Hygiene hypothesis

The idea of a link between parasite infection and immune disorders was first suggested in 1968 before the advent of large scale DNA sequencing techniques. The original formulation of the hygiene hypothesis dates from 1989, when David Strachan proposed that lower incidence of infection in early childhood could be an explanation for the rise in allergic diseases such as asthma and hay fever during the 20th century. The hygiene hypothesis has also been expanded beyond allergies, and is also studied in the context of a broader range of conditions affected by the immune system, particularly inflammatory diseases. These include type 1 diabetes, multiple sclerosis, and cancer.. ---> For example, the global distribution of multiple sclerosis is negatively correlated with that of the helminth Trichuris trichiura and its incidence is negatively correlated with Helicobacter pylori infection. The hypothesis states 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 proposed that coevolution with these species has resulted in their gaining a role in immune system development. 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". The rise of autoimmune diseases and acute lymphoblastic leukemia in young people in the developed world was linked to the hygiene hypothesis. Autism may be associated with changes in the gut microbiome and early infections. 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. == History ==

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. The increased occurrence of allergies had previously been thought to be a result of increasing pollution. "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 helminths and their association. These bacteria and parasites have commonly been found in vegetation, mud, and water throughout evolution. holds that diversity of microbes in the gut and other sites is a key factor for priming the immune system, rather than stable colonization with a particular species. Exposure to diverse organisms in early development builds a "database" that allows the immune system to identify 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. == 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. 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 might be a model for this theory but is not shown in-vivo. 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, helminths 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. Helminths 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. == Biological basis ==

The primary proposed mechanism of the hygiene hypothesis is an imbalance between the TH1 and TH2 subtypes of T helper cells. However, this explanation 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] Allergic conditions are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response, TH2 cells produce interleukin 4, interleukin 5, interleukin 6, interleukin 13 and predominantly stimulate immunoglobulin E production. 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. For example, all chronic inflammatory disorders show evidence of failed immunoregulation. 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. == Evidence ==

There is a significant amount of evidence supporting the idea that microbial exposure is linked to allergies or other conditions, although scientific disagreement still exists. The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases, and increased asthma rates are also associated with birth by Caesarean section. However, at least one study suggests that personal hygienic practices may be unrelated to the incidence of asthma. The hygiene hypothesis has difficulty explaining why allergic diseases also occur in less affluent regions. == Treatment ==

Current research suggests that manipulating the intestinal microbiota may be able to treat or prevent allergies and other immune-related conditions. However, probiotic bacteria have been found to reduce allergic symptoms in some studies. Helminthic therapy is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth larva or ova. Helminthic therapy emerged from the search for reasons why the incidence of immunological disorders and autoimmune diseases correlates with the level of industrial development. The exact relationship between helminths and allergies is unclear, in part because studies tend to use different definitions and outcomes, and because of the wide variety among both helminth species and the populations they infect. The infections induce a type 2 immune response, which likely evolved in mammals as a result of such infections; chronic helminth infection has been linked with a reduced sensitivity in peripheral T cells, and several studies have found deworming to lead to an increase in allergic sensitivity. The development of drugs that mimic the effects without causing disease is in progress. == Public health ==

The reduction of public confidence in hygiene has significant possible consequences for public health. Hygiene is essential for protecting vulnerable populations such as the elderly from infections, preventing the spread of antibiotic resistance, and for combating emerging infectious diseases such as SARS and Ebola. The effective communication of science to the public has been hindered by the presentation of the hygiene hypothesis and other health-related information in the media. 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. Infectious diseases continue to exert a heavy health toll. Preventing pandemics and reducing antibiotic resistance are global priorities, and 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. == See also ==