Brief history of thereveals robust evidence for the original concept. That original concept is preceded by at least two key studies that birthed the essential feature of the concept, namely, inverse correlation between infection history and risk of autoimmunity or allergies.
- First, a 1968 study in Nigeria. Low occurrence of the autoimmune disease rheumatoid arthritis (RA) with high prevalence of parasitic infections was linked to the ‘immunological disturbances produced‘ by the latter (1).
- Second, a 1976 Canadian survey on the prevalence of asthma, and (hives) in white and Cree Indian communities (2). Whites had higher prevalence of allergic diseases while Cree Indians, living on reserves, had increased prevalence of helminths as well as untreated viral and bacterial diseases. The authors of this 2nd study concluded, ‘It is suggested that atopic disease is the price paid by some members of the white community for their relative freedom from diseases due to viruses, bacteria and helminths‘ (2, quoted in ).
In 1989, having followed >17000 children born in 1958 for >23 years, David P. Strachan proposed the hygiene hypothesis to explain inverse correlation between larger family size and hay fever risk (allergic rhinitis). Idea was higher load of minor infections during childhood was beneficial for proper development of infant immune system (, ). Numerous other studies over the decades concurred and >25 years later with an even larger study of >500000 children in 52 countries ( ), Stracher decidedly confirmed an inverse association between risk of hay fever and eczema and total number of siblings. Thus, the original hygiene hypothesis stands well-substantiated.
In the succeeding decades, the hygiene hypothesis expanded as an umbrella term to explain higher prevalence of allergic and autoimmune diseases among individuals living in societies with greater hygiene. Hygiene refers to unprecedented access to clean water, sanitation, medicine that over the course of the 20th century fundamentally changed, even reduced, human exposure to microbes, at least in economically wealthy countries. Now, the hygiene hypothesis is expanding to incorporate the microbiota concept, that proper colonization by microbes, both sequence and abundance, is critical for proper training of the immune system in early life.
Rather than recap highlights in the scientific literature, what if we focused on one specific phenomenon with increasing evidence for inverse correlation between proper microbial exposure and allergy/autoimmunity risk? Cesarean section (C-section) and its long-term health consequences. Rising steadily since the 1970s, C-sections have increased tremendously (see figure below from) in economically wealthy countries, the same ones with increasing rates of allergies and autoimmunity.
Yet few C-sections are elective, i.e., chosen by the mother-to-be. Why the increase then? Numerous reasons are cited. Newer technology enables continuous fetal monitoring after mother’s hospital admission, medical malpractice pressures drive defensive medicine, perverse financial incentives drive doctors and hospitals to prioritize c-section over natural vaginal delivery. Whatever the reason though, a steady drumbeat of studies shows long-term adverse health consequences, specifically w.r.t. allergies and GI tract issues.
A newborn has not one but two immediate urgent challenges. Learn to live independently outside mother’s womb and acquire microbiota. After all, we largely acquire microbiota, our final tissue, post-birth and in doing so, change from an individual into a human-microbe ecosystem. Initial colonizers are ‘starter‘ or ‘keystone‘. Once they seed the newborn human body, they change local milieu such that specific other species can colonize and in this way, a daisy chain of distinct microbial species colonize various parts of the body, specifically the skin, GI tract and other mucosal surfaces. In-built in such a process is the idea of the ‘‘, early colonizers serving as sinks/attractors for later ones. Obviously, implicit in the small world idea is the notion that differences in starter/keystone species in the beginning would amplify into even bigger differences in the final microbiota that gets established (see figures below from ).
With natural vaginal delivery, microbial colonization starts during passage through the birth canal. With C-section deliveries, the initial colonizers are those on mother’s skin and surrounding environment. The former ensures early-life sequence of microbial colonization recapitulates the evolutionary process while process is more or less random with the latter.
Difference in long-term health outcomes between natural vaginal and C-section delivery favors the expanded hygiene hypothesis. Adverse health outcomes (see table below from) associated with C-section range from higher propensity for
- Allergic rhinitis ( , n = 8953): Modest increase in risk.
- Asthma (11): 20% increased risk from meta-analysis of 20 studies with different study designs done in different countries with different measures of asthma.
- Celiac disease ( , ): Increased risk with elective but not emergency C-section, n = 11749.
- Type I diabetes ( ): 20% increased risk from meta-analysis of 20 studies.
- Multiple sclerosis (15) n = 1.7X10^6 with total of 930 MS cases of whom 80% were delivered by C-section.
The prevailing idea is difference in initial microbial seeding of newborn drives difference in immune system training with predictable consequences to long-term health (see figure below from 9).
Most of the links between C-sections and childhood diseases are correlations. Are C-sections causal? That’s as yet unknown. Role of confounding factors remain unclear and there are plenty of those. Obvious ones include difference between pre-labor versus in-labor C-sections, roles of antepartum and intrapartum antibiotics, both common in C-sections, not to mention indiscriminate antibiotic use later in life.
Finally, the ‘Old Friends‘ rather than the hygiene hypothesis better explains the mechanistic connection between the recent profound change in microbial exposure of humans and increase in allergies, asthma, autoinflammatory (e.g., celiac, IBD*) and autoimmune (e.g., RA, MS*) diseases. According to Graham Rook‘s Old Friends hypothesis (, , , ), microbes and worms with a primarily immunoregulatory function co-evolved with humans for thousands of years from the hunter-gatherer stage through to rural living on farms in close proximity to animals. These included among others helminths, mycobacteria, toxoplasma, Helicobacter pylori, hepatitis A. OTOH, Rook argues microbes now common in childhood such as measles, mumps, chickenpox didn’t co-evolve with us, can either kill or induce strong immune responses, and represent ‘crowd infections‘, i.e., requiring large populations in close proximity to persist and spread. In sum, modern sanitation, hygiene and ever larger populations living in close proximity to each other may have unwittingly compromised proper immune system education in early life, setting the stage for persistent immune dysregulation that predisposes to allergies and autoimmunity.
* IBD = inflammatory bowel disease, MS – multiple sclerosis
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