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Interpretation of the hygiene and microflora hypothesis for allergic diseases through epigenetic epidemiology
Jong-Myon Baeorcid
Epidemiol Health 2018;40:e2018006.
DOI: https://doi.org/10.4178/epih.e2018006
Published online: March 10, 2018
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Department of Preventive Medicine, Jeju National University School of Medicine, Jeju, Korea

Correspondence: Jong-Myon Bae  Department of Preventive Medicine, Jeju National University School of Medicine, 102 Jejudaehak-ro, Jeju 63243, Korea  E-mail: jmbae@jejunu.ac.kr
• Received: December 20, 2017   • Accepted: March 10, 2018

©2018, Korean Society of Epidemiology

This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • The hygiene hypothesis (HH) proposed by Strachan in 1989 was expanded to explain the inverse association between the occurrence of allergy disorders and the risk of infectious diseases and parasite infestation. The microflora hypothesis (MH) suggests that gut microbial dysbiosis in early life might trigger hypersensitivity disorders. The sharing concept of both HH and MH is gene-environment interaction, which is also a key concept in epigenetics. The amalgamation of epidemiology and epigenetics has created a scientific discipline termed epigenetic epidemiology. To accomplish an era of gene-environment-wide interaction studies, it is necessary to launch a national human epigenome project.
Based on the results that repeated exposures to infection in early life after birth led to fewer incidences of hypersensitive immune diseases, Strachan [1] proposed the hygiene hypothesis (HH) in 1989. Epidemiological evidence that supports HH can be summarized into two categories [2]. First, there is a geographically inverse distribution between the levels of various infective diseases, including parasites and the prevalence of allergy/autoimmune diseases [3]. Second, an immigrant study showed that the prevalence of immune disease increased in the second generation after moving to a country with a high prevalence of diseases [4]. In addition, the experimental functions of HH were summarized to five and four mechanisms by Okada et al. [2] and Bach & Chatenoud [4], respectively (Table 1).
Thus, HH has been the major hypothesis to explain epidemiological phenomena, in which the prevalence of allergic diseases, including atopy, increases in addition to the improvement of hygiene after the Industrial Revolution and the environmental change brought about by vaccines that have reduced the risk of infection [2,5-9]. Furthermore, HH is applied to explain the trends in autoimmune diseases, such as type 1 diabetes mellitus, multiple sclerosis [3-5], and chronic inflammatory diseases, including inflammatory bowel disease and neuro-inflammatory disorder [7].
The epidemiology of HH shows that immune tolerance is induced by infection in early life, which leads to the reduction of immunity-related diseases [5]. Therefore, environmental changes, including lifestyle, which reduce the risk of infection during early life, affect the immune system [2,6,9-11]. In particular, the variation in the prevalence of immune disease based on rapid environmental changes is unable to be explained by genetic factors alone [6]; instead, the gene-environment interaction should be involved in the interpretation [9]. Hence, as it has been broadly interpreted that environmental changes in early life affect lifetime disease occurrence [12,13], the theory of ‘The Developmental Origins of Health and Disease’ (DoHaD) was proposed [12-14].
Parasites, bacteria, and viruses were major targets of the studies of infectious agents that affect immunity in early life [5,7,10]. In addition, it has been known that microflora in the body, particularly, gut microbiota, as well as infectious agents, affect immunoregulation [5,8]; thus, the previous HH has been replaced with the microflora hypothesis (MH) [9,11,15]. To emphasize that MH is a new interpretation of HH, rather than a new hypothesis, HH was considered an alias as the ‘old friends hypothesis’, which focuses on parasitic infection in classic epidemiology [5].
According to MH, the immune regulatory function is affected by gut microbial dysbiosis that is caused by feeding (breast feeding vs. bottle feeding), childbirth type (vaginal delivery vs. cesarean section), and exposure to antibiotics [5,8,10,11].
In addition to MH, the previously mentioned DOHaD theory suggested that the genotype was predetermined by fertilization, but that the disease risk was determined by the exposure to external environments in early life; therefore, studies related to this theory correspond to epigenetic studies [16-18]. Epigenetics refers to ‘heritable changes in gene expression not caused by changes in the DNA sequence’, which was first used by Conrad Hal Waddington in approximately 1950 [19]. Although there is no change in the genetic information of DNA, the mechanisms to induce epigenetic changes include DNA methylation, histone modification, and microRNAs [20]. Thus, in 2007, Bird [21] proposed to redefine epigenetics as ‘the structural adaptation of chromosomal regions’.
Currently, the epigenetic interpretation of allergic diseases can be summarized as follows: the incidence of diseases results from (1) epigenetic alterations by exposure to various environmental factors; and (2) epigenetic modification of mediators that function for genetic sensitivity [17,18]. In such trends, epigenetic epidemiology study has been performed to understand the occurrence of common complex diseases with respect to gene-environment interactions, which takes advantages of epidemiology to identify influential environmental factors and epigenetics, which can reveal cellular and molecular mechanisms [22,23].
Waterland & Michels [24] defined epigenetic epidemiology as ‘the study of the association between epigenetic variations and the risk of disease in humans’. Exposure factors that cause epigenetic variations include the lifestyle of parents, such as smoking, alcohol consumption, and diet [25], and the exposure to various physical, chemical, biological, and social environments during early life [14, 16,26,27]. The resulting diseases include allergies and autoimmune diseases, as well as various complex diseases such as cancer, diabetes mellutus, obesity, arteriosclerosis, autism, and mental diseases, et cetera [17,20,22]. Furthermore, the inter-generational transmission phenomenon that inherits diseases resulted from epigenetic alteration should become another subject of study [14].
As epigenetic alteration by environmental exposure differs depending on age, studies of epigenetic epidemiology need to secure age-matched controls [22]. In addition, a cohort study is required to repeatedly gather samples to examine variations and to assess them over the long term [23,27].
As such, epigenetic epidemiology can reveal whether an epigenetic alteration is a causal factor, biomarker, or modifier of a specific disease, which then can be utilized for preventive treatment, early diagnosis, and the intervention treatment of the disease [5, 17,23], respectively. As it evaluates the relationship between epigenetic alteration and the disease risk for each individual, epigenetic epidemiology is directly linked with personalized medicine [15].
Recently, An [28] emphasized the necessity of the national genome study. Given the burden of cancer and cardiovascular diseases, which represents the major causes of mortality in Korea, a nationwide epigenetic epidemiology study is of great importance. Moreover, the sample types, collection timing, and sample size for epigenetic epidemiology studies are significantly different from those of the genomic epidemiology studies [20,26], so that a foundation for the study of epigenetic epidemiology should be newly established in Korea, which would facilitate gene-environment-wide interaction studies [29,30], the ultimate goal of epidemiology.

The author has no conflicts of interest to declare for this study.

Supplementary Material: Korean version is available at http://www.e-epih.org/.
Table 1.
Mechanisms of the hygiene hypothesis
Okayda et al. (2010) [2] Bach et al. (2012) [4]
Th1-Th2 deviation Identification of infectious agents and their protective constituents
Antigenic competition/ homeostasis Role of anti-infectious immune responses on lymphocyte homeostasis and immunoregulation
Immuno-regulation Stimulatory role of toll-like receptors
Non-antigenic ligands Other mechanisms
Gene-environment interactions

Th, T helper type.

  • 1. Strachan DP. Hay fever, hygiene, and household size. BMJ 1989;299:1259-1260.ArticlePubMedPMC
  • 2. Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol 2010;160:1-9.Article
  • 3. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911-920.ArticlePubMed
  • 4. Bach JF, Chatenoud L. The hygiene hypothesis: an explanation for the increased frequency of insulin-dependent diabetes. Cold Spring Harb Perspect Med 2012;2:a007799.ArticlePubMedPMC
  • 5. Stiemsma LT, Reynolds LA, Turvey SE, Finlay BB. The hygiene hypothesis: current perspectives and future therapies. Immunotargets Ther 2015;4:143-157.ArticlePubMedPMC
  • 6. Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clin Exp Allergy 2006;36:402-425.ArticlePubMedPMC
  • 7. Rook GA. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology 2009;126:3-11.ArticlePubMedPMC
  • 8. Versini M, Jeandel PY, Bashi T, Bizzaro G, Blank M, Shoenfeld Y. Unraveling the hygiene hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications. BMC Med 2015;13:81.ArticlePubMedPMCPDF
  • 9. Martinez FD. The coming-of-age of the hygiene hypothesis. Respir Res 2001;2:129-132.ArticlePubMedPMC
  • 10. MacGillivray DM, Kollmann TR. The role of environmental factors in modulating immune responses in early life. Front Immunol 2014;5:434.ArticlePubMedPMC
  • 11. Stiemsma LT, Turvey SE. Asthma and the microbiome: defining the critical window in early life. Allergy Asthma Clin Immunol 2017;13:3.ArticlePubMedPMCPDF
  • 12. Fleming TP, Velazquez MA, Eckert JJ. Embryos, DOHaD and David Barker. J Dev Orig Health Dis 2015;6:377-383.ArticlePubMed
  • 13. Braun MM, Ahlbom A, Floderus B, Brinton LA, Hoover RN. Effect of twinship on incidence of cancer of the testis, breast, and other sites (Sweden). Cancer Causes Control 1995;6:519-524.ArticlePubMed
  • 14. Miller M, Bailey B, Govindarajah V, Levin L, Metzger T, Pinney SM, et al. A community survey on knowledge of the impact of environmental and epigenetic factors on health and disease. Perspect Public Health 2016;136:345-352.ArticlePubMedPMC
  • 15. Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbiol 2005;3:431-438.ArticlePubMedPDF
  • 16. Winett L, Wallack L, Richardson D, Boone-Heinonen J, Messer L. A framework to address challenges in communicating the developmental origins of health and disease. Curr Environ Health Rep 2016;3:169-177.ArticlePubMedPMCPDF
  • 17. Potaczek DP, Harb H, Michel S, Alhamwe BA, Renz H, Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications. Epigenomics 2017;9:539-571.ArticlePubMed
  • 18. Kuriakose JS, Miller RL. Environmental epigenetics and allergic diseases: recent advances. Clin Exp Allergy 2010;40:1602-1610.ArticlePubMedPMC
  • 19. Slack JM. Conrad Hal Waddington: the last renaissance biologist? Nat Rev Genet 2002;3:889-895.ArticlePubMedPDF
  • 20. Riancho J, Del Real A, Riancho JA. How to interpret epigenetic association studies: a guide for clinicians. Bonekey Rep 2016;5:797.ArticlePubMedPMC
  • 21. Bird A. Perceptions of epigenetics. Nature 2007;447:396-398.ArticlePubMed
  • 22. Michels KB. Epigenetic epidemiology. New York: Springer; 2012. p 1-20.
  • 23. Bakulski KM, Fallin MD. Epigenetic epidemiology: promises for public health research. Environ Mol Mutagen 2014;55:171-183.ArticlePubMedPMC
  • 24. Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007;27:363-388.ArticlePubMed
  • 25. Giordano C, Benyshek DC. DOHaD research with populations in transition: a case study of prenatal diet remote recall with Yup’ik Alaskan women. J Dev Orig Health Dis 2015;6:79-87.ArticlePubMed
  • 26. Foley DL, Craig JM, Morley R, Olsson CA, Dwyer T, Smith K, et al. Prospects for epigenetic epidemiology. Am J Epidemiol 2009;169:389-400.ArticlePubMedPMCPDF
  • 27. Ng JW, Barrett LM, Wong A, Kuh D, Smith GD, Relton CL. The role of longitudinal cohort studies in epigenetic epidemiology: challenges and opportunities. Genome Biol 2012;13:246.ArticlePubMedPMC
  • 28. An JY. National human genome projects: an update and an agenda. Epidemiol Health 2017;39:e2017045.ArticlePubMedPMCPDF
  • 29. Khoury MJ, Wacholder S. Invited commentary: from genomewide association studies to gene-environment-wide interaction studies—challenges and opportunities. Am J Epidemiol 2009;169:227-230.ArticlePubMedPDF
  • 30. Vercelli D. Gene-environment interactions in asthma and allergy: the end of the beginning? Curr Opin Allergy Clin Immunol 2010;10:145-148.ArticlePubMedPMC

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