Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Defining microbiome function

Abstract

Why does a microorganism associate with a host? What function does it perform? Such questions are difficult to unequivocally address and remain hotly debated. This is partially because scientists often use different philosophical definitions of ‘function’ ambiguously and interchangeably, as exemplified by the controversy surrounding the Encyclopedia of DNA Elements (ENCODE) project. Here, I argue that research studying host-associated microbial communities and their genomes (that is, microbiomes) faces similar pitfalls and that unclear or misapplied conceptions of function underpin many controversies in this field. In particular, experiments that support phenomenological models of function can inappropriately be used to support functional models that instead require specific measurements of evolutionary selection. Microbiome research also requires uniquely clear definitions of ‘who the function is for’, in contrast to most single-organism systems where this is implicit. I illustrate how obscuring either of these issues can lead to substantial confusion and misinterpretation of microbiome function, using the varied conceptions of the holobiont as a current and cogent example. Using clear functional definitions and appropriate types of evidence are essential to effectively communicate microbiome research and foster host health.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: The relationship between CR and SE functions.

References

  1. 1.

    McFall-Ngai, M. et al. Animals in a bacterial world, a new imperative for the life sciences. Proc. Natl Acad. Sci. USA 110, 3229–3236 (2013).

  2. 2.

    Casadevall, A. & Fang, F. C. Descriptive science. Infect. Immun. 76, 3835–3836 (2008).

    CAS  Article  Google Scholar 

  3. 3.

    Martiny, J. B. H., Jones, S. E., Lennon, J. T. & Martiny, A. C. Microbiomes in light of traits: a phylogenetic perspective. Science 350, aac9323 (2015).

    Article  Google Scholar 

  4. 4.

    Amundson, R. & Lauder, G. V. Function without purpose: the uses of causal role function in evolutionary biology. Biol. Philos. 9, 443–469 (1994).

    Article  Google Scholar 

  5. 5.

    Wright, L. Functions. Philos. Rev. 82, 139–168 (1973).

    Article  Google Scholar 

  6. 6.

    Cummins, R. Functional analysis. J. Philos. 72, 741–765 (1975).

    Article  Google Scholar 

  7. 7.

    Millikan, R. G. In defense of proper functions. Philos. Sci. 56, 288–302 (1989).

    Article  Google Scholar 

  8. 8.

    Neander, K. The teleological notion of ‘function’. Australas. J. Philos. 69, 454–468 (1991).

    Article  Google Scholar 

  9. 9.

    Doolittle, W. F., Brunet, T. D. P., Linquist, S. & Gregory, T. R. Distinguishing between ‘function’ and ‘effect’ in genome biology. Genome Biol. Evol. 6, 1234–1237 (2014).

    Article  Google Scholar 

  10. 10.

    Doolittle, W. F. & Brunet, T. D. P. On causal roles and selected effects: our genome is mostly junk. BMC Biol. 15, 116 (2017).

    Article  Google Scholar 

  11. 11.

    Godfrey-Smith, P. A modern history theory of functions. Nous 28, 344–362 (1994).

    Article  Google Scholar 

  12. 12.

    Lande, R. & Arnold, S. J. The measurement of selection on correlated characters. Evolution 37, 1210–1226 (1983).

    Article  Google Scholar 

  13. 13.

    Okasha, S. Evolution and the Levels of Selection (Oxford Univ. Press, Oxford, 2006).

    Google Scholar 

  14. 14.

    Gould, S. J. & Lewontin, R. C. The spandrels of San Marco and the panglossian paradigm: a critique of the adaptationist programme. Proc. R. Soc. B Biol. Sci. 205, 581–598 (1979).

    CAS  Article  Google Scholar 

  15. 15.

    Mayr, E. Cause and effect in biology. Science 134, 1501–1506 (1961).

    CAS  Article  Google Scholar 

  16. 16.

    Tinbergen, N. On aims and methods of Ethology. Z. Tierpsychol. 20, 410–433 (1963).

    Article  Google Scholar 

  17. 17.

    Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

    CAS  Article  Google Scholar 

  18. 18.

    Mahowald, M. A. et al. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc. Natl Acad. Sci. USA 106, 5859–5864 (2009).

  19. 19.

    Baquero, F. & Nombela, C. The microbiome as a human organ. Clin. Microbiol. Infect. 18, 2–4 (2012).

    CAS  Article  Google Scholar 

  20. 20.

    Bordenstein, S. R. & Theis, K. R. Host biology in light of the microbiome: ten principles of holobionts and hologenomes. PLoS Biol. 13, e1002226 (2015).

  21. 21.

    Theis, K. R. et al. Getting the hologenome concept right: an eco-evolutionary framework for hosts and their microbiomes. mSystems 1, e00028–16 (2016).

    Article  Google Scholar 

  22. 22.

    Mushegian, A. A. & Ebert, D. Rethinking ‘mutualism’ in diverse host-symbiont communities. BioEssays 38, 100–108 (2016).

    Article  Google Scholar 

  23. 23.

    Kopac, S. M. & Klassen, J. L. Can they make it on their own? Hosts, microorganisms, and the holobiont niche. Front. Microbiol. 7, 1647 (2016).

    Article  Google Scholar 

  24. 24.

    Ebert, D. The epidemiology and evolution of symbionts with mixed-mode transmission. Annu. Rev. Ecol. Evol. Syst. 44, 623–643 (2013).

    Article  Google Scholar 

  25. 25.

    David, L. A. et al. Host lifestyle affects human microbiota on daily timescales. Genome Biol. 15, R89 (2014).

    Article  Google Scholar 

  26. 26.

    The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Article  Google Scholar 

  27. 27.

    Archie, E. A. & Tung, J. Social behavior and the microbiome. Curr. Opin. Behav. Sci. 6, 28–34 (2015).

    Article  Google Scholar 

  28. 28.

    Smillie, C. S. et al. Ecology drives a global network of gene exchange connecting the human microbiome. Nature 480, 241–244 (2011).

    CAS  Article  Google Scholar 

  29. 29.

    Byndloss, M. X. et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

    CAS  Article  Google Scholar 

  30. 30.

    Fitzpatrick, B. M. Symbiote transmission and maintenance of extra-genomic associations. Front. Microbiol. 5, 46 (2014).

    Article  Google Scholar 

  31. 31.

    Lynch, M. The frailty of adaptive hypotheses for the origins of organismal complexity. Proc. Natl Acad. Sci. USA 104, 8597–8604 (2007).

  32. 32.

    Sharon, G. et al. Commensal bacteria play a role in mating preference of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 107, 20051–20056 (2010).

  33. 33.

    Brucker, R. M. & Bordenstein, S. R. The hologenomic basis of speciation: gut bacteria cause hybrid lethality in the genus Nasonia. Science 341, 667–669 (2013).

  34. 34.

    Brooks, A. W., Kohl, K. D., Brucker, R. M., van Opstal, E. J. & Bordenstein, S. R. Phylosymbiosis: relationships and functional effects of microbial communities across host evolutionary history. PLoS Biol. 14, e2000225 (2016).

  35. 35.

    Zilber-Rosenberg, I. & Rosenberg, E. Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiol. Rev. 32, 723–735 (2008).

    CAS  Article  Google Scholar 

  36. 36.

    Rosenberg, E. & Zilber-Rosenberg, I. The Hologenome Concept: Human, Animal and Plant Microbiota (Springer International Publishing, Cham, 2013).

    Google Scholar 

  37. 37.

    Roughgarden, J., Gilbert, S. F., Rosenberg, E., Zilber-Rosenberg, I. & Lloyd, E. A. Holobionts as units of selection and a model of their population dynamics and evolution. Biol. Theory 13, 44–65 (2018).

    Article  Google Scholar 

  38. 38.

    Moran, N. A. & Sloan, D. B. The hologenome concept: helpful or hollow? PLoS Biol. 13, e1002311 (2015).

  39. 39.

    Douglas, A. E. & Werren, J. H. Holes in the hologenome: why host-microbial symbioses are not holobionts. mBio 7, e02099–15 (2016).

    CAS  Article  Google Scholar 

  40. 40.

    Janzen, D. H. When is it coevolution? Evolution 34, 611–612 (1980).

    Article  Google Scholar 

  41. 41.

    Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    CAS  Article  Google Scholar 

  42. 42.

    Casadevall, A. & Fang, F. C. Rigorous science: a how-to guide. mBio 7, e01902–16 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Dunham, I. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    CAS  Article  Google Scholar 

  44. 44.

    Graur, D. An upper limit on the functional fraction of the human genome. Genome Biol. Evol. 9, 1880–1885 (2017).

    Article  Google Scholar 

  45. 45.

    Eddy, S. R. The C-value paradox, junk DNA and ENCODE. Curr. Biol. 22, R898–R899 (2012).

    CAS  Article  Google Scholar 

  46. 46.

    Doolittle, W. F. Is junk DNA bunk? A critique of ENCODE. Proc. Natl Acad. Sci. USA 110, 5294–5300 (2013).

  47. 47.

    Brunet, T. D. P. & Doolittle, W. F. Getting ‘function’ right. Proc. Natl Acad. Sci. USA 111, E3365 (2014).

  48. 48.

    Kellis, M. et al. Defining functional DNA elements in the human genome. Proc. Natl Acad. Sci. USA 111, 6131–6138 (2014).

  49. 49.

    Price, G. R. Selection and covariance. Nature 227, 520–521 (1970).

    CAS  Article  Google Scholar 

  50. 50.

    Webster, N. S. & Reusch, T. B. H. Microbial contributions to the persistence of coral reefs. ISME J. 11, 2167–2174 (2017).

    Article  Google Scholar 

  51. 51.

    Govaert, L., Pantel, J. H. & De Meester, L. Eco-evolutionary partitioning metrics: assessing the importance of ecological and evolutionary contributions to population and community change. Ecol. Lett. 19, 839–853 (2016).

    Article  Google Scholar 

  52. 52.

    Rocha, E. P. C. Evolutionary patterns in prokaryotic genomes. Curr. Opin. Microbiol. 11, 454–460 (2008).

    CAS  Article  Google Scholar 

  53. 53.

    Hurst, L. D. The Ka/Ks ratio: diagnosing the form of sequence evolution. Trends Genet. 18, 486 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

I thank the members of the Klassen lab and J. P. Gogarten for their helpful feedback on earlier versions of this manuscript. Funding for this work was provided by NSF IOS-1656475 and the University of Connecticut. These funders had no role in the conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jonathan L. Klassen.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Klassen, J.L. Defining microbiome function. Nat Microbiol 3, 864–869 (2018). https://doi.org/10.1038/s41564-018-0189-4

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing