Tag Archives: farming

Schutz vor Allergie auf dem Bauernhof: Ist das zentrale Paradigma falsch?

Keine Frage – Lebensbedingungen auf Bauernhöfen sind anders. Mehr Tiere, mehr Dreck, mehr frische Luft, alles ist anders als in einer Großstadt. Das kann auf Selektionsbedingungen zurückzuführen sein, z. B. gut  zu sehen in einer der ersten Studien vor 30 Jahren.

Clin Exp Allergy. 1999 Jan;29(1):28-34. https://doi.org/10.1016/S0140-6736(01)06252-3

Auch die Eltern hatten schon weniger Allergien, und damit logischerweise auch die Kinder.

Wenn man genau hinschaut, dann haben alle Bauernhofstudien doch immer wieder dieselbe Argumentationsstruktur – weil die Bedingung X dort so, dann kann die Folge Y dort auch auf die Bedingung X zurückgeführt werden. Immer mehr Beschreibungen von X machen die Story aber nicht glaubwürdiger.

Keine der jemals beschriebenen Bedingungen X, ist aus dem Bauernhofmilieu heraus aber auch auf allgemeine Situationen mit Folge Y übertragbar gewesen, von einem einzigen weitgehend verunglückten Versuch einmal abgesehen. Keine einzige Bedingung X  ist nach 30 Jahren verallgemeinerbar, so dass nun alles doch nach einer einzigen Blase aussieht.

Natürlich hat ein hoher Endotoxin Spiegel auf den Bauernhöfen eine bestimmte Wirkung –  zumindest bei einigen Menschen und bei einigen Mäusen – aber ist das wirklich  mehr als ein modifizierender Faktor?

Da Lebensbedingungen auf dem Bauernhof angeblich protektiv sind, müsste auch mal ein einziges Kind präsentiert werden, das eigentlich eine Allergie haben muss, weil seine beiden Eltern allergisch waren.  Aber dieses Kind gab es nie, weil auch schon die Eltern keine Allergien haben.

 

Farming and allergy prevention could be caused by Berkson’s fallacy

Lets look at the Wikipedia definition first

Berkson’s fallacy is a result in conditional probability and statistics which is often found to be counterintuitive, and hence a veridical paradox. It is a complicating factor arising in statistical tests of proportions. Specifically, it arises when there is an ascertainment bias inherent in a study design … The most common example of Berkson’s paradox is a false observation of a negative correlation between two positive traits, i.e., that members of a population which have some positive trait tend to lack a second.

The original example is developed unsing the example of an hospital based group of patients. The only thing to know is that diabetes is a risk for cholecystitis in the general population.

Any given hospital in-patient without diabetes must have another disease (otherwise he would not be there), for example cholecystitis. And by definition this will be cholecystitis without diabetes caused by some other risk facors (female, fat, forty…) So in this group of in-patients there maybe a spurious negative association between cholecystitis and diabetes.

My example here is with families who are living on farms. Since around 1960  [Leynaert 2001] there is this interesting observation that farming families have less allergy, an effect that I found back in 1989 and that is most likely a healthy farmer effect.
This selected farm population has a lower allergy prevalence and of course their children will also have less allergy. All the negative correlations (that are interpreted as protection) with endotoxin, microbiome, etc could be caused by Berkson’s fallacy. The observation will also be even replicated as the same selection criteria are also present in the replication sample.

Many more cognitive biases could also be involved: anchoring, availability cascade, confirmation and expectation bias and of course: law of the instrument.

What is wrong with the 2011 NEJM paper?

N Engl J Med 2011;364:701-9 is another paper with 1000+ citations  that had a lasting impression on some but not all people.

First, I can’t remember of any study with such an enormous selection bias  where >94% of individuals have been lost.

Second, we should not forget that farm is not protective per se – farmers may just avoid a known allergy risk factor.  The PARSIFAL participants in this study included Steiner schools — anthroposophic medicine mostly avoids vitamin D (another ref). This is of course a major issue for any cross-sectional study that doesn’t take into account the temporality of events.

Third, in PARSIFAL dust from children’s mattresses were collected by vacuuming — it is not very likely that many helminthic eggs were transported  from stable to bedroom. In GABRIELA, only airborne dust samples  were collected which may miss helminth eggs although being highly present in stable dust.

Fourth, more  microbial exposure and more fungal taxa on farms are a trivial finding.

The inverse associations of the diversity scores with asthma were not confounded by status with respect to living on a farm because adjustment did not change the respective point estimates for asthma (Table 2), although the associations became nonsignificant.

Small sample size, borderline p-values even after a long fishing expedition? And what do these strange “probability” plots  really show – the probability of asthma or the probability to live on a farm?

N Engl J Med 2011;364:701-9 Figure 3 Does it refute any general effect of diversity?

The plots are misleading if adjustment for farm living does not change the parameter estimates for bacterial/fungal diversity. Does that really mean that farm are irrelevant?

Sixth – even many years later, the main findings of this study could not be replicated. There is not any single study that shows listeriosis (Listeria) or diphtheria (Corynebacterium)  to be protective.

Allergy protection on farms – why also studies in mice could have failed

There are  many immunological differences in humans and mice (follow my link) that a re never discussed not even in Science 2015;349/6252:1106.

Ignoring the long-standing paradox that endotoxin is also acting as a natural adjuvant to atopic inflammation, the credibility of the Science paper is further reduced.

And it is a strange experimental condition to have all animals on a standard vitamin D diet – a known co-sensitizers – and looking then for A20 which is co-regulated by vitamin D

Does a healthy worker effect explain the “allergy protection” at Bavarian farms?

Unfortunately most studies in the farming environment did not report the prevalence of parental history nor did they report the effect size of parental risk in the farming population. This is, however, a critical issue as the so called healthy worker effect HEW may be a rather trivial explanation of the results.

Specifically, it is a sampling bias: the kind of subjects that voluntarily enroll in a clinical trial and actually follow the experimental regimen are not representative of the general population. They can be expected, on average, to be healthier as they are concerned for their health [or as ill people already dropped out]

At least Braun-Fahrländer 1999 reported that allergic parents were seen much less at farms: allergic rhinitis 12.7% versus 29.4% (P=0.001). A history of allergy therefore is no more a risk factor as it is in the general population.

Leynaert 2001 showed only a slightly reduced prevalence of “allergy” (39.1% vs 41.5%, NS) while her table 4 is most interesting. The association started only after year 1960 which points towards misclassification as far as the analysis is not stratified by year of birth.

Remes 2002 showed a dose dependent effect decline between farming (36.2%) and controls (31.6%, P=0.075),

Perkin 2006 also found some significant lower prevalence in farmers 47.3% versus 57.7%, P<0.001.

A HWE is therefore likely.

In total, I found indeed six studies (Thelin 1994, Braback 2006, Chenard 2007, Thaon 2011, Elholm 2013 and Spierenburg 2015) that examined in detail a possible relationship of HWE, allergy and farming. Unfortunately the examination period in five of these studies is too short for any conclusion with Braback 2006 being the only reliable study.

Also from this study, we can safely conclude, that there is a significant HWE.

 

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.

 

medRxiv

ArXiv is operational since 1991, bioRxiv since 2013 and since 2019 there is now also medrxiv. More details  at https://www.bmj.com/content/365/bmj.l2301

The main arguments in favour of sharing work in its preliminary form are, firstly, that science works faster if work is made available sooner after it is completed and, secondly, that articles are improved by feedback from a wider group of readers, alongside formal peer review by a few experts. Simple estimates suggest that halving the delay to sharing a research result can double the speed at which research progresses. Ambitious research funders are now embracing preprints and other measures that aim to accelerate the pace of research.

Although there was a mixed reception in the beginning, see Science back in 2017

MedArXiv will have a hard time attracting preprints if mainstream medical journal editors decide they won’t publish final versions of the papers. Currently, The BMJ and The Lancet are among the few medical journals that have explicitly said that posting a preprint doesn’t preclude publication; Nature and Science, which both occasionally publish medical studies, have the same policy. But at the JAMA Network, which publishes a dozen journals, the issue is hotly debated.

@MedArXiv opened on June 6. So far they have only 304 followers on Twitter (and no allergy paper in the archive).

As the current “Allergy” editor and the publisher (John Wiley and Sons A/S)  agreed to preprints last week, I have submited now my first preprint paper.

The endotoxin phantom – discrepancies in the NEJM 2002 farm paper

N Engl J Med 2002; 347:869-877 made a strong point that the farm effect is mediated by endotoxin but showed just a 1,7 fold higher endotoxin exposure at farms.

N Engl J Med 2002; 347:869-877 table 1 shows environmental exposure between farm and non-farming households

LPS therefore can not even explain the farm protection as endotoxin effects are so much similar between farming and non-farming (table 2. Why is only the result of the total sample given here and not the farm result?).

N Engl J Med 2011; 364:701-709 table 2 endotoxin effect is not stronger at farms – more some unspecific immunosuppressive effect?

What is the reason for the lower IL10 capacity in Figure 2D to respond to LPS exposure – exhaustion, adaptation? And even more important: What is the reason for the lower allergy rate at farms?

If we now go back to table 1 there is a 5,0 fold Der p1 excess in farm – much higher than the 1,7 fold increase of endotoxin.

As nearly all allergens have helminth homologues –  the question is what did the authors really measure? Da Costa Santiago 2015 has a nice table that could give an answer.

J Immunol. 2015 Jan 1;194(1):93-100 shows Der p1 homologs

Der p1 is a cysteine protease of 25kDa that has homologues for example in Loa loa. Loa loa is unlikely at Bavarian farms – and more common in tropical Africa. Cysteine proteases are nevertheless a big tool for helminths –  in Schistosoma japonicum a cathepsin B2 cysteine protease is considered the main penetration tool.

Usually cysteine proteases are not allergenic, but the excessive (and rather isolated) rise combined with a reduced Der  p1 sensitization in the children,  is definitely an unusual finding. The Dermatophagoides pteronyssinus habitat is cosmopolitan, house dust,  influenced by altitude and climate, but there is no known reasons for this excess in farms. Is the Der p1 value just a false positive and has it helminthic and not mite origin?

I am therefore blasting Der p1  sequence (P08176) against all known cow endoparasite genomes. Fasciola has a strong hit with CL6, a papain family cysteine protease with e+48.

Wormbase blastp results – e+ values are somewhat lower than my local blast result at the same locus

With an identity values between 40% and 70% there could well be a confusion of mite Der p1 and  helminth (Fasciola?) CL6, which should be tested for cross-reactivity.

The story even gets more interesting when reading more about parasites

Helminth parasites have complicated life cycles … at the same time as skewing the immune system toward a Th2-driven response, they have a general suppressive effect on the host immune system that prevents their elimination and reduces immune-mediated tissue damage. It has been suggested that cytokines of the anti-inflammatory network, particularly IL-10 and transforming growth factor- (TGF-), that are produced in response to continual stimulation of the immune system by parasite antigens, are pivotal to regulating the damage they cause and that, coincidentally, these have a bystander protective affect against allergic reactions.

This is exactly what N Engl J Med 2002; 347:869-877 showed: increasingly exhausted IL10 capacity. May the x-axis label should not be LPS but  CL6?

N Engl J Med 2002; 347:869-877 Figure 2. Smoothed Plots of the Log-Transformed Capacity of Peripheral-Blood Leukocytes (PBL) to Produce Interleukin-10 (Panel D) after Stimulation with Lipopolysaccharide (LPS) or Staphylococcal Enterotoxin B (SEB) in Relation to the Log-Transformed Endotoxin-Load Values.

 

 

The Amish paradox in NEJM 2016 explained

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.

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.

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 already 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 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.

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.