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COMMENTHISTORY ReappraisingAristotle as the firstscientist p.250

AGEING A call for more socialscience on the culturalaspects of longevity p.253

POLICY Proposed definition ofinvasive threatens nativebiodiversity p.253

SPACE Exploring ournearest neighbour,Venus p.252

Microbiome science needs ahealthy dose of scepticismTo guard against hype, those interpreting research on the bodys microscopic

communities should ask five questions, says William P. Hanage .

of California, Davis, bestows awards foroverselling the microbiome; he finds noshortage of worthy candidates.

Previous omics fields have faltered aftermurky work slowed progress 2. Techno-logical advances that allowed researchers tocatalogue proteins, metabolites, genetic vari-ants and gene activity led to a spate of asso-ciations between molecular states and healthconditions. But painstaking further workdampened early excitement. Most initial con-nections were found to be spurious or, at best,more complicated than originally believed.

The history of science is replete with

analysis of the microbial content of faecalsamples, promising consumers enlighteninginformation. Separate analyses from the sameperson can, however, vary considerably, evenfrom the same stool sample. Faecal trans-plants have been proposed some moresensible than others for conditions rangingfrom diabetes to Alzheimers disease. Withhow-to instructions proliferating online, des-perate patients must be warned not to attemptthese risky procedures on themselves.

Microbiomics risks being drowned in atsunami of its own hype. Jonathan Eisen, amicrobiologist and blogger at the University

Explorations of how the microscopiccommunities that inhabit the humanbody might contribute to health ordisease have moved from obscure to ubiq-uitous. Over the past five years, studies havelinked our microbial settlers to conditions asdiverse as autism, cancer and diabetes.

This excitement has infected the publicimagination. We Are Our Bacteria, pro-claimed one headline in The New YorkTimes . Some scientists have asserted thatantibiotics are causing a great extinction ofthe microbiome, with dire consequences forhuman health 1. Companies offer personalized

A scanning electron micrograph of bacteria in human faeces, in which 50% of species originate from the gut.

E Y E O F S C I E N C E / S P L

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examples of exciting new fields thatpromised a gold rush of medicines and healthinsights but required scepticism and years ofslogging to deliver even partially. As such, thecriteria for robust microbiome science areinstructive for all researchers. As excitementover the microbiome has filtered beyond aca-demic circles, the potential mischief wrought

by misunderstanding encompasses journal-ists, funding bodies and the public.

CRUCIAL QUESTIONSHere are five questions that anyone conduct-ing or evaluating this research should ask tokeep from getting carried away by hype.

Can experiments detect differences thatmatter? Profiling a microbiome could pro-duce a catalogue at the level of phyla, speciesor genes. Much work relies on analysis of16S rRNA , an ancient gene that tolerateslittle variation and so is reliably found across

the bacterial kingdom. But this allows onlya coarse sorting. For example, microbiomesassociated with obesity have been distin-guished by different ratios of bacterial phyla,which encompass a staggering range of diver-sity. If this criterion were used to characterizeanimal communities, an aviary of 100 birdsand 25 snails would be considered identical toan aquarium with 8 fish and 2 squid, becauseeach has four times as many vertebrates asmolluscs. Even within a single species, strainsoften differ greatly in the genes they contain.

Modern technology now allows for finerdistinctions: we can study more genes ina sample, an ability that may enable us todecipher metabolic networks revealing thebiochemical reactions that a microbiome canperform. This kind of analysis could identifygene combinations, potentially from multi-ple species across a microbial community,that affect health for good or ill. However,pinning an outcome to any particular entityis likely to be hard unless the networks arealready well characterized.

To take a simple example from a singlebacterial species, we could show that vacci-nation eliminated 30% of known pneumo-coccal strains in a human population butonly because we knew in advance to focus onthe genes targeted by the vaccine 3. Our abil-ity to identify functional differences in closelyrelated genes is rarely sophisticated enough topull out important genes or networks if we donot know what to look for in the first place.Moreover, genomes are littered with cluesboth true and false, such as hypothetical pro-teins and genes that are understood poorlyor not at all, but could make for importantdifferences in what metabolic networks do.

We need to be able to identify func-tional differences in closely related genesfrom sequence alone. Until then, we mustremember that apparent similarities mightcloak important differences.

Does the study show causation or justcorrelation? A separate question is raisedwhen distinct microbiomes can be identi-fied and associated with diseases or otherconditions. Then we are left with the chest-nut of causes and correlates. Sometimes, aparticular microbiome found in associationwith disease will be merely a bystander 4.

A 2012 article comparing the gut micro-biomes of old people living in care homeswith those of old people living in the com-munity found distinct microbiomes thatcorrelated with multiple scores of frailty 5.After accounting for some potentially con-

founding factors, theauthors proposeda causal relation-ship: diet altered themicrobiome, whichin turn altered health.This explanationfits the data, but the

reverse causality the potential for poorhealth to alter the gut microbiome was notexplored. Frailer people probably have lessactive immune systems and differences indigestion (such as the time required for foodto pass through the stomach and intestines) factors that could change the microbiome.This work is not the only example of this sortof confusion.

What is the mechanism? All scientists aretaught the catechism that correlation is notcausation, but correlation almost alwaysimplies some sort of causal relationship. We just dont know what it is. We must determineit with careful experiments.

In the past three or four years, studies haveadvanced from characterizing a broad com-munity of mainly unculturable microbes toidentifying functional elements, individualtaxa or particular properties. We can nowdesign experiments to precisely defineactions of components of the microbiome 6,for example by reconstituting communitiesbut leaving out specific taxa, or by preciselymeasuring the biochemical activity of anexperimental microbiome in an organ on achip7. A return to a reductionist approach isessential if we are to pinpoint both whetherthe microbiome affects human health, andexactly how it does so.

How much do experiments reflect reality? Even if the microbiome can have an experi-mental effect, it may not be an importantcause of the symptoms seen in ill people.

Much work has addressed the role that gutflora have in obesity, and several studies havefound associations between the gut micro-biome and weight gain 8. To assess whetherthis association was cause or consequence,researchers collected gut-microbiome sam-ples from human twins (one obese, one not)

and introduced the microbiota to mice. Micepreviously colonized with an obese micro-biome lost weight when supplied with a leanmicrobiome, but only if also fed a normalor low-fat diet. Diet alone had little effect 9.Although this elegantly controlled experi-ment suggests great potential for the micro-biome and related therapies to affect health,

it also shows the microbiomes limits: theeffect was dependent on other factors, inthis case diet.

Microbiome studies often rely on germ-free mice. These animals allow researchersto readily introduce an experimental micro-biota. But they do not represent the animalsnatural state and are typically unhealthyowing to the lack of a microbiome. So resultsmay not predict responses in animals withflourishing microbiomes. Mice and theirmicrobiomes are also adapted to a rather dif-ferent niche from humans, so results may notbe generalizable.

Could anything else explain the results? There are good reasons to think that bacteriainfluence us in a host of ways. But there aremany other possibly more important influences, such as diet in the earlier exam-ple. Whenever a study links a microbiometo a disease, wise critics should ask whetherother contributors to disease are considered,compared and reported.

The hype surrounding microbiomeresearch is dangerous, for individuals whomight make ill-informed decisions, andfor the scientific enterprise, which needsto develop better experimental methods togenerate hypotheses and evaluate conclu-sions. Funding agencies must not let theirpriorities be distorted by the buzz aroundthe field, but look dispassionately at the data.Press officers must stop exaggerating results,and journalists must stop swallowing themwhole. In pre-scientific times when some-thing happened that people did not under-stand, they blamed it on spirits. We mustresist the urge to transform our microbialpassengers into modern-day phantoms.

William P. Hanage is associate professor ofepidemiology at the Harvard School of PublicHealth in Boston, Massachusetts, USA.e-mail: whanage@hsph.harvard.edu

1. Blaser, M. J. Missing Microbes: How the Overuse of Antibiotics is Fueling our Modern Plagues (HenryHolt and Co., 2014).

2. Wilkins, M. R. et al. Proteomics 6, 48 (2006).3. Croucher, N. J. et al. Nature Genet. 45, 656663

(2013).4. Shanahan, F. Nutr. Rev. 70 (suppl. 1), S31S37

(2012).5. Claesson, M. J. et al. Nature 488, 178184 (2012).6. Goodman, A. L. et al. Proc. Natl Acad. Sci. USA

108, 62526257 (2011).7. Huh, D. et al. Nature Protocols 8, 21352157

(2013).8. Ley, R. E. Curr. Opin. Gastroenterol. 26, 511

(2010).9. Ridaura, V. K. et al. Science 341, 1241214 (2013).

Press officersmust stopexaggeratingresults, and journalistsmust stopswallowing

them whole.

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