful nature, their results seem to be consistent with the “microbial diversity” hypothesis as well (1). This theory argues that proper maturation and regulation of the human immune system depends on exposure not only to specific pathogens but also to a wide variety of microorganisms in different sites throughout the body. The reasoning is that this varied exposure could be helping to “calibrate” the immune system to react appropriately towards both harmful pathogens and innocuous antigens.

In particular, the hypothesis stresses the importance of well-developed gut and skin microbiota, and furthermore, that exposure to diverse microorganisms is especially crucial in the first few months of development and also after birth (1). Previous research has already established that disrupting normal intestinal microbiota can contribute to some forms of IBD (8). Emerging studies now also suggest that delivery by Caesarian section, which reduces exposure to microbes in the birth canal, correlates with higher incidence of allergies, while breastfeeding during infancy, which exposes the baby to bacteria in the mother’s breastmilk, decreases the risk for allergies (3) (9).

The results of these and further studies can also provide some insight on the specific types of human “hygiene” which are really responsible for the rising prevalence of immunoregulatory disorders. There are numerous longstanding public health measures in developed countries which could have contributed to this epidemiological increase, including higher sanitation standards, improved water quality, and reduced exposure to livestock and rural environments (1). Scientists believe these factors probably played the greatest role in nearly eradicating many dangerous infectious pathogens – and perhaps beneficial “old friends” too. On the other hand, domestic and personal hygiene habits, such as hand-washing and frequent bathing, have likely had a comparatively low impact on the overall variety of microorganisms people encounter in their homes (1). After all, it is virtually impossible for homes to become completely sanitary, and moreover, there have not been any conclusive studies showing a correlation between cleanliness of homes and increased incidence of atopic or autoimmune conditions. Nonetheless, personal hygiene can still prevent the spread of common infectious agents, including those causing pneumonia and influenza, and so should probably not be foregone (1).

So what exactly does this mean for people in developed countries? Have we doomed ourselves to a life of allergies and autoimmune disorders in return for sanitary water and cleaner cities? The answer is still unclear, as scientists have not yet determined which –if any- microbial exposures are truly crucial for mitigating immunoregulatory diseases. However, there do seem to be some ways for individuals to decrease their risk of developing such disorders, without sacrificing their hygienic lifestyles. These include limiting antibiotic use, which can easily disturb gut microbiota, eating more natural and raw foods, and simply spending more time outdoors, especially in rural or wooded habitats (1). With further research, scientists may discover more effective ways to provide individuals with the microbial exposure they need for proper immune regulation. In the meantime, we can probably continue our hand-washing habits –it seems we’re not too clean yet after all.



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