A recent study in the NEJM found remarkable differences in the asthma prevalence between Amish and Hutterite populations. The lifestyle of both communities is similar but their farming practice is distinct as the Amish follow a more traditional style of outdoor grazing whereas the Hutterities use industrialized farming practices. Gene expression data in the Amish children have been interpreted as „intense exposure to microbes“ because protection of experimental asthma by Amish derived house dust was nearly abrogated in mice deficient for MyD88.
Any helminth exposure has been excluded due to low IgE and eosinophil counts in the children while I still think that this could be an explanation in particular as the attempt to show an effect of bacterial exposure was unsuccessful since the discovery of the farming effect.
One difference between conventional stable (Hutterites) and outdoor grazing (Amish) is the higher helminthic infection rate on pasture, mainly with Fasciola, Ostertagia, Eimeria, Cooperia, Dictyocaulus and Trichostrongylos species.
Infected cattle rarely demonstrate clinical disease, while it is known that Fasciola (as for example Schistosome) has numerous immunosuppressive functions in the host. IgE is not always raised as Fasciola can degrade human immunoglobulin or even induce eosinophil apoptosis.
Re-analysis of Gene Expression Network using string-db.org (String Consortium 2019). The gene expression network in Amish children {Stein et al., 2016, #73074} in the upper area has similarities with the network observed in sheep after Fasciola infection {Fu et al., 2017, #6751} module #1 and #3, in the lower plot.
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
Already the first sentence is wrong if we look at the following plot where asthma is clearly levelling off.
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 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 any reviewer ever look at the plots or tables?
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.
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?
The FaRMI calculation is overly complicated. Probably the calculation can never be replicated by changing software, changing samples, unclear wording, suboptimal dimension reduction and data snooping.
Farm home microbiota-like community composition was modeled in LUKAS1 with logistic regression analysis (PROC LOGISTIC statement, SAS version 9.3). The home location on a farm or non-farm rural environment was the dependent variable and the main components of PCoA axis scores of β-diversity matrices were the predictor variables. Bacterial and fungal microbiota were investigated separately. For both bacteria and fungi, separate models were built using axis scores from PCoA of abundance-unweighted and -weighted β-diversity matrices. The PCoA axes were selected based on the scree plot method including axes above the point at which the variance explained by the additional axes levels off (Supplementary Fig. 3). The models give an estimate of the probability that the sample is from a farm home. The farm home likeness of the microbial composition in the LUKAS2 non-farm homes was then estimated by applying the regression coefficients obtained from the LUKAS1-based models to the corresponding microbial data from LUKAS2 samples.Some analyses were performed in non-farm homes of both LUKAS2 and LUKAS1 to obtain increased sample size and power if results remain comparable as was observed. Due to the discovered association with asthma, the probability that was modeled based on the relative abundance-weighted bacterial/archaeal β-diversity was named FaRMI and was studied further in greater detail.
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…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 future studies.
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 code?
Using R heredoc syntax I can rewrite 20 unreadable by 8 readable lines.
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=paste(getwd(),out,"/")
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 just for that reason?
These reviews do not tell you so much about the regulation while regulation 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.
Worms 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.
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.
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: Continue reading Forgotten papers: Allergy origins in the gut→
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?
