Sanitizing the hygiene hypothesis:
Health lessons from human co-evolution with microorganisms

Report from a Workshop led by
Kathleen Barnes, Department of Medicine,
Johns Hopkins University and
Erika von
Mutius, Professor of Pediatrics, University Children’s Hospital, Munich

One of five workshops in a conference on
Evolution and Diseases of Modern Environments
Organized by Randolph Nesse, at the Berlin Charité,  October 13-14, 2009
In conjunction with The World Health Summit
Sponsored by the Volkswagen Foundation

Introduction: There is a large body of research work addressing the potential beneficial role of microbial exposures for the development of asthma, allergies and autoimmune disorders. A seminal publication by David Strachan in 1989 coined the ‘hygiene hypothesis’ in an attempt to explain his observation of protection from hay fever when having many older siblings. The ‘hygiene hypothesis’ has since undergone numerous revisions and alterations with respect to potential underlying immunological mechanisms, the type of infectious / microbial stimuli and the potential link to autoimmune diseases. It has become apparent over the years that many open research questions have not been answered; therefore, we have drafted a qualitative overview on the existing evidence of a protective effect of microbial exposures for the onset of asthma, allergies and autoimmune diseases.

Evidence: The Working Group agreed there is compelling evidence from population-based studies in humans to suggest that the ‘hygiene hypothesis’ may be operative in asthma, allergies, SLE, sarcoidosis, and ankylosing spondylitis, and suggestive evidence exists for type I diabetes, inflammatory bowel disease (IBD) and multiple sclerosis. The most robust effects for asthma and allergies have been observed for helminths, hepatitis A and bacteria with their compounds, whereas there is still considerable debate with respect to tuberculosis in epidemiological studies.  The Working Group also felt also identified suggestive evidence for exposure to malaria and the development of SLE. In addition to population-based studies, many experimental studies, mostly in murine models, have been undertaken to study the relationship between microbial exposure and allergic and autoimmune diseases. NOD, BALB/c, EAE and IBD mice as well as dogs have been used as models, the later for studies in eczema. A variety of exposures has been investigated, such as helminths and their compounds, bacteria and their compounds, ligands for innate immune receptors, and viruses.

Potential mechanisms: Potential mechanisms for this relationship are likely to involve immune responses, in particular the balance of pro- and anti-inflammatory mechanisms and the induction of innate and adaptive regulatory responses. The genetic background of an exposed person is likely to play an important role. Various genes have been implicated in these diseases, a number of which overlap across diseases. Variation in the HLA region has repeatedly been observed. Multiple non HLA loci are also likely to contribute with small effects. The evolution of the human genome will most likely have occurred under strong microbial and infectious pressures varying according to biogeography. But environmental changes may also strongly have contributed to the incidence of allergies and autoimmune diseases. The most compelling evidence suggests an important role for childhood farm exposure, improved sanitation and decreasing family size. The eradication of helminths and the modification of flora and fauna may also have played a role.

Gaps in knowledge :

There are numerous unknown mechanisms and inconclusive findings to date. The scientific community lacks well-designed epidemiological studies relating increased or decreased microbial exposures to the incidence and prevalence of autoimmune diseases and mental disorders, all of which are associated with immune dysregulation.

We know little about the relevant exposures. The potential role of viruses has not been explored. Standardized approaches for the assessment of environmental microbial and allergen exposures are lacking and must urgently be developed. There is large uncertainty with respect to the potential beneficial effects of probiotics: Do they have an effect? How do probiotics interact with gut microbiota? Which strains should be selected for clinical trials? Also, very little is known about other dietary substances affecting the gut microbiota.

The timing of exposure has been shown to be critical in experimental and epidemiological studies. Yet, we still do not know whether prenatal or postnatal exposures matter and what the significant time windows of exposure are for conferring an effect.

The Working Group also felt that the use of comparative animal models has not sufficiently been explored among both wild and domesticated animals, including non-human primates, and can be investigated under varying environmental exposures,.

With respect to mechanistic studies, the simplistic Th1 / Th2 concept must be refined. The Group felt that T cell plasticity in the context of microbial exposures demands more attention and that potential interactions of immune responses with endocrine and neuroendocrine systems should be taken into account. Finally, gender differences and sexual selection have not been investigated. Reproducible gene-environment interactions on well-characterized and sufficiently powered populations also need further attention. The use of gnotobiotic mice may help to unravel mechanisms in immune regulation. There was consensus that a major limitation in the understanding of underlying mechanisms was the inaccessibility of target organs in humans.

Finally, there is an urgent need to investigate potential consequences of medical interventions such as treatment with antibiotics and paracetamol (acetaminophen), eradication of helminths, and the supplementation of vitamin D and folic acid.

Applications:

Prevention: Several studies using animal models of allergic and autoimmune disease have been successful in the prevention of these diseases by exposing the animals to infections and microbial products. We can learn more about dose, potential side effects, and mechanistic pathways to eventually translate such substances into safe pharmacological preparations for use in humans. Based on these studies, novel prevention strategies can be developed in the future.

Therapy: Initial trials with helminths (Trichuris suis) has shown benefit in inflammatory bowel disease patients. However, the administration of live microorganisms may not be practicable for large scale treatment in the future. Studies in animal models have shown that substances isolated from microorganisms account for the therapeutic effect; therefore, the effective substances of microbial origin can likely must be identified in well-designed studies and translated into pharmaceutical preparations for use in humans.

Recommendations: We consider it too early to provide recommendations on an individual level with respect to personal hygiene. However, we strongly feel that this field of research is advancing rapidly and will offer innovative approaches to treatment and prevention of a number of inflammatory diseases in the near future. A consensus is that western countries have experienced drawbacks of life styles deficient in microbial exposures which are likely to result in allergies and autoimmune disorders. Therefore, potential consequences of public health measures to improve sanitation and hygiene should be recognized in developing countries.