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Reference topic 18: The Immune System's Education

The hygiene hypothesis: allergies, asthma and the immune system

ProbableEvidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials.69 sources5 graded recommendationsTopic hub: Gut and immunity

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After the Second World War, a redrawn border divided the region of Karelia between Finland and the Soviet Union. Scientists who studied both halves call them "strictly separated by the iron curtain." The Finnish side grew richer, more urban and more industrial. On the Russian side, people went on farming on a small scale and largely fed themselves.1 The two populations are neighbors who share a climate and, in part, an ancestry.23

The Karelia Allergy Study, begun in 1998, found a huge gap.2 In 2003, more than a quarter of Finnish schoolchildren reacted to birch pollen on a skin-prick test, against 2% of Russian Karelian children. Asthma was more than five times as common on the Finnish side, and hay fever more than ten times. "Food allergy was rare," the investigators noted, "and peanut allergy unknown among Russian children."1

Mismatch card

The system

The immune system and the tolerance it must learn.

What it expects

Early years full of microbes from siblings, animals, soil, water and food, and early tastes of lifelong foods.

What it gets

Small families, indoor lives, fewer animals and, until recently, advice to delay allergenic foods.

What happens in the gap

Tolerance fails outward as allergy and inward as autoimmune disease, diagnosed in about one person in 10 in the UK over two decades.

The handrail

Early peanut and egg, animals and outdoor play, antibiotics only when needed, plain-soap handwashing (●●○)

Strength of evidence

●●○ Natural experiments and cohorts link microbe-rich early lives to less allergy and trials show food tolerance can be taught, but microbial mechanisms rest largely on mice.

What this topic covers

  • ·Attack and Tolerate
  • ·Older Siblings and Old Friends
  • ·Cows, Horses and House Dust
  • ·The Security Guards
  • ·The Worm Trials
  • ·The Peanut Reversal

The practical version is in the book: Chapter 6, The Gut That Expects Dirt.

The handrail

Each recommendation carries the strength of the evidence behind it. How the grades work.

  1. Introduce peanut and well-cooked egg early, and keep them in the diet

    StrongEvidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism.

    Evidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism. for peanut in high-risk babies·Evidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials. for egg and other babies

    Under the 2017 US guidance, babies with severe eczema, egg allergy or both start peanut-containing food "as early as 4 to 6 months of age," after a clinician has considered allergy testing. Babies with mild to moderate eczema start "around 6 months of age," and others freely, with other solids. Once peanut is in, the panel's target is about 6 to 7 g of peanut protein a week over three or more feedings.63 A 2021 consensus from the main US and Canadian allergy societies went further: introduce peanut and egg to all infants around 6 months of age, not before 4, with screening beforehand not required.[^fleischer21] European guidance adds "well-cooked, but not raw" egg from four to six months.64 Never give whole nuts to children under five, or peanut butter from a spoon or in lumps to children under four. If your baby has severe eczema or a known food allergy, plan the first peanut feeding with a clinician. For any baby, stop and seek care at signs of a reaction.63

  2. Let young children live with animals and play outdoors

    ProbableEvidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials.

    Evidence grade: Probable. Good observational evidence with a plausible mechanism, or small or few trials. for dogs and farm animals·Evidence grade: Emerging. Early, small, animal-only, or actively contested. for soil

    A dog or farm animals in the first year are linked to less asthma at school age.26 A small Finnish pilot, not randomized, laid forest floor in daycare yards. Within a month it shifted children's skin bacteria and immune markers, but it measured no disease (Topic 12).65 Supervise babies with pets and wash hands after handling animals. If someone at home is already allergic to animals, do not get a pet just to prevent allergy.

  3. Take antibiotics when needed, not just in case

    StrongEvidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism.

    Evidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism. for avoiding unneeded courses·Evidence grade: Emerging. Early, small, animal-only, or actively contested. that this prevents allergy

    About 30% of US outpatient antibiotic prescriptions are likely inappropriate.66 Never refuse or stop a prescribed antibiotic without a clinician's advice (Topic 20).

  4. Keep washing your hands, with plain soap

    StrongEvidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism.

    Handwashing prevents diarrheal illness.57 In 2016 the US Food and Drug Administration barred triclosan and 18 other antibacterial ingredients from consumer washes. Makers had not shown them both safe for long-term daily use and more effective than plain soap and water.67 Keep vaccinations up to date (Topic 20).

  5. Skip raw milk, worms and immune-training supplements

    StrongEvidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism.

    Evidence grade: Strong. Multiple randomized controlled trials, or consistent large cohort studies with a well-understood mechanism. for raw milk's infection risk·Evidence grade: Emerging. Early, small, animal-only, or actively contested. for the products

    In the study that linked farm milk to less asthma, boiled farm milk showed no such link.68 Raw milk can carry Listeria, E. coli and other germs most dangerous to young children, pregnant women, older adults and people with weakened immunity.69 European guidelines make no call for or against probiotics (live bacteria) or prebiotics (fibers that feed them) to prevent food allergy, and worm treatment is unproven.6444

The skeptic's corner

The case against this topic, from the research itself.

The hygiene hypothesis is widely misread as a case against cleanliness. In a UK online poll, nearly a quarter of the public agreed that children need exposure to germs to build a strong immune system. Sally Bloomfield, the hygiene researcher who reported it, calls the idea that broad exposure to germs boosts general immunity to infection "a myth."56 Infections do not seem to protect against allergy.18 Promoting handwashing in day care centers and schools in rich countries prevents about a third of bouts of diarrhea.57 The protective exposures in this chapter are animals, siblings, farm dust, outdoor microbes and early foods, not dirty hands or skipped vaccines.

Farm and pet studies are observational, and farm families differ in many ways. In two European studies, the wider variety of microbes that farm children met explained only part of their protection; a more mature infant gut explained 19% of it.2558 In Sweden, the link between antibiotics in pregnancy and childhood asthma vanished when siblings were compared. The link with antibiotics for airway infections shrank, pointing to family factors and the infections themselves.59 Finland built a decade-long allergy program on the Karelia findings and reported that asthma hospital days halved, but with no control group. Its leaders write, "We cannot be sure whether the favourable result would have emerged even without the Programme."1

Nor is a simple more-microbes theory complete. In their first year, Russian Karelian babies had less diverse gut microbes than Finnish ones, mainly because they carried more Bifidobacterium, a common infant gut bacterium.36 Irish babies born into the 2020 lockdown had more eczema at age two than an earlier group but less egg allergy, perhaps because of earlier solid foods and fewer antibiotics.60 Bottling the old environment has failed so far. A bacterial extract did not prevent wheezing illness in high-risk young children,61 and daily moisturizer from birth did not prevent eczema but did raise skin infections.62 A randomized trial in which a microbial exposure, not a food, prevented allergy or autoimmunity would change the picture.

Terms this topic defines

Related topics

Sources cited above

  1. 1.Haahtela, T., Alenius, H., Auvinen, P., Fyhrquist, N., et al. (2023). "A short history from Karelia study to biodiversity and public health interventions." Frontiers in Allergy, 4, 1152927. https://doi.org/10.3389/falgy.2023.1152927 (The Finnish side saw "urbanization, industrialization and an improved living standard"; on the Russian side people "continued their small-scale, self-supporting agricultural lifestyle." Soviet leaders left parts of the borderland "as kind of a barrier against western influence." Schoolchildren aged 7 to 16 in 2003: birch-pollen sensitization 26.6% in Finland vs 2% in Russian Karelia; doctor-diagnosed asthma 8.8% vs 1.6%; hay fever 15.6% vs 1.2%.)
  2. 2.Haahtela, T., Laatikainen, T., Alenius, H., Auvinen, P., et al. (2015). "Hunt for the origin of allergy: comparing the Finnish and Russian Karelia." Clinical & Experimental Allergy, 45(5), 891-901. https://doi.org/10.1111/cea.12527
  3. 3.Kondrashova, A., Mustalahti, K., Kaukinen, K., Viskari, H., et al. (2008). "Lower economic status and inferior hygienic environment may protect against celiac disease." Annals of Medicine, 40(3), 223-231. https://doi.org/10.1080/07853890701678689 (1,988 Karelian and 3,654 Finnish children screened; biopsy confirmed celiac disease in four of the eight antibody-positive Karelian children; the abstract notes the two populations "share partly the same ancestry"). (Biopsy-confirmed celiac disease in 1 in 107 schoolchildren screened in Finland and 1 in 496 in Russian Karelia.)
  4. 4.Ruokolainen, L., Fyhrquist, N., Laatikainen, T., Auvinen, P., et al. (2020). "Immune-microbiota interaction in Finnish and Russian Karelia young people with high and low allergy prevalence." Clinical & Experimental Allergy, 50(10), 1148-1158. https://doi.org/10.1111/cea.13728 (69 Finnish and 75 Russian Karelians aged 15-20).
  5. 5.Kondrashova, A., Reunanen, A., Romanov, A., Karvonen, A., et al. (2005). "A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland." Annals of Medicine, 37(1), 67-72. https://doi.org/10.1080/07853890410018952 (Incidence in the 1990s: 41.4 per 100,000 a year in Finland vs 7.4 in Russian Karelia.)
  6. 56.Bloomfield, S.F. (2019). "RSPH and IFH call for a clean-up of public understanding and attitudes to hygiene." Perspectives in Public Health, 139(6), 285-288. https://doi.org/10.1177/1757913919878367 (reporting a Royal Society for Public Health online poll of 2,000 members of the public). (Poll conducted in 2019; 23% agreed.)
  7. 18.Benn, C.S., Melbye, M., Wohlfahrt, J., Björkstén, B., and Aaby, P. (2004). "Cohort study of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life." BMJ, 328(7450), 1223. https://doi.org/10.1136/bmj.38069.512245.FE (incidence rate ratio 1.08 per infectious disease before six months; 0.86 per additional exposure). (24,341 Danish mother-child pairs.)
  8. 57.Ejemot-Nwadiaro, R.I., Ehiri, J.E., Arikpo, D., Meremikwu, M.M., and Critchley, J.A. (2021). "Hand-washing promotion for preventing diarrhoea." Cochrane Database of Systematic Reviews, 2021(1), CD004265. https://doi.org/10.1002/14651858.CD004265.pub4
  9. 25.Ege, M.J., Mayer, M., Normand, A.C., Genuneit, J., et al. (2011). "Exposure to environmental microorganisms and childhood asthma." NEJM, 364(8), 701-709. https://doi.org/10.1056/NEJMoa1007302 (Microbial variety "explains a substantial fraction" of the farm effect.)
  10. 58.Depner, M., Taft, D.H., Kirjavainen, P.V., Kalanetra, K.M., et al. (2020). "Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma." Nature Medicine, 26(11), 1766-1775. https://doi.org/10.1038/s41591-020-1095-x
  11. 59.Örtqvist, A.K., Lundholm, C., Kieler, H., Ludvigsson, J.F., et al. (2014). "Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis." BMJ, 349, g6979. https://doi.org/10.1136/bmj.g6979 (fetal exposure: hazard ratio 1.28 in the cohort, 0.99 in sibling analyses; antibiotics for respiratory infections: 4.12 in the cohort, 2.36 in sibling analyses).
  12. 36.Vatanen, T., Kostic, A.D., d'Hennezel, E., Siljander, H., et al. (2016). "Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans." Cell, 165(4), 842-853. https://doi.org/10.1016/j.cell.2016.04.007 (The DIABIMMUNE study followed 222 babies. The authors wrote: "Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.")
  13. 60.Hurley, S., Franklin, R., McCallion, N., Byrne, A.M., et al. (2023). "Atopic outcomes at 2 years in the CORAL cohort, born in COVID-19 lockdown." Pediatric Allergy and Immunology, 34(9), e14013. https://doi.org/10.1111/pai.14013 (eczema 21.3% vs 15.9%; egg allergy 0% vs 2.9%). (365 Irish babies born into the 2020 lockdown.)
  14. 61.Morgan, W.J., Mauger, D.T., Bacharier, L.B., Bauer, C.S., et al. (2026). "Use of the bacterial lysate OM-85 for the primary prevention of wheezing lower respiratory illness in preschool children: a randomised, placebo-controlled trial." The Lancet, 408(10560), 1103-1113. https://doi.org/10.1016/S0140-6736(26)01443-1 (822 high-risk babies and toddlers.)
  15. 62.Chalmers, J.R., Haines, R.H., Bradshaw, L.E., Montgomery, A.A., et al. (2020). "Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial." The Lancet, 395(10228), 962-972. https://doi.org/10.1016/S0140-6736(19)32984-8
  16. 63.Togias, A., Cooper, S.F., Acebal, M.L., Assa'ad, A., et al. (2017). "Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel." Journal of Allergy and Clinical Immunology, 139(1), 29-44. https://doi.org/10.1016/j.jaci.2016.10.010
  17. 64.Halken, S., Muraro, A., de Silva, D., Khaleva, E., et al. (2021). "EAACI guideline: preventing the development of food allergy in infants and young children (2020 update)." Pediatric Allergy and Immunology, 32(5), 843-858. https://doi.org/10.1111/pai.13496
  18. 26.Fall, T., Lundholm, C., Örtqvist, A.K., Fall, K., et al. (2015). "Early exposure to dogs and farm animals and the risk of childhood asthma." JAMA Pediatrics, 169(11), e153219. https://doi.org/10.1001/jamapediatrics.2015.3219 (1,011,051 children born 2001-2010; the school-age analysis included 276,298 children, of whom 22,629 were exposed to dogs and 958 to farm animals; odds ratios 0.87, 95% CI 0.81-0.93, for dogs and 0.48, 0.31-0.76, for farm animals).
  19. 65.Roslund, M.I., Puhakka, R., Grönroos, M., Nurminen, N., et al. (2020). "Biodiversity intervention enhances immune regulation and health-associated commensal microbiota among daycare children." Science Advances, 6(42), eaba2578. https://doi.org/10.1126/sciadv.aba2578
  20. 66.Fleming-Dutra, K.E., Hersh, A.L., Shapiro, D.J., Bartoces, M., et al. (2016). "Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011." JAMA, 315(17), 1864-1873. https://doi.org/10.1001/jama.2016.4151 (an estimated 353 of 506 prescriptions per 1,000 people a year judged likely appropriate).
  21. 67.U.S. Food and Drug Administration (2024). Skip the antibacterial soap; use plain soap and water (Consumer Update, content current as of 12 December 2024). https://www.fda.gov/consumers/consumer-updates/skip-antibacterial-soap-use-plain-soap-and-water
  22. 68.Loss, G., Apprich, S., Waser, M., Kneifel, W., et al. (2011). "The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study." Journal of Allergy and Clinical Immunology, 128(4), 766-773.e4. https://doi.org/10.1016/j.jaci.2011.07.048
  23. 69.Centers for Disease Control and Prevention (2025). Raw milk (last reviewed 31 January 2025). https://www.cdc.gov/food-safety/foods/raw-milk.html [^fleischer21]: Fleischer, D.M., Chan, E.S., Venter, C., Spergel, J.M., et al. (2021). "A consensus approach to the primary prevention of food allergy through nutrition: guidance from the American Academy of Allergy, Asthma, and Immunology; American College of Allergy, Asthma, and Immunology; and the Canadian Society for Allergy and Clinical Immunology." Journal of Allergy and Clinical Immunology: In Practice, 9(1), 22-43.e4. https://doi.org/10.1016/j.jaip.2020.11.002 (abstract: "both peanut and egg should be introduced around 6 months of life, but not before 4 months. Screening before introduction is not required, but may be preferred by some families.")
  24. 44.Schölmerich, J., Fellermann, K., Seibold, F.W., Rogler, G., et al. (2017). "A randomised, double-blind, placebo-controlled trial of Trichuris suis ova in active Crohn's disease." Journal of Crohn's and Colitis, 11(4), 390-399. https://doi.org/10.1093/ecco-jcc/jjw184. Registry: ClinicalTrials.gov NCT01279577 (TRUST-2, sponsor Dr. Falk Pharma GmbH). (The TRUST-2 trial: remission after 12 weeks was 38.5%, 35.2% and 47.2% on the three doses of eggs, and 42.9% on placebo.)

This topic carries 69 notes in the research manuscript; the 24 above are those behind the material on this page. Full source register.