Enviromental endotoxin is downregulating the vitamin D receptor and (probably) also vitamin sensitivity in Zhao et al. Enviromental endotoxin downregulating the vitamin D receptor? weiterlesen
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…
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.
hypothesized that prenatal vitamin D supplementation could induce tolerogenic DC at birth. To evaluate this hypothesis in an epidemiological setting, we quantiï¬ed the gene expression levels of ILT3 and ILT4 in cord blood (CB) samples of a population-based birth cohort of farm and reference children.
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
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.
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.
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.
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.
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!
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.
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.
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?
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.
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.
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.
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.“
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.
As always, a longer literature search prevents from new discoveries… Here comes a nice piece from 1952 on the antagonistic effect of LPS on vitamin D (Is that really LPS or did I interpret it wrong?). Although not included in my recent review on vitamin D and allergy – I attributed the effect to Lyakh et al. – here is the first description of this effect. A factor in hay prevents vitamin D action weiterlesen
A report in Biospektrum 07.07/13:762 about the production of endotoxin free ovalbumin by a German company now reveals that nearly all commercially available ovalbumin preparations are highly contaminated with endotoxin. Company A included 723, company B 1038, company C 257 and company D 342 EU/mg LPS. As all mice are usually also on a vitamin D supplement diet, recent mouse studies may have produced largely artifacts if both – agonist and antagonist – are included in an uncontrolled manner, yea, yea.
Instead of highlighting the best paper in 2007, I decided to nominate now the most under valued paper in 2007. There are so many interesting (and probably highly important) studies that do not get enough initial attention and consecutively fail to enter the high citation track. Here is one of these papers that is as interesting as on the day of publication: Forgotten papers: Allergy origins in the gut weiterlesen
Blackley found already in 1873 an interesting explanation of the “no allergy in farming children” effect by referring to some kind of auto desensitization in this particular environment – e.g. the high pollen and LPS exposure.
Do you know that a commercial allergen preparation used for desensitization already includes a LPS derivate, 3-o-desacyl-4′ monophosphoryl lipid A as an adjuvant? It is believed to push the pollen reaction into a IL12 – IFNg – Th1 pathway. This therapeutic approach already perfectly fits the early explanation of Blackley.
When will the allergy farming lobby ultimately close their files?
I am currently doing some historical studies if the vitamin hypothesis fits also the temporal relationship of allergy prevalence. While ordering RKI files for my next trip to the Berlin document center, I found that farming and lower allergy sensitization is known much longer than I anticipated. Time to give Blackley the credit he deserves weiterlesen
I will present this poster next Monday in San Francisco at the Annual Conference of the American Thoracic Society. Lactase variants in Europe – any connection to allergy? weiterlesen
Cultured immature DCs capture antigen but only process and present it on MHC II after exposure to inflammatory stimuli or TLR ligation.