Hygiene hypothesis

In medicine, the hygiene hypothesis is a hypothesis that states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g. gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system. In particular, the lack of exposure is thought to lead to defects in the establishment of immune tolerance.

The hygiene hypothesis has also been called the "biome depletion theory" and the "lost friends theory".[1]

Overview

The original formulation of the hygiene hypothesis dates from 1989 when Strachan proposed that lower incidence of infection in early childhood could be an explanation for the rapid 20th century rise in allergic diseases such as asthma and hay fever.[2]

It is now also recognised that the "reduced microbial exposure" concept applies to a much broader range of chronic inflammatory diseases than asthma and hay fever, which includes diseases such as type 1 diabetes[3] and multiple sclerosis,[4] and also some types of depression[4][5] and cancer.[6]

In 2003 Graham Rook proposed the "old friends hypothesis" which seems to offer a more rational explanation for the link between microbial exposure and inflammatory disorders.[7] He argues that the vital microbial exposures are not colds, influenza, measles and other common childhood infections which have evolved relatively recently over the last 10,000 years, but rather the microbes already present during mammalian and human evolution, that could persist in small hunter gatherer groups as microbiota, tolerated latent infections or carrier states. He proposes that we have become so dependent on these "old friends" that our immune systems neither develop properly nor function properly without them.

Strachan's original formulation of the hygiene hypothesis also centred around the idea that smaller families provided insufficient microbial exposure partly because of less person to person spread of infections, but also because of "improved household amenities and higher standards of personal cleanliness".[2] It seems likely that this was the reason he named it the "hygiene hypothesis". Although the "hygiene revolution" of the nineteenth and twentieth centuries may have been a major factor, it now seems more likely that, although public health measures such as sanitation, potable water and garbage collection were instrumental in reducing our exposure to cholera, typhoid and so on, they also deprived us of our exposure to the "old friends" that occupy the same environmental habitats.[8][9]

The rise of autoimmune diseases and acute lymphoblastic leukemia in young people in the developed world was linked to the hygiene hypothesis.[10][11]

Some evidence indicates that autism is correlated to factors (such as certain cytokines) that are indicative of an immune disease.[12][13][14][15][16] One publication speculated that the lack of early childhood exposure could be a cause of autism.[17]

The risk of chronic inflammatory diseases also depends on factors such as diet, pollution, physical activity, obesity, socio-economic factors and stress. Genetic predisposition is also a factor.[18][19][20]

History

Hygiene

Although the idea that exposure to certain infections may decrease the risk of allergy is not new, Strachan was one of the first to formally propose it, in an article published in the British Medical Journal (now the BMJ), in 1989.[21] This article proposed to explain the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were presumably exposed to more infectious agents through their siblings, than in children from families with only one child.

The hypothesis was extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of chronic inflammatory disorders. It explains the increase in allergic diseases that has been seen since industrialization and the higher incidence of allergic diseases in more developed countries. Epidemiological studies continue to confirm the protective effect of large family size and of growing up on a farm. However, exposure to common childhood infections such as chickenpox or measles is not thought to be protective.

Old friends

The "old friends hypothesis" proposed in 2003[7] may offer a better explanation for the link between microbial exposure and inflammatory diseases.[5][7] This hypothesis argues that the vital exposures are not common childhood and other recently evolved infections, over the last 10,000 years, but rather microbes already present in hunter-gatherer times when the human immune system was evolving. Conventional childhood infections are mostly "crowd infections" that kill or immunise and thus cannot persist in isolated hunter-gatherer groups. Crowd infections started to appear after the neolithic agricultural revolution, when human populations increased in size and proximity. The microbes that co-evolved with mammalian immune systems are much more ancient. Humans became so dependent on them that their immune systems can neither develop nor function properly without them.

Rook proposed that these microbes most likely include:

The modified hypothesis later expanded to include exposure to symbiotic bacteria and parasites.[22]

“Evolution turns the inevitable into a necessity,” this means that the majority of mammalian evolution took place in mud and rotting vegetation and more than 90 percent of human evolution took place in isolated hunter-gatherer communities and farming communities. Therefore, the human immune systems have evolved to anticipate certain types of microbial input, making the inevitable exposure into a necessity. The organisms that are implicated in the hygiene hypothesis are not proven to cause the disease prevalence, however there are sufficient data on lactobacilli, saprophytic environment mycobacteria, and helminthes and their association. These bacteria and parasites have commonly been found in vegetation, mud, and water throughout evolution.[5][7]

Multiple possible mechanisms have been proposed for how the ‘Old Friends’ microorganisms prevent autoimmune diseases and asthma. They include:74 1. Reciprocal inhibition between immune responses directed against distinct antigens of the Old Friends microbes which elicit stronger immune responses than the weaker autoantigens and allergens of autoimmune disease and allergy respectively. 2. Competition for cytokines, MCH receptors and growth factors needed by the immune system to mount an immune response. 3. Immunoregulatory interactions with host TLRs.[23]

Microbial diversity

The "microbial diversity" hypothesis, proposed by Paolo Matricardi[24] and developed by von Hertzen,[25] holds that diversity and turnover of bacterial species in the gut mucosa and other sites is a key factor for priming and regulating the immune system, rather than stable colonisation with a particular species. It is not clear whether diversity per se, or that a diverse population will include certain organisms without which the immune system fails to develop. Rook likened the embryonic immune system to a computer that contains programmes but little data. During gestation and infancy exposure to diverse organisms builds a "database" that allows the immune system to identify and respond to harmful agents and normalize once the danger is eliminated.

For allergic disease, the most important times for exposure are: early in development; later during pregnancy; and the first few days or months of infancy. Exposure needs to be maintained over a significant period. This fits with evidence that delivery by Caesarean section may be associated with increased allergies, whilst breastfeeding can be protective.[8] The extent to which exposures need to be maintained after infancy and whether these conditions could be managed by on-going exposure is as yet unknown.

Evolution of the adaptive immune system

Humans and the microbes they harbor have co-evolved for thousands of centuries; however, it is thought that the human species has gone through numerous phases in history characterized by different pathogen exposures. For instance, in very early human societies, small interaction between its members has given particular selection to a relatively limited group of pathogens that had high transmission rates. When societies became larger, the introduction of agriculture some 10,000 years ago made the spreading of new pathogens more likely, and thus exposures to pathogens that favored high population densities to thrive. Furthermore pastoralism has made zoonotic pathogen transmissions even more favorable. It is considered that the human immune system is likely subjected to a selective pressure from pathogens that are responsible for down regulating certain alleles and therefore phenotypes in humans, the thalassemia genes that are shaped by the Plasmodium species expressing the selection pressure being a model for this theory.

Recent comparative genomic studies have shown that immune response genes (protein coding and non-coding regulatory genes) have less evolutionary constraint, and are rather more frequently targeted by positive selection from pathogens that coevolve with the human subject. Of all the various types of pathogens known to cause disease in humans, helminthes warrant special attention, because of their ability to modify the prevalence or severity of certain immune-related responses in human and mouse models. In fact recent research has shown that parasitic worms have served as a stronger selective pressure on select human genes encoding interleukins and interleukin receptors when compared to viral and bacterial pathogens. Helminthes are thought to have been as old as the adaptive immune system, suggesting that they may have co-evolved, also implying that our immune system has been strongly focused on fighting off helminthic infections, insofar as to potentially interact with them early in infancy. The host-pathogen interaction is a very important relationship that serves to shape the immune system development early on in life.[26][27][28][29]

Biological basis

Allergic conditions are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response, TH2 cells produce IL-4,IL-5,IL-6, IL-13, and predominantly IgE.[23] Many bacteria and viruses elicit a TH1-mediated immune response, which down-regulates TH2 responses. TH1 immune responses are characterized by the secretion of pro-inflammatory cytokines such as IL-2, IFNγ, and TNFα. Factors that favor a predominantly TH1 phenotype include: older siblings, large family size, early day care attendance, infection (TB, measles, or hepatitis), rural living, or contact with animals. A TH2-dominated phenotype is associated with high antibiotic use, western lifestyle, urban environment, diet, and sensitivity to dust mites and cockroaches. TH1 and TH2 responses are reciprocally inhibitory, so when one is active, the other is suppressed.[30] [31] [32]

The mechanism of action of the hygiene hypothesis was insufficient stimulation of the TH1 arm, stimulating the cell defence of the immune system and leading to an overactive mother TH2 arm, stimulating the antibody-mediated immunity of the immune systems, which in turn led to allergic disease.[33]

This explanation however, cannot explain the rise in incidence (similar to the rise of allergic diseases) of several TH1-mediated autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and type I diabetes. [Figure 1Bach] However, the North South Gradient seen in the prevalence of Multiple Sclerosis has been found to be inversely related to the global distribution of parasitic infection.[Figure 2Bach] Additionally, research has shown that MS patients infected with parasites displayed TH2 type immune responses as opposed to the proinflammatory TH1 immune phenotype seen in non-infected multiple sclerosis patients.[Fleming] Parasite infection has also been shown to improve Inflammatory Bowel Disease and may act in a similar fashion as it does in multiple sclerosis.[Lee]

An alternative explanation is that the developing immune system must receive stimuli (from infectious agents, symbiotic bacteria, or parasites) to adequately develop regulatory T cells. Without that stimuli it becomes more susceptible to autoimmune diseases and allergic diseases, because of insufficiently repressed TH1 and TH2 responses, respectively.[34] For example, all chronic inflammatory disorders show evidence of failed immunoregulation.[18] Secondly, helminths, non-pathogenic ambient pseudocommensal bacteria or certain gut commensals and probiotics) drive immunoregulation. They block or treat models of all chronic inflammatory conditions.[35][36] Thirdly, some such organisms (or molecules that they secrete), specifically expand populations of regulatory T cells (Treg),[35][37] or cause dendritic cells to switch to regulatory forms that preferentially drive immunoregulation.[38] Finally, when multiple sclerosis patients become infected with helminths, the disease stops progressing and circulating myelin-recognising regulatory T cells appear in the peripheral blood.[39] This indicates that helminths act as adjuvants for regulatory T cells. This observation led to clinical trials.[40]

Epidemiological evidence

The hygiene hypothesis is supported by epidemiological data. Studies have shown that various immunological and autoimmune diseases are much less common in the developing world than the industrialized world and that immigrants to the industrialized world from the developing world increasingly develop immunological disorders in relation to the length of time since arrival in the industrialized world. This is true for asthma[41] and other chronic inflammatory disorders.[5]

Recently, Opisthorchis felineus chronic helminthic infection in the endemic region of Russia was found to be associated with lower total serum cholesterol levels and a significant attenuation of atherosclerosis in humans.[42]

Mouse studies have shown that exposure of young mice to viruses can result in a decreased incidence of type I diabetes.[43] However timing is crucial, and coxsackieviruses, rotaviruses and lymphocytic choriomeningitis virus that can be protective when given very early and can provoke autoimmunity when given late (for instance at weaning).[19][44][45] Rook also reviewed this issue.[20]

In developed countries where childhood diseases were eliminated, the asthma rate for youth is approximately 10%. In the 19th century, hay-fever, an easily recognisable allergy, was a very rare condition.[46]

Longitudinal studies in Ghana demonstrate an increase in immunological disorders as it grew more affluent and presumably cleaner.[47] These results have been replicated by Weinberg et. al. who amassed data from a variety of African countries comparing urban and rural environments as well as high and low socioeconomic status(SES). In all four countries urban and high SES groups had a higher prevalence of exercise induced bronchospasm.[48] The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases.[49] The use of antibacterial cleaning products has also been associated with higher incidence of asthma. Increased asthma rates are associated with birth by Caesarean section.[50][51] The data supporting links to antibiotic use and caesarean section (but not to antibacterial use) are rapidly strengthening.[52][53]

Antibiotic usage, which reduces the diversity of gut microbiota, is another cited factor. Although several studies have shown associations between antibiotic use and later development of asthma or allergy, other studies suggest that the effect is due to more frequent antibiotic use in asthmatic children. Trends in vaccine use may also be relevant, but epidemiological studies provide no consistent support for a detrimental effect of vaccination/immunisation on atopy rates.[8] In support of the old friends hypothesis, the intestinal microbiome was found to differ between allergic and non-allergic Estonian and Swedish children but this finding was not replicated in a larger cohort and the biodiversity of the intestinal flora in patients with Crohn’s disease was diminished.[23]

In 2015, a study found that washing dishes by hand as opposed to using a dishwasher, along with eating food directly from a farm or fermented food, might lead to reduced risk of certain conditions, including asthma, eczema, and possibly hay fever, though the data found on hay fever was not regarded as statistically significant. It was stated, however, that more research was needed to determine if there was an actual causal effect between these practices and a reduced risk of allergies and asthma.[54]

Experimental evidence

King et al. 2004 showed that when short lived T cells were replaced during a state of too few long lived T-cells (memory T cell), because of lack of infections, the risk of developing autoimmune diseases increases. They showed that in a state of too few long lived T-cells, because of lack of infections, not enough short lived T cells could be produced by long lived T cells during homeostatic expansion. Therefore, more auto reactive T cells divide in such a state, causing multiplying auto reactive T cells with a greater risk of causing autoimmune diseases like type I diabetes or multiple sclerosis.[55]

Cooke showed that NOD mice (which spontaneously develop type 1 diabetes) had significantly reduced incidence of this disease when infected with the helminth parasite Schistosoma mansoni. Other animal models, also showing that helminth infections block or treat various chronic inflammatory disorders, were comprehensively reviewed recently.[36]

In November 2009 showed that Staphylococci helped reduce inflammation.[56][57]

Early life exposure to specific microbe-enriched environments decreases susceptibility to diseases such as inflammatory bowel disease and asthma, whereas its absence, as in antibiotic treatment during childhood, may have the opposite effect. Olszak and colleagues,[58] compared germ-free mice and specific-pathogen-free mice, challenged with aerosol ovoalbumin to promote allergen-induced airway inflammation. They found that early exposure to conventional microbiota protected animals from developing asthma.

Public health trends

Since allergies and other chronic inflammatory diseases are largely diseases of the last 100 years or so, the "hygiene" revolution of the last 200 years came under scrutiny as a possible cause. During the 1800s radical improvements to sanitation and water quality occurred in Europe and North America. The introduction of toilets and sewer systems and the cleanup of city streets, and cleaner food were part of this program. This in turn led to a rapid decline in infectious diseases, particularly during the period 1900-1950, through reduced exposure to infectious agents.[8][9]

Public health activities have also played a part in affecting diet and lifestyle, such as physical activity levels and locations.

It has been suggested that public awareness of the initial form of the "hygiene hypothesis" has led to an "increased disregard" for hygiene in the home.[59]

Treatment

While no hygiene-related treatments are part of the standard of care, various approaches are under investigation. Helminth therapy is one alternative.[40] Probiotics (drinks or foods) have never been shown to reintroduce microbes to the gut. As yet, therapeutically relevant microbes have not been specifically identified.[60]

Lifestyle changes could increase microbial exposure, but whether this on balance improves the balance of risks remains the subject of research. Proposals include natural childbirth, sustained breast feeding and physical interaction between siblings, and encouraging children to spend more time in "uncleaned" outdoor environments.

Should these therapies become accepted, public policy implications include providing green spaces in urban areas or even providing access to agricultural environments for children.[61]

Helminthic therapy

Main article: Helminthic therapy

Helminthic therapy is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth larva or ova. Helminthic therapy is currently being studied as a promising treatment for several (non-viral) autoimmune diseases including Crohn's disease,[62][63][64][65] multiple sclerosis,[66] asthma,[67][68] and ulcerative colitis.[69] Autoimmune liver disease can be modulated by active helminth infections.[70]

The anti-inflammatory effects of helminth infection are prompting interest and research into diseases that involve inflammation but that are not currently considered to include autoimmunity or immune dysregulation as a causative factor. Heart disease and arteriosclerosis both have similar epidemiological profiles as autoimmune diseases and both involve inflammation. Their increased incidence cannot be solely attributed to environmental factors. Recent research explored the eradication of helminths as contributing to this discrepancy.[71]

Helminthic therapy emerged from the search for reasons why the incidence of immunological disorders and autoimmune diseases correlates with the level of industrial development.[68][72][72][73][74]

Related therapies include use other types of infectious organisms, such as protozoa.[75]

Cleanliness

No evidence supports the idea that reducing modern practices of cleanliness and hygiene would have any impact on rates of chronic inflammatory and allergic disorders, but a significant amount of evidence that it would increase the risks of infectious diseases.[8][9]

If home and personal cleanliness contributes to reduced exposure to vital microbes, its role is likely to be small. The idea that homes can be made “sterile” through excessive cleanliness is implausible. The evidence shows that, as fast as they are removed by cleaning, microbes are replaced, via dust and air from outdoors, by shedding from the body and other living things as well as from food.[8][9][76][77] The key point may be that the microbial content of urban housing has altered, not because of home and personal hygiene habits, but because they are part of urban environments. Diet and lifestyle changes also affects the gut, skin and respiratory microbiota.

At the same time that concerns about allergies and other chronic inflammatory diseases have been increasing, so also have concerns about infectious disease.[8][9][78][79] Infectious diseases continue to exert a heavy health toll. Preventing pandemics and reducing antibiotic resistance are global priorities. Hygiene is a cornerstone of containing these threats.

Infection risk management

The International Scientific Forum on Home Hygiene has developed a risk management approach to reducing home infection risks. This approach uses microbiological and epidemiological evidence to identify the key routes of infection transmission in the home. These data indicate that the critical routes involve the hands, hand and food contact surfaces and cleaning utensils. Clothing and household linens involve somewhat lower risks. Surfaces that contact the body, such as baths and hand basins, can act as infection vehicles, as can surfaces associated with toilets. Airborne transmission can be important for some pathogens. A key aspect of this approach is that it maximises protection against pathogens and infection, but is more relaxed about visible cleanliness in order to sustain normal exposure to other human, animal and environmental microbes.[76]

Alternative hypotheses

There are other hypotheses that try to explain the increase in allergies in developed nations. Major areas of focus include infant feeding, over-exposure and exposure to certain pollutants.

Infant feeding topics includes breastfeeding, when babies begin to eat solid foods and the type of these foods, cow's milk vs other milks and variations in milk processing.

Over-exposure to allergens in occupational situations can cause allergic responses, such as Laboratory animal allergy, bird lung, farmer's lung and bakers lung (See Wheat allergy).

Another theory suggests that pollution (such as diesel exhaust) might be responsible; however, improvements in air quality since the 1970s do not self-evidently support such claims. The pool chlorine hypothesis was proposed by Albert Bernard and his colleagues as an alternative hypothesis based on epidemiological evidence in 2003.[80]

Extensions

The rising incidence of metabolic disease, including obesity, diabetes and hypertension has been hypothesized to be exacerbated by the absence of certain infections.[81] Inflammation has long been recognized as a major etiological factor for metabolic diseases. Chronic inflammation leading to insulin resistance is a major etiological factor for metabolic conditions apart from obesity and type-2 diabetes. Insulin resistance typically starts as an organ-specific inflammation affecting the major organs of insulin action namely adipose tissue, skeletal muscles and liver. With disease progression, the inflammation becomes more systemic and starts affecting blood vessels leading to endothelial dysfunction, a pre-stage for vasculopathies. In fact the inflammation associated with macrovasculopathies like cardio-vascular disease, cerebrovascular disease and perivascular disease seems to be very different from microvascular complications like diabetic retinopathy, nephropathy and neuropathy. The exact cause of inflammation in IR is not known even though dietary, genetic and a variety of environmental factors have been implicated.

The reduced prevalence of lymphatic filariasis among diabetic subjects compared to non-diabetic and pre-diabetic subjects was noted, and supported the influence of childhood helminth infestations. Within the diabetic subjects, those who were filarial positive had reduced levels of pro-inflammatory markers compared to those who were filarial negative.[81]

In mice, animals infected with helminths had lesser disease severity compared to uninfected subjects in a diet-induced obesity mice model that is well-recognized for metabolic diseases.[82][83][84] In light of these findings, the decreasing incidence of filarial infection due to mass drug administration could potentially have an unexpected adverse impact on the prevalence of diabetes in developing countries.[81] Infections serve as an important source of inflammation and inflammation itself can serve as a link between infections and metabolic diseases. In general, infections that promote inflammation are thought to augment metabolic diseases while those that dampen inflammation by immunomodulation can confer protection against metabolic diseases. A much higher level of complexity is brought about by the recently identified helminth induced immunomodulation in conferring protection against inflammation and insulin resistance.

See also

References

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