Allergy rates have risen substantially in developed countries over the past several decades, with the steepest increases in the latter half of the twentieth century. In my reading of the literature, this is one of the more compelling examples of an environmental mismatch hypothesis gaining serious empirical support — though the mechanism is considerably more specific than the original formulation suggested.
The Original Strachan Hypothesis
David Strachan’s 1989 paper in the BMJ is the foundational text. Strachan analyzed data from a large British birth cohort and found that hay fever prevalence decreased with increasing family size — children with more older siblings had lower rates of allergic disease. He proposed that early childhood infections transmitted by older siblings provided protective exposure that prevented allergic sensitization. The formulation that emerged from this finding — that improved hygiene was depriving children of infection exposure necessary to train the immune system — became known as the hygiene hypothesis.
The hypothesis was compelling in its simplicity and in its potential to explain the epidemiological pattern of rising allergy rates coinciding with industrialization, improved sanitation, and decreased infectious disease burden in developed countries. However, subsequent research refined and substantially modified the original formulation in important ways.
The “Old Friends” Refinement
Graham Rook (2012), in PNAS, proposed the “old friends” hypothesis as a more mechanistically precise reformulation. Rook’s central argument is that the relevant exposures are not infections from other children — which are evolutionarily recent and often genuinely harmful — but specifically the organisms with which humans co-evolved over hundreds of thousands of years: helminths (parasitic worms), saprophytic mycobacteria from soil and water, and commensal organisms from natural environments. These “old friends” were omnipresent in the human ancestral environment and appear to have trained the immune regulatory system — specifically Treg cell populations producing IL-10 and TGF-beta — to maintain appropriate tolerance and avoid inflammatory overreaction.
What I find important to clarify here is that this reframing changes the implication dramatically. The original hygiene hypothesis could be misread as arguing against cleanliness or sanitation. The old friends hypothesis argues against the specific loss of exposure to evolutionarily co-evolved organisms — not general dirt or common childhood infections. Modern sanitation, vaccines, and antibiotics for bacterial infections are not the targets of this critique.
The Ege Farm Study
Ege et al. (2011), published in the New England Journal of Medicine, provided some of the most striking epidemiological evidence for the old friends framework. The PARSIFAL study compared rates of asthma, hay fever, and atopic sensitization in farm-raised children in rural Europe versus non-farm rural children in the same regions. Farm-raised children had dramatically lower rates of allergic disease — not merely lower, but in some categories several-fold lower.
Crucially, the investigators examined which specific farm exposures correlated most strongly with protection. The most protective factors were consumption of raw farm milk, regular contact with farm animals, and time in farm stables. Simply living in a rural area without farm contact provided substantially less protection. This points toward specific microbial exposures from farm environments — the microbiome of animals, hay, soil, and unpasteurized milk — rather than rural lifestyle factors in general.
Antibiotic Use and the Microbiome Connection
Martin Blaser’s work at NYU has documented a related pathway: early childhood antibiotic use and its effects on the developing microbiome. Antibiotic courses in early life alter microbiome composition in ways that persist and that are associated in longitudinal studies with increased risk of allergic disease, asthma, and obesity. Helicobacter pylori — a bacterium that colonized the human stomach for tens of thousands of years before being largely eliminated in developed countries through antibiotic use and improved sanitation — has been associated in some studies with reduced asthma risk. Its near-universal eradication in developed populations represents another loss of an “old friend” co-evolved organism, with potentially complex immunological consequences.
These findings do not argue against treating bacterial infections with antibiotics when clinically indicated. They argue for thoughtful antibiotic stewardship — avoiding unnecessary courses in early childhood when the microbiome is being established — and for the development of microbiome-preserving antibiotic strategies.
What This Means and Doesn’t Mean Practically
The LEAP study (Du Toit et al., 2015, New England Journal of Medicine) is the clearest translation of old friends hypothesis principles into clinical action. The study demonstrated that early, regular introduction of peanuts in high-risk infants (those with severe eczema or known egg allergy) reduced the development of peanut allergy by approximately 80% compared to avoidance. This overturned decades of clinical guidance recommending avoidance of major allergens in high-risk infants and is now reflected in current guidelines recommending early allergen introduction.
What this body of evidence supports: microbiome diversity in early life is important; excessive and unnecessary antibiotic use in early childhood warrants more conservative prescribing practices; early allergen introduction is beneficial rather than harmful in most infants. What it does not support: avoiding vaccines, deliberately exposing children to infections, abandoning basic hygiene, or expecting probiotic supplement products to meaningfully substitute for the complex microbial exposures the farm environment research describes. Supplements are single or limited-strain products; the relevant microbial diversity is orders of magnitude greater in complexity.
Not medical advice. Content is informational only. Consult a qualified healthcare provider before making changes to your health regimen.
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