Re: The “hygiene hypothesis” for allergic disease is a misnomer
William Parker’s paper, now published as a "Personal View", but originally submitted as a multi-author editorial, offers a constructive critique on a hypothesis which I advanced 25 years ago. My comments on the original submission, as external peer-reviewer, may be of interest to readers:
The wisest strategy, when held to account for a troublesome child in public, is to deny paternity...
As the authors correctly point out, the term "hygiene hypothesis", which is often attributed to my BMJ 1989 paper, is actually shorthand for a line of argument established much earlier. When presenting my own work, I regularly remind my audience that the ideas presented in the BMJ 1989 paper were inspired by David Barker's publications on acute appendicitis a year or two before. However, as the authors acknowledge, Barker's "hygiene hypothesis for appendicitis" was in turn influenced by earlier thinking.
I also recount that the inclusion of "hygiene" in the title of my paper (along with "hay fever" and "household size") owed more to an alliterative tendency than to my aspiration to claim a new scientific paradigm. What interested me over the subsequent years was how, after initial disdain on grounds of implausibility, the immunological community enthusiastically endorsed the concept of the "hygiene hypothesis" as soon as they had proposed a cellular mechanism to explain it!
The question that arises from this paper is whether it is useful to replace this scientific shorthand with another: "biome depletion". Whereas I tend to agree that "hygiene" is a rather vague term and can easily be misinterpreted, I am sceptical that "biome" will be any more helpful in communicating with the general public. More fundamentally, where is the scientific evidence that "the biome depletion paradigm forms a cornerstone of modern immunology and can no longer be considered a hypothesis"? Experiments with germ-free animals are not readily or reliably extrapolated to free-living human beings, and the epidemiological evidence that diversity of the human microbiome is a major predictor of allergic sensitisation or clinicial atopic disease is lacking, largely because prospective studies with comprehensive longitudinal assessment of the neonatal commensal flora are so challenging. Nor is there robust experimental evidence for the authors' suggestion of the "intuitive solution to the problem of biome depletion: biome enrichment or restoration."
Indeed, the frustration over 25 years of epidemiological and immunological investigation is that so little progress has been made in identifying the biologically relevant exposures which "explain" the frequently replicated epidemiological observations linking allergic sensitisation and atopic disease (inversely) to family size and to "unhygienic" environments such as farming, separately and in combination [for example, Genuneit J, Strachan DP, et al. The combined effects of family size and farm exposure on childhood hay fever and atopy. Pediatr Allergy Immunol 2013;24:293-8. PMID: 23551831.]
The authors suggest that "Strachan's advance was not the already long-held view that hygiene was a problem, but rather to identify a loss of species diversity from the ecosystem of the human body as a problem." This is too generous. My thinking at the time was as much around specific infections, particularly at critical time-windows in immunologicial development, as it was around "biome depletion" as the authors conceive it. The latter concept has become more fashionable only in the last decade, as probiotics have become prominent in food science and in some branches of clinical medicine.
Colleagues from the fields of asthma epidemiology and clinical immunology have suggested that the seminal contribution in my 1989 BMJ paper was the speculation that the rising prevalence of allergy might be due to removal of a protective factor, rather than the prevailing view that it was due to increased exposure to a provocative agent. This concept was developed in a specific context: the purported epidemic of allergic diseases, but has since been generalised to a wide range of other conditions.
What is not at all clear is whether the underlying biological mechanisms for allergic, autoimmune and other inflammatory disorders can be reconciled with a unifying "hygiene hypothesis", let alone the more specific concept of "biome depletion". Delayed exposure to specific infectious agents, far from being a "disproven view" may be the cause of some "diseases of Westernisation" (such as type 1 diabetes), whereas lack of species diversity in commensal flora acquired in infancy may be the cause of others (such as childhood inflammatory bowel disease). Robust epidemiological evidence is lacking, partly because of the challenges of measuring the microbiome effectively in large birth cohorts, and partly because the diversity of specific infections, and timing of these infections, has yet to be addressed comprehensively by serological or other biomarkers.
As an epidemiologist, I remain to be convinced that it is helpful to "rebrand" a general hypothesis as a more specific one, until there is firmer evidence, particularly from free-living populations, that "biome depletion" is associated with one or more specific disease outcomes. I am certainly open to the suggestion that "biome depletion" is one specific example of a potential family of "hygiene hypotheses", but I would be reluctant to rule out the possibility that delayed exposure to specific microbial agents could explain the epidemiology of some diseases associated with Westernisation.
Although I deny paternity, I still have an intellectual "soft spot" for that "enfant terrible"...!
David P Strachan
Professor of Epidemiology
Population Health Research Institute
St George's, University of London
Cranmer Terrace, London SW17 0RE
Competing interests: No competing interests