Public Health struggles to square hygiene with diversity

Abstract

The ‘Hygiene Hypothesis’ to explain the rise in allergies is being replaced by a more nuanced picture of how the immune system interacts with environmental microbes.

The hygiene hypothesis came to prominence around 30 years ago to explain the notable rise in allergic diseases such as asthma and hay fever, pinning it on reduced exposure to pathogens during childhood. Originally formulated in 1989 by David Strachan, it was exploited in public health messaging with the aim of persuading people that excessive cleanliness was detrimental to their health.

But the hypothesis quite quickly fell into disfavor among both immunologists and public health experts. First, they saw it as leading the public astray by convincing them that good hygiene practices such as keeping kitchen surfaces clean or washing hands before preparing food were themselves unnecessary or even harmful. Second, the notion that infectious childhood diseases was the key factor in training a healthy immune system was seen at best as misleading, if not totally incorrect.

Evolution of a hypothesis

This led to development of the “Old Friends Hypothesis” in 2003 by Graham Rook and colleagues at University College London, who replaced childhood infections with microbes, especially bacteria, encountered more generally in the environment. Rook argues that common childhood infections such as measles evolved at most 12,000 years ago with the emergence of agriculture and concomitant greater population density and are therefore almost irrelevant in terms of immune system training, because they have been only present for a tiny fraction of human history. These “crowd infections” cannot persist in isolated hunter–gatherer groups and entered the human population from animal sources after the Neolithic agricultural revolution when human populations grew sufficiently large and dense. Rook's argument was that the key agents of immune training were ancient microbes, most of which are commensal or mutually symbiotic, that co‐evolved with the mammalian immune systems. In their absence, immune systems do not develop optimally and malfunction, leading to increased risk of allergy, inflammatory disorders, autoimmune disease, and even pathogenic infections.

… the notion that infectious childhood diseases was the key factor in training a healthy immune system was seen at best as misleading, if not totally incorrect.

Rook originally proposed that these ancient microbes included three broad categories of micro‐organism with some obvious overlap. First are ambient species that share the human environment wherever people roam. Second are those organisms that inhabit the human skin, gut, and respiratory tract, as well as domestic animals. Third are those organisms that establish chronic infections or at least are carried with some tolerance by humans and have co‐evolved a specific immunoregulatory relationship with the immune system. These include viruses and the parasitic helminth worms.

The hypothesis later expanded to include symbiotic bacteria and parasites and eventually morphed into the biodiversity hypothesis, which embodied the idea that not all relevant microbes that play key roles in immune system development can be regarded as friends. “The biodiversity hypothesis seeks to extend the old friend's hypothesis to take account of contact with a greater number of different microbes to detect friend from foe, or self from non self”, explained Martin Breed, a Restoration Ecologist at the University of Adelaide in Australia.

Rook though dismissed the idea of a clear distinction between friend and foe. “The friend or foe concept is not really viable”, he said. “Most of the organisms in your gut, where they are friends, would kill you if they got into your brain, or even, in many cases, into the circulation”. What matters, according to Rook, is exposure to microbes that we have co‐evolved with over the bulk of human evolution and not just the relatively short period since the first larger densely populated settlements emerged almost 12,000 years ago.

As he puts it, the microorganisms we meet, or should meet, especially in childhood, provide three interrelated components vital for immune system development. First, they provide specific antigens, which select B cells and T cells from the vast pool generated by random mutation. Second, they provide molecular signals that set the type and level of background innate immunity against pathogenic infection, while inducing tolerance against self as well as harmless microorganisms. Third, such exposure enriches the microbiota, as many microorganisms join. “The crucial point is that all these processes are needed to set up the immunoregulatory mechanisms, the negative feedback that the immune system, like all biological systems, needs to keep it under control”, Rook explained. “For example, it was shown many years ago that animals with no gut microbiota are not rendered tolerant to an allergen that is given by mouth early in life, whereas tolerance develops if the gut microbiota is intact. Many mechanisms are involved, for example, some gut organisms cause proliferation of regulatory T lymphocytes. This is very relevant to contemporary human children”.

… the key agents of immune training were ancient microbes, most of which are commensal or mutually symbiotic, that co‐evolved with the mammalian immune systems.

Such considerations have led Rook to argue that the term “hygiene hypothesis” should be buried once and for all to avoid misunderstanding and reflect better knowledge of how immune systems interact with the environment. “It needs to be dropped permanently”, Rook insisted. “It seems impossible to update it, so we need to replace it with ‘Old Friends’ or ‘Biodiversity’”.

Implications for public health

Indeed, Rook, along with Sally Bloomfield from the London School of Hygiene and Tropical Medicine and Chairman of the International Scientific Forum on Home Hygiene (IFH), have been part of a campaign to bring this about. Bloomfield agreed that the key point is to understand the relationship between the developing immune system, the microbiome, and the environment, and identify what can go wrong when dysbiosis occurs. But she concurred that attempts to disassociate the word hygiene from healthy immune development have been largely unsuccessful so far, in part because media have kept the disingenuous connection alive.

One problem is that there is no single word to describe the various themes assumed to have played a role in the rise in allergies: overuse of antibiotics, urban lifestyle, more limited diets, increased bottle feeding of babies, number of pets in the home, and even exercise or lack of it. These disparate factors cannot all be pinned on single slogans. “No, there isn't any sign of people stopping using the term ‘hygiene hypothesis’, because it's become received wisdom”, Bloomfield said.

The COVID‐19 pandemic has exposed the whole field to renewed scrutiny given the hygiene measures to inhibit spread of the virus, such as regular handwashing. Bloomfield had hoped that the pandemic might help educate the public about the distinction between targeted hygiene, which is an essential component in public health, and cleanliness, but which, in excess, is detrimental by reducing exposure to harmless pathogens in the environment. “The IFH has been claiming since 1997 that we must adopt a smarter approach to hygiene, targeted hygiene”, she said, but signs so far are that it has not led to greater public enlightenment. “The RSPH (Royal Society for Public Health) did a poll and found relatively little understanding of targeted hygiene as a result of the epidemic”, Bloomfield added. “We had hoped that COVID‐19 would have changed that because it's a text‐book example of the journey of the germ”.

Evidence from epidemiological studies

In the scientific community though, attempts to move on from the hygiene hypothesis have been more successful. There has been a steadily accumulating body of evidence to associate exposure to microbial diversity and incidence of a wide range of conditions relating to immune system malfunction, especially allergy. One documented example of this correlation is studies of the Amish and Hutterite people in the USA. Both groups have Swiss German origins and are quite similar genetically but have contrasting lifestyles. While Amish people have retained their traditional lifestyle and practices from the 18^th and 19^th century, Hutterites have adopted modern agricultural practices. A 2016 study found that hay fever was almost nonexistent among Amish children and asthma incidence very low, triggered mostly by viral infections without need for regular anti‐inflammatory medication. Conversely, Hutterites, whose lifestyles were otherwise very similar, have a prevalence of asthma and allergic sensitization, respectively, in excess of 15% and 40% (Hrusch et al, 2015).

Similar findings have come from Finland, which has become a hot bed of comparative studies between sub‐populations in close proximity with contrasting microbial exposures. A recent study provided evidence that relative exposures to one particular bacterium common in the rural environment, Acinetobacter, correlates with a striking difference in allergy risk between infants in Finland and nearby Estonia (Ruokolainen et al, 2020).

… the microorganisms we meet, or should meet, especially in childhood, provide three interrelated components vital for immune system development.

This study reported significant differences in microbial diversity and community composition with the genus Acinetobacter more abundant among Estonians whose children have a lower risk of allergy than Finnish children. It also found that land‐use patterns, for example green areas as opposed to urban landscapes, was not associated much with microbiota as a whole, but did affect the prevalence of Acinetobacter bacteria, which occur commonly in the environment, especially in fresh water and soils. Another finding was that breastfeeding affected gut microbial composition and seemed to protect against later sensitization to allergens, including various pollens.

Caution should be exercised interpreting such studies, especially when they cross borders and involve wildly different confounding variables including access to health care and income levels, according to Breed. “Finland is much more advanced and, while there could certainly be microbial influences, being able to control for variables such as access to hospitals, education, or caesarian section rates, or breast‐feeding rates and household confounding factors, diet, siblings and pets, is difficult”, he said.

Breed is not challenging the underlying ideas though. Indeed, another study comparing people in the Finnish and Russian Karelia, two adjacent socioeconomically distinct but ecologically similar areas straddling the border between the two countries, found that allergy prevalence was greater on the Finnish than the Russian side (Haahtela et al (2015). “In the Karelia study, the confounders have been well taken into account, but, of course, not all possible data have been available”, said Tari Haahtela, specialist in biodiversity and immune tolerance at the University of Helsinki, and first author. “We have looked at the basic genetics (GWAS) and the differences are about 1% and not connected to the relevant inflammatory pathways. The differential gene expression in PBMCs (Peripheral Blood Mononuclear Cells) is strongly associated with microbiome differences, in skin and nasal mucosa, and there we find the activation of relevant pathways important to allergy. […] We have looked at common environmental chemicals, which yielded no explanation. The only biologically plausible explanation then emerges from the different microbiota”.

A broader perspective on microbes

While there has been a lot of focus on the gut microbiome in the context of immune system development, Haahtela believes that a broader perspective is needed, starting with a distinction between the internal host and external microbial environment. “The internal environment is dependent on the external, but is constantly modified by genetic and epigenetic effects and liabilities”, he explained. “We interconnect internal with environmental macrodiversity/microdiversity by eating, drinking, breathing and touching. Your senses guide you to do it safely. Environmental macrodiversity is often also a surrogate marker of the life‐style. Living in the woods or city center modifies strongly what you eat, drink, breathe and touch”.

This has implications for immune system health beyond childhood, especially for example in the event of fundamental changes in location, such as moving from a rural to urban location, or vice versa. It is also relevant when considering human health consequences of migration. Haahtela referred to a recent study showing that immigration into the USA had an almost immediate deleterious effect on microbiome diversity that was then accentuated over time (Vangay et al, 2018). It was based on analysis of stools, food consumed, and various anthropometric measurements from 514 individuals from SE Asian Hmong and Karen populations, some in Thailand and some the USA, including first‐ and second‐generation immigrants. The authors used 16S and deep shotgun metagenomic DNA sequencing to identify bacteria in the host and found an immediate loss of gut microbiome diversity and function with immigration. The impacts were also compounded by metabolic developments including obesity that were associated with lifestyle and the changing microbiome.

There might be a link to immunity against infectious diseases and susceptibility to COVID‐19. It had been noted for example that minority groups of various ethnic origins in developing countries seem to be more susceptible both to infection and more severe outcomes such as pneumonia when they live in developed nations and have adopted associated lifestyles. This has often been framed in contexts such as occupational exposure and health inequality, but there have been calls for research to look at the role of the microbiome. “Poverty, poor diet, poor housing and limited opportunities for spending time in green space result in suboptimal exposures to the microbiota of the natural environment, suboptimal gut microbiota and suboptimal regulation of the immune system. These effects would be exacerbated by stress, lack of exercise and lower vitamin D levels in those with pigmented skin. This possibility should be researched”, Rook commented.

It is about to be researched, according to Nanna Fyhrquist, Senior researcher at the Institute of Environmental Medicine at the Karolinska Institute in Stockholm, Sweden. “We are actually currently planning a project which will have a look into how a healthy, well balanced human microbiota impacts on the invasiveness or infectiveness of corona sars‐2 virus, compared with a disrupted/dysbiotic human microbiota”, she confirmed. The basic idea is that exposure to a very large range of biodiverse and mostly harmless organisms, beginning in the womb, generates a relevant lymphocyte repertoire. “This increases the probability that you have a T cell clone that by chance recognizes even novel viruses, such as HIV or SARS”, Rook said. “Basically this is about evolution again. All life forms, and viruses, are fundamentally derived from the same building blocks, so despite evolution and modification over the millennia, cross‐reactivity is there, if you have primed a big repertoire. The other crucial point is that the diverse microbiota from the natural environment also set up immunoregulatory circuits. So without the biodiverse input, the immune system attacks harmless things such as allergens, as well as self and gut contents”.

Association with mental health

There is also growing evidence that a depleted microbiome contributes through inflammation to stress and psychiatric disorders. While there is no smoking gun and perhaps never will be, there is accumulating literature on the links between the microbiome and mental health, including mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer's and Parkinson's diseases (Bastiaanssen et al, 2019) Such findings also shed new light on psychological impacts of immigration. “It is generally assumed that urbanization and immigration modulate the prevalence and expression of psychiatric disorders via psychosocial stress, and no doubt stress plays a role, but evidence for other effects mediated via the immune system is now compelling”, Rook said.

There is also growing evidence that a depleted microbiome contributes through inflammation to stress and psychiatric disorders.

“Depression in immigrants is also very revealing. Mexicans, Cubans, and African/Caribbean peoples have a two‐ to three‐fold increase in the prevalence of depression if immigration to the United States occurred when the individual was less than 13 years old or was born in the United States, compared to the prevalence in those who migrated after the age of 13”, Rook added (Breslau et al, 2009). This implies that there is a protective effect of early environmental influences, as has been shown for autoimmune disorders and IBD [Inflammatory Bowel Disease].

Such protective influences are mediated by the gut/brain axis, which can also allow microbes to escape and trigger inflammatory processes. A number of bacteria have been associated with this, including Helicobacter pylori, which became notorious for association with gut ulcers. Since then, however, its reputation has to some extent been restored through discovery that it also can play a role in microbial health. “More recently, the story has changed in an interesting way”, Rook said. “We often eliminate H. pylori with antibiotics in order to reduce the risk of peptic ulceration, but this reveals another problem. Since over the course of a lifetime H. pylori reduces gastric acid production, elimination of H. pylori by antibiotics might indeed have led to the waning of the ‘epidemic’ of peptic ulcers, but it has led to the appearance of esophagitis, short‐ and long‐segment Barrett's esophagus, and its malignant complications”.

… the field is gravitating away from individual organisms towards looking at the role of the metabolites of the entire gut ecosystem.

This raises the question of why if H. pylori can play a protective role, it can trigger peptic ulcers and sometimes cancer. The answer may be that humans in the past had the bacterium present in their guts alongside helminth parasites that suppressed the associated inflammation leading to ulceration. “That idea is that if you have helminths as well, their anti‐inflammatory effect compensates for the presence of the HP”, Rook explained. ”But Europeans lost the helminths while they retained [H. pylori], so they got ulcers”. There has been some evidence for this hypothesis in animal models (Whary et al, 2014).

This case certainly gives some insight into the intricacies and dependencies involved in the microbiome, as well as the futility of separating individual microorganisms into friends and foes. Instead, the field is gravitating away from individual organisms toward looking at the role of the metabolites of the entire gut ecosystem. Evidence for this came from a study finding that levels of inflammatory cytokines were related to metabolites produced by the gut microbiome (Schirmer et al, 2016). If so, an “Old Friends Hypothesis”, or “Biodiversity Hypothesis” rather than a “Hygiene Hypothesis” may help to contribute to research and point to potential solutions to address the prevalence of allergies and inflammatory diseases by providing the environmental and evolutionary perspectives.

EMBO Reports (2020) 21: e51540