hygiene hypothesis hygiene hypothesis in medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms (such as the gut flora and helminth parasites) protects against allergic diseases by contributing to the development of the immune system. in particular, a lack of exposure is thought to lead to defects in the establishment of immune tolerance. the time period for exposure begins in utero and ends at school age. while early versions of the hypothesis referred to exposure to microbes in general, updated versions apply to a specific set of microbial species that have co-evolved with humans. the updates have been given various names, including the microbiome depletion hypothesis, the microflora hypothesis, and the "old friends" hypothesis. there is a significant amount of evidence supporting the idea that lack of exposure to these microbes is linked to allergies or other conditions, although scientific disagreement still exists. the term "hygiene hypothesis" has been described as a misnomer because people incorrectly interpret it as referring to personal cleanliness. reducing personal hygiene, such as not washing hands before eating, is expected to simply increase the risk of infection without having any impact on allergies or immune disorders. 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 ebola or covid-19. the hygiene hypothesis does not suggest that having more infections during childhood would be an overall benefit. overview the idea of a link between parasite infection and immune disorders was first suggested in 1968. 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 also some types of depression 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. strachan's original hypothesis could not explain how various allergic conditions spiked or increased in prevalence at different times, such as why respiratory allergies began to increase much earlier than food allergies, which did not become more common until near the end of the 20th century. in 2003 graham rook proposed the "old friends hypothesis" which has been described as a more rational explanation for the link between microbial exposure and inflammatory disorders. 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". 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 people of their exposure to the "old friends" that occupy the same environmental habitats. 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. 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 in 1989. 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 increased occurrence of allergies had previously been thought to be a result of increasing pollution. the hypothesis was extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of chronic inflammatory disorders. the "old friends hypothesis" proposed in 2003 may offer a better explanation for the link between microbial exposure and inflammatory diseases. this hypothesis argues that the vital exposures are not common cold and other recently evolved infections, which are no older than 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. according to this hypothesis, 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: ambient species that exist in the same environments as humans species that inhabit human skin, gut and respiratory tract, and that of the animals we live with organisms such as viruses and helminths (worms) that establish chronic infections or carrier states that humans can tolerate and so could co-evolve a specific immunoregulatory relationship with the immune system. the modified hypothesis later expanded to include exposure to symbiotic bacteria and parasites. "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. multiple possible mechanisms have been proposed for how the 'old friends' microorganisms prevent autoimmune diseases and asthma. they include: 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. competition for cytokines, mhc receptors and growth factors needed by the immune system to mount an immune response. immunoregulatory interactions with host tlrs. the "microbial diversity" hypothesis, proposed by paolo matricardi and developed by von hertzen, 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. insufficient activation of the th1 arm would stimulate the cell defense of the immune system and lead to an overactive th2 arm, stimulating the antibody-mediated immunity of the immune systems, which in turn led to allergic disease. 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. 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. 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. parasite infection has also been shown to improve inflammatory bowel disease and may act in a similar fashion as it does in multiple sclerosis. 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. 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 interleukin 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. 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