Tag Archives: farming

FaRMI

I will add now a special collection of farming studies here as many of them are just candidates for the Ig nobel prize.

The most recent study introduces FaRMI, a “bacterial relative abundance farm home microbiota index”, probably introduced as the authors couldn’t find anything else. It reminds me very much to the polygenic risk score that rescues your study if you could not find the gene.

Asthma prevalence has increased in epidemic proportions with urbanization

Clearly already the first sentence is wrong if we look at the following plot.

Urbanization happened in the late späten 19th century and not after 1950. Source of plot: The prevalence of asthma in children: a reversing trend ( ERJ 2005 )

Unfortunately, the difference between farm and non farm children is never explained in the Kirjavainen et al. paper.

What is for example the average distance of a non farm house to a farm house? Are there any joint school or sports activities of children from farms and non farms (allergens travel in the classroom)? And why is there such a strong conclusion in the title?

Farm-like indoor microbiota in non-farm homes protects children from asthma development

A lower risk score is not equivalent to protection.

And did somebody of the authors or reviewers ever look at the plots?

I do not understand Figure 3c. It even makes only sense when I cross out the top labels. But even then it menas: GABRIELA does not show a significant replication.

or tables?

What should these values tell us? 5 times p<0.05 in a grid of 6×11=66 tests? Quantile regression that has been “adjusted” by the data?

And isn’t that  just an association that may have a rather simple explanation?

As FaRMI is weakly associated with muramic acid concentration in dust, the authors make Gram-positive bacteria responsible for the effect. The rhizosphere of soil is extremly rich of bacteria. The world’s first soil atlas showed  hundreds of taxa but never differentiated between water resistant, gram positive and less water resistant gram-negative taxa. Maybe Gram positive Streptococcaceae are ubiquitous and depend on where you draw your samples?

FaRMI is found in non farm / rural children by bacterial/archaeal operational taxonomic units (OTUs) of soil origin which basically confirms my initial assumption: There was the same contamination of soil both in farm and non-farm homes if we look at supplement table 6 where walking indoors with outdoor shoes results in significant higher FaRMI values…

In conclusion, while the asthma-protective effect of farming is intriguing, it has little practical relevance unless the protective effect can be functionally transferred to non-farming environments.

I do not find this data derived score intriguing. Maybe the microbiome hype is already over.

Our results warrant translational studies to confirm the causal relationship through indoor microbial exposure-modifying intervention that may also form a novel strategy for primary asthma prevention.

Good luck with your translational studies, as we are now somewhere in the nowhere.

 

BTW – The scripts at Github are useless references to shell and Python scripts that will never run due to “—” characters. And what about that baby girl code?

writerow <- paste("Eigenvalue min / max: ", min.eigen, " / ", max.eigen, sep="")
write(writerow, file=eigenfile, append=F)
writerow <- paste("Sum of all eigenvalues: ", round(neg.eigensum, digits=6), sep="")
write(writerow, file=eigenfile, append=T)
writerow <- paste("Sum of all eigenvalues (negatives as 0): ", round(nonneg.eigensum, digits=6), sep="")
write(writerow, file=eigenfile, append=T)
writerow <- "Eigenvalues (pos & neg): "
write(writerow, file=eigenfile, append=T)
writerow <- paste(pcoa$value$Eigenvalues, collapse="\t")
write(writerow, file=eigenfile, append=T)
writerow <- "Percents (Negatives as negatives): "
write(writerow, file=eigenfile, append=T)
writerow <- paste(paste(neg.percent, " %", sep=""), collapse="\t")
write(writerow, file=eigenfile, append=T)
writerow <- "Percents (Negatives as 0): "
write(writerow, file=eigenfile, append=T)
writerow <- paste(paste(nonneg.percent, " %", sep=""), collapse="\t")
write(writerow, file=eigenfile, append=T)

Using R heredoc syntax I can rewrite 18 unreadable to 10 readable lines. And 9x disc access to 1x just doing

tmp <- 'Eigenvalue min / max: min.eigen / max.eigen
Sum of all eigenvalues: neg.eigensum
Sum of all eigenvalues (negatives as 0): nonneg.eigensum
Eigenvalues (pos & neg): pcoa
Percents (Negatives as negatives):  neg.percent %
Percents (Negatives as 0): nonneg.percent %'
for (i in c("min.eigen","max.eigen","neg.eigensum","nonneg.eigensum","pcoa$value$Eigenvalues","neg.percent","nonneg.percent") ) { tmp <- gsub(i,get(i),tmp) }
write(tmp, file=eigenfile)

And why moving to SAS for a simple logistic regression? Is there anyone else in the academic world who pays $8,700 annually for a basic SAS Windows Analytics package?

IL33, allergy and helminths: Shot in the leg?

Ever since the NEJM paper in 2010 that showed an IL33/ST2 association there are new studies on a daily basis.

Grotenboer 2013 did a functional annotation of the gene and it’s receptor in humans while there is no more doubt about the involvement of IL33 in human allergy.  Right now IL33 suppression is even used as an experimental screening test for allergic reactivity with ongoing phase II studies of anti-IL33 or anti ST2. Good IL33 reviews can be found for example in frontiers in immunology by Tataori et al. or in nature immunology by Smith. These reviews do not tell you so much about the regulation but this has recently elucidated by Gour et al. who describe a tropomyosin–dectin-1 interaction of the human host. Why is tropomyosin such a frequent target of human IgE?

Muscle protein tropomyosin is an important IgE target in a number of nematode infections; Onchocerca volvulus ; Ascaris lumbricoides; Anisakis simplex; and tropomyosin from the blood fluke Schistosoma mansoni is also a human IgE antigen. Tropomyosin is highly conserved across many invertebrates and is responsible for much of the IgE cross-reactivity between Ascaris and dust-mites.

I haven’t found any good  answer to this question. As tropomyosin affects contractility – this seems like “shooting into the leg” of worms whenever they attempt to invade.
Maybe Gour et al. did not know the earlier dissertation from Berlin that already showed a reduced inflammation in the OVA mouse model by administration of recombinant tropomyosin.

The broad cross reactivity to tropomyosin gives rise to the question if helminth tropomyosin could induce allergic reactions to itself and/or tropomyosin of different organisms. Considering the fact that filarial nematodes express tropomyosin on their surface […] and that the continuing turnover of microfilariae confronts the host with relevant amounts of tropomyosin makes this question even more appropriate.

The worm seems to be attacked by anti-worm-surface-tropomyosin IgE whenever the worm tries to invade  the epithelium during an acute infection. During invasion extracellular IL33 is cleaved into a shorter form with enhanced activity attracting more immune cells.
During chronic infestation nothing happens as long as the worm does not invade and doesn’t trigger any IL33 alarmin. As there is continuous tropomyosin antigen antigen contact, the host is slowly desensitzed, clearing IgE in favor of IgG4.

Is this also a model that explains allergy? We don’t know the details but maybe this antigen recognition / response system is being disturbed where allergens like Der p1 mimicking a worm infection by tropomyosin can trigger the allergic reaction in particular as Der p1 a cysteine protease also mimicks an invasion signal.

Enviromental endotoxin downregulating the vitamin D receptor?

Enviromental endotoxin is downregulating the vitamin D receptor and (probably) also vitamin sensitivity in Zhao et al. Continue reading Enviromental endotoxin downregulating the vitamin D receptor?

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…

Bacteria, vitamin D and allergy

Bacterial (and fungal) gut diversity are believed to influence primary allergic sensitization as well as early vitamin D supplementation. The question  is – again –  could there be any connection? Continue reading Bacteria, vitamin D and allergy

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.

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?

Dung hill counting

Wikipedia writes about Imre Lakatos (1922-1974), 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, the newest review is convincing: it’s the milk. Are you still reading 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 of dung hill height but “distance between dung hill and house 50 meters”).

And did you also wonder why paternal history is no more a risk as in virtually all studies? Because there is no 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”??
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.

A factor in hay prevents vitamin D action

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. Continue reading A factor in hay prevents vitamin D action

Severe flaw in mouse allergy studies

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.

Forgotten papers: Allergy origins in the gut

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: Continue reading Forgotten papers: Allergy origins in the gut