Tag Archives: hygiene

City-Country-River

It was the first big study as a Postdoc, that I did in 1989, comparing the City of Munich and Upper Bavaria but we did not findmany differences.  Suddenly, however, there is an increased interest in city – urban differences. Two papers appeared yesterday, one in ScienceVulnerability of the industrialized microbiota” and in Environment InternationalUrban-associated diseases: Candidate diseases, environmental risk factors, and a path forward“. Continue reading City-Country-River

Claim to fame of the hygiene hypothesis

The recent encyclopedia article about the hygiene hypothesis seems to be well written. At least on the first instance … in reality it is more a novel than a scientific review.

For many years already, the hygiene hypothesis has been called an outdated concept; various times it was revised and transformed, and finally it gave birth to novel hypotheses.

In other words, the hypothesis has been rejected for being wrong . Even many revisions did not change that. There seem to be only one proven fact – the obsession of some authors with hygiene and nouvel Rousseauism.

Anyway, the hygiene hypothesis has promoted radical rethinking of infections, microbiota, and coevolution of mankind and microbes.

There is nothing radical in backward thinking. We still carry tons of microbes, freezer and antibiotics only did some qualitative but not so much quantitative changes,

With the advent of novel high-throughput sequencing technologies the human microbiome, which is sometimes called the ‘forgotten organ,’ has attracted much attention and is currently being implemented in a wider concept of self-foreign relationship, which may even include recognition of the nonmicrobial nonself as a vital stimulus to a well-developing immune system.

  1. So the interest is technology and not science driven.
  2. The microbiome is not an organ.
  3. The hype is already over.
  4. The Self is not defined by any bacterium.
  5. Most bacteria are excreted and not vital stimulus.

Given the many molecule classes regulating immune functions across individuals such as short RNAs, the hygiene hypothesis may eventually come back as a surprising explanation of the phenomena evoked by crowding, day care, sibship size, orofecally transmitted diseases, and respiratory infections.

Why that?
A comeback of the hygiene hypothesis by short RNA?
The listed phenomena are not intrinsically related, but are occuring only at the same time scale.

Even the old birth order effect might be rediscovered as epigenetic programming someday. Admittedly, these notions are entirely hypothetical, but without hypotheses, proven or not, science hardly advances.

So if David Strachan’s birth order effect would be really caused by  epigenetic programming – why would that be related to hygiene at all?

Science is is not so much about proven or unproven but about reasonable and non reasonable hypotheses.

 

Window of Opportunity

I very much liked the “Window of Opportunity” in the Nestle Nutrition Workshop Series 61, published by Karger in 2008. Page 180 has an interesting account of the hygiene hypothesis:

Dr. Bier: … The other is the issue of the hygiene hypothesis, the cleaner environment. We are just in a somewhat less dirty environment, we are not in a clean environment, and that is the problem I have with that particular approach.

So, I am not alone

Dr. Barker:… I am guilty of inventing the term “hygiene hypothesis” as an explanation of the epidemic of appendicitis that followed the introduction of running hot water into housing of Western countries.

According to Sozanska et al. the hygiene hypothesis has more fathers

In 1970, Peter Preston1 posed the following question: ‘‘Is the atopic syndrome a consequence of good hygiene?’’ If this was the case, he argued that ‘‘the manifestations of atopy . would have appeared in given areas only after standards of hygiene . had been raised to high levels.‘‘

while David Strachan calls  it a misnomer since I know him. The last occasion was in the BMJ in August 2014

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!
[…]
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…

Allergy, Vitamin D Receptor and Parabacteriodes

There was a congress abstract earlier this year by Rachid, Rima A et al. in  Journal of Allergy and Clinical Immunology:  “Food Allergy in Infancy Is Associated with Dysbiosis of the Intestinal Microbiota” where 137 infants (52 food-allergic and 85 controls) were enrolled and differences in fecal microbiota tested between the 2 groups. Food-allergic babies at 1-6 months of age had decreased abundances of genera in Bacteroidetes (Parabacteroides and Alistipes).

Interestingly, a new genome-wide association study of the gut microbiota using two cohorts from Northern Germany identified genome-wide significant associations for microbial variation and individual taxa at multiple genetic loci, including the VDR gene.  To further explore this association, they analyzed gut microbiota data fin Vdr−/− mice, confirming that loss of Vdr in mice substantially affects diversity. A more detailed exploration also showed that VDR consistently influences individual bacterial taxa such as Parabacteroides.

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So, is this a missing link?-Can vitamin D supplementation influence the gut microbial flora? This could explain even other observations. Right now rs7974353 is a rare human intronic SNP with no disease annotation.

Farm life does not prevent from asthma

In most farm children, asthma is not being prevented. And even in those children who might have had a benefit from being raised on a farm, it is not clear where the protection is mediated by: Some biological agent like endotoxin? Some healthy worker effect? Less medical interventions like antibiotics, Caesarean or vitamin D? It looks like other researchers are sceptical too

Others who study the hygiene hypothesis caution that the newly uncovered mechanism does not entirely explain the protective effect of dairy farm life. Drinking unprocessed milk also seems to ward off asthma in kids, points out Gary Huffnagle of the University of Michigan, Ann Arbor—and that effect is unlikely to involve the lung epithelium. What’s more, endotoxin levels are not that much higher on farms than in cities, suggesting “it’s too simple an answer,” says asthma genetics researcher William Cookson of Imperial College London, who thinks changes in living microbial communities in the lungs and gut may be just as important.

On verification

Most recently, I came across of another euphoric hygiene hypothesis review and wonder how this could ever happen. The evidence here is mixed and largely ambiguous.
Probably it would be best to follow some basic journalistic rules as summarized in the online “Verification Handbook for investigative reporting”

As with the verification of user-generated content in breaking news situations, some fundamentals of verification apply in an investigative context. Some of those fundamentals, which were detailed in the original Handbook, are:

– Develop human sources.
– Contact people, and talk to them.
! Be skeptical when something looks, sounds or seems too good to be true.
! Consult multiple, credible sources.
– Familiarize yourself with search and research methods, and new tools.
– Communicate and work together with other professionals — verification is a team sport.

Journalist Steve Buttry, who wrote the Verification Fundamentals chapter in the original Handbook, said that verification is a mix of three elements:

– A person’s resourcefulness, persistence, skepticism and skill
– Sources’ knowledge, reliability and honesty, and the number, variety and reliability of sources you can find and persuade to talk
– Documentation

Is this a retraction of the hygiene hypothesis?

There are news about the hygiene hypothesis.

Home cleanliness resulted only in quantitative reduction of floor dust, which mainly indicates removal of superficial dirt with a rather cosmetic effect. Conventional cleaning does not eradicate microorganisms sustainably, because emptied microbial niches are instantly recolonized by ventilation and living carrier.

Sure. Continue reading Is this a retraction of the hygiene hypothesis?

An epidemic of nonsense

13 € for a paperback, this is “An Epidemic of Absence. A new way of understanding allergies and autoimmune disease”. It is written by Moises Velasquez-Manoff , a journalist otherwise working for the “The Christian Science Monitor”. As his online bio reports “he dreamed of writing novels”. I would wish he would done so.

The outset is rather clear – Velasquez-Manoff wants to find a cure for his own autoimmmune disease. While this may be a legitimate justification for collecting information about a given topic, the method by Velasquez-Manoff is not. At a first glance, it looks like a serious book, well written, interesting facts presented in a coherent manner followed by numerous references. Maybe that made such an impression on the (numerous) positive reviewers. Maybe all the positive reviewers are experienced science journalists that judged by the overall impression plus some common sense plus some specific knowledge. But, Velasquez-Manoff did never hear the other side (on p.310, he even admits who has read and commented on sections of the manuscript: exclusively scientists in favor of the hygiene hypothesis). To recognize that you need to be a scientist – journalists would not notice that.

I compiled a long list the errors but feel now, that it would be too time consuming to write that down here. As far as it concerns me (p. 99) there was no grant to win in Munich as the study Velasquez-Manoff is talking about was a commissioned study. And sorry (p.100) I wrote the full grant application comparing East and West Germany children and did large part of the field study. Furthermore, I am not convinced (p.101) that the East West German differences ever supported the hygiene hypothesis, it is something different. And it was not in 2000 (p.102) that someone published on day care (p. 102), we wrote that already in 1999. Audiatur et altera pars, yea, yea.

Will the bacterial flora protect you from you allergies?

Here is another post as the field seems to progress so fast with a new study on enterotypes of the human gut microbiome from

22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific.

The 3 clusters are Bacteroides (enterotype 1), Prevotella (enterotype 2) and Ruminococcus (enterotype 3) – no idea if these are under selective pressure from the host (genes!), from enviroment (antibiotics!) or from microbial competitors. When we look, however, at another study published also last week at Science magazine, it seems that at least one cluster has it’s own trick to get the right of residence by synthesizing a symbiosis factor. Continue reading Will the bacterial flora protect you from you allergies?

Tolerogenic effects of vitamin D?

A new allergy study published last month

hypothesized that prenatal vitamin D supplementation could induce tolerogenic DC at birth. To evaluate this hypothesis in an epidemiological setting, we quantified the gene expression levels of ILT3 and ILT4 in cord blood (CB) samples of a population-based birth cohort of farm and reference children.

ILT3/IL4 as a marker of tolerogenic DCs may be justified by data published by Chang but not by newer data Continue reading Tolerogenic effects of vitamin D?

Bleach use and allergy

Here is another paper that supports my long-standing view that the hygiene hypothesis may be wrong

We identified 3626 participants of the European Community Respiratory Health Survey II in 10 countries who did the cleaning in their homes and for whom data on specific serum IgE to 4 environmental allergens were available …The use of bleach was associated with less atopic sensitization (odds ratio [OR], 0.75; 95% CI, 0.63-0.89).

yea, it says less not more! And there is another paper that ask about the hygiene hypothesis “Do we still believe in it?”

This has little relationship with ‘hygiene’ in the usual meaning of the word. The term ‘hygiene hypothesis’ is unfortunate, as it is misleading. A better term would be ‘microbial deprivation hypothesis’.

I even think that microbial deprivation is questionable.

Tired of the hygiene hypothesis

A new Thorax review finds

The hypotheses have arisen from a desire to explain epidemiological differences, and those such as the “hygiene” hypothesis had a seemingly corroboratory immunological explanation. However, they have not taken us to the point where we can proudly announce a primary preventive strategy.

I agree with the last statement but have severe doubts on any “immunological explanation” Continue reading Tired of the hygiene hypothesis

Dung hill counting

Wikipedia writes about Imre Lakatos the famous Hungarian mathematician and philosopher who graduated 1961 in Cambridge with “Essays in the Logic of Mathematical Discovery”

He showed that in some cases one research programme can be described as progressive while its rivals are degenerative. A progressive research programme is marked by its growth, along with the discovery of stunning novel facts, development of new experimental techniques, more precise predictions, etc. A degenerative research program is marked by lack of growth, or growth of the protective belt that does not lead to novel facts.

 

One of these degenerate research program relates to the hypothesis that farming protects you from allergy

E 2006:

There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role … Both atopic sensitization … and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects … Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16

Keep in mind – it’s the farm animal.

K 2008:

Several epidemiological studies have shown that the farm environment impacts allergy protection mechanisms in children … In investigating the link between farming lifestyle and prevention of childhood allergy, we examined the prevalence of Listeria spp. in dust specimens from the environment of rural children … The dominant species found by culturing methods were L. innocua (n=12) and L. monocytogenes (n=8).

Sorry – it’s listeria.

K 2006:

There is increasing evidence that the farming environment has a protective effect as regards allergic diseases. Exposure to animal parasites, particularly helminth infections, is common in the farming environment. Exposure to nematodes, as determined by the levels of antibody to A. lumbricoides, was more frequent among farmers’ children than non-farmers’ children… This positive serology was found to be significantly associated with high total IgE levels … and eosinophilia.

Sorry again – it’s ascaris.


E 2007
:

In recent years, studies have shown a protective effect of being raised in a farm environment on the development of hay fever and atopic sensitization…Inverse relations with a diagnosis of asthma were found for pig keeping …, farm milk consumption …, frequent stay in animal sheds …, child’s involvement in haying …, and use of silage … Protective factors were related with higher expression levels of genes of the innate immunity.

Sorry, it’s everything: the pig, the milk, haying and silage.

W 2007:

Some studies in rural environments claimed an inverse association between consumption of farm-produced dairy products … Farm milk consumption ever in life showed a statistically significant inverse association with asthma… rhinoconjunctivitis … and sensitization to pollen and the food mix fx5 …, and sensitization to horse dander.

Hey, milky ways ahead something new: the horse!

K 2007:

There is still uncertainty about the determinants of atopic eczema … In multivariate analyses, helping with haying was the only variable related to a farming environment having a consistent inverse association with both current symptoms and a doctor’s diagnosis of AE.

Yes,  haying makes sense with hayfever.

W 2005:

An increasing number of studies report pet exposure to be associated with lower risk of asthma and allergies … Current contact with dogs was inversely associated with diagnosed hay fever (OR 0.26, 95% CI 0.11-0.57), diagnosed asthma (OR 0.29, 95% CI 0.12-0.71), sensitization…

Oh no, the dog.

V 2008:

Numerous epidemiologic studies have demonstrated an allergy-protective effect of farm life early in childhood …In vitro, B. licheniformis spores activated a T(H)1 cytokine expression profile. In vivo application of these spores resulted in less spore-specific but long-lasting immune activation preventing eosinophilia and goblet cell hyperplasia; however, they provoked an influx of neutrophils in lung tissue of asthmatic mice.

What about bacillus spores?

vM 2008

Contact with farm animals, at least in childhood, likely confers protection; other factors have not been completely identified. Also, the consumption of milk directly from the farm during childhood has been shown to be beneficial with respect to childhood asthma and allergies.

Ok, it is milk. Are you still readings here?

This week I am back with the most exciting research

Previous cross-sectional surveys have suggested that maternal exposure to animal sheds during pregnancy exerted a protective effect on atopic sensitization in children lasting until school age … Different sensitization patterns in cord blood of farm and nonfarm children were observed. In multivariable analysis consumption of boiled, but not unboiled, farm milk during pregnancy was positively associated with specific IgE to cow’s milk independently from maternal IgE.

This paper counts dung hills The authors even invent a new classification (sorry, not dung hill height but “50 m distance between dung hill and house”).

And did you also wonder why paternal history is no more a risk in thesel studies? There are only a few allergic parent due to healthy worker effect…
No adjustment for multiple testing “because it will lead to fewer errors of interpretation when the data under evaluation are not random numbers but actual observations on nature” That is one of the most stupid sentences I have ever read.

The overall response rate in this study is 32% and the strongest risk for cord blood IgE is maternal IgE. Is there any statistical model that can account for poor data by contamination of newborn cord blood with maternal IgE? And uhh, 32% response is that really a representative sample?

Did you notice that being a farm child now suddenly becomes a risk for seasonal sensitization (OR=1.18, NS) and food allergy as well (OR=1.25, NS)? And that farm milk consumption is suddenly a risk! for IgE to cow’s milk (OR=3.64, p=0.01)?

The mantra at the beginning at each of the abstract above is certainly necessary to let us believe in the rest of these papers.

Addendum 8/8/2008
Poster E3269: Prenatal exposure to a farm environment affects atopic sensitization at birth at ERS Berlin Tuesday, October 7, 2008.

Furthermore, inverse associations of CB IgE to seasonal allergens with positive maternal records for Toxoplasma (T.) gondii (adjusted odds ratio = 0.37 [0.17-0.81]) and rubella virus (adjusted odds ratio = 0.35 [0.13-0.96]) were found.

gotcha – Toxoplasma + Rubella.

Addendum 11/12/2009
a new paper & a new cowshed derived bacterium: Acinetobacter

Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis.

Addendum 28/2/2011
a new press release Eurotium

Mikrobielle Vielfalt allein reicht vermutlich allerdings nicht aus, um Asthma zu verhindern. Wahrscheinlich ist es eine Kombination spezifischer Arten, die eine Schutzwirkung entfalten kann. „Im gesamten untersuchten Spektrum fanden sich einige Keime, die besonders interessant sein könnten”, berichtet Ege, „dazugehören außer bestimmten Bazillen und Staphylokokken – etwa die Art Staphylococcus sciuri – auch Schimmelpilze der Gattung Eurotium.“

Addendum 1/1/2018
The research above has now lead to the highest German Science Prize, an honorary doctorate, an ERC advanced grant, a Leopoldina and Bavarian Academy membership.