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.

  • Article
  • Published:

An efficient and scalable top-down method for predicting structures of microbial communities

Abstract

Modern applications involving multispecies microbial communities rely on the ability to predict structures of such communities in defined environments. The structures depend on pairwise and high-order interactions between species. To unravel these interactions, classical bottom-up approaches examine all possible species subcommunities. Such approaches are not scalable as the number of subcommunities grows exponentially with the number of species, n. Here we present a top-down method wherein the number of subcommunities to be examined grows linearly with n, drastically reducing experimental effort. The method uses steady-state data from leave-one-out subcommunities and mathematical modeling to infer effective pairwise interactions and predict community structures. The accuracy of the method increases with n, making it suitable for large communities. We established the method in silico and validated it against a five-species community from literature and an eight-species community cultured in vitro. Our method offers an efficient and scalable tool for predicting microbial community structures.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Schematic of EPICS.
Fig. 2: Structure prediction of in silico microbial communities.
Fig. 3: Robustness to parameter variations.
Fig. 4: Structure prediction of large communities and subcommunities.
Fig. 5: Capturing the abundances in a five-species gut microbial community of Drosophila melanogaster.
Fig. 6: Capturing the abundances in an eight-species oral microbial community.

Similar content being viewed by others

Data availability

Source Data are provided with this paper.

Code availability

The computer code used to implement EPICS is available on GitHub (https://github.com/narendradixit/EPICS/tree/v1) and on Zenodo62.

References

  1. Baldrian, P. Forest microbiome: diversity, complexity and dynamics. FEMS Microbiol. Rev. 41, 109–130 (2017).

    Google Scholar 

  2. Jansson, J. K. & Hofmockel, K. S. Soil microbiomes and climate change. Nat. Rev. Microbiol. 18, 35–46 (2020).

    Article  Google Scholar 

  3. Sunagawa, S. et al. Structure and function of the global ocean microbiome. Science 348, 1261359 (2015).

    Article  Google Scholar 

  4. Cani, P. D. Human gut microbiome: hopes, threats and promises. Gut 67, 1716–1725 (2018).

    Article  Google Scholar 

  5. Huttenhower, C. et al. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

    Article  Google Scholar 

  6. Lamont, R. J., Koo, H. & Hajishengallis, G. The oral microbiota: dynamic communities and host interactions. Nat. Rev. Microbiol. 16, 745–759 (2018).

    Article  Google Scholar 

  7. Valdes, A. M., Walter, J., Segal, E. & Spector, T. D. Role of the gut microbiota in nutrition and health. Brit. Med. J. 361, k2179 (2018).

    Article  Google Scholar 

  8. Belkaid, Y. & Hand, T. W. Role of the microbiota in immunity and inflammation. Cell 157, 121–141 (2014).

    Article  Google Scholar 

  9. Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313–323 (2009).

    Article  Google Scholar 

  10. Valles-Colomer, M. et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat. Microbiol. 4, 623–632 (2019).

    Article  Google Scholar 

  11. Angulo, M. T., Moog, C. H. & Liu, Y.-Y. A theoretical framework for controlling complex microbial communities. Nat. Commun. 10, 1045 (2019).

    Article  Google Scholar 

  12. Fuhrman, J. A. Microbial community structure and its functional implications. Nature 459, 193–199 (2009).

    Article  Google Scholar 

  13. Inda, M. E., Broset, E., Lu, T. K. & de la Fuente-Nunez, C. Emerging frontiers in microbiome engineering. Trends Immunol. 40, 952–973 (2019).

    Article  Google Scholar 

  14. Prosser, J. I. et al. The role of ecological theory in microbial ecology. Nat. Rev. Microbiol. 5, 384–392 (2007).

    Article  Google Scholar 

  15. Sheth, R. U., Cabral, V., Chen, S. P. & Wang, H. H. Manipulating bacterial communities by in situ microbiome engineering. Trends Genet. 32, 189–200 (2016).

    Article  Google Scholar 

  16. Xiao, Y., Angulo, M. T., Lao, S., Weiss, S. T. & Liu, Y.-Y. An ecological framework to understand the efficacy of fecal microbiota transplantation. Nat. Commun. 11, 3329 (2020).

    Article  Google Scholar 

  17. Bittleston, L. S., Gralka, M., Leventhal, G. E., Mizrahi, I. & Cordero, O. X. Context-dependent dynamics lead to the assembly of functionally distinct microbial communities. Nat. Commun. 11, 1440 (2020).

    Article  Google Scholar 

  18. Lawson, C. E. et al. Common principles and best practices for engineering microbiomes. Nat. Rev. Microbiol. 17, 725–741 (2019).

    Article  Google Scholar 

  19. Aroniadis, O. C. & Brandt, L. J. Fecal microbiota transplantation: past, present and future. Curr. Opin. Gastroenterol. 29, 79–84 (2013).

    Article  Google Scholar 

  20. Chng, K. R. et al. Metagenome-wide association analysis identifies microbial determinants of post-antibiotic ecological recovery in the gut. Nat. Ecol. Evol. 4, 1256–1267 (2020).

    Article  Google Scholar 

  21. Zhou, K., Qiao, K., Edgar, S. & Stephanopoulos, G. Distributing a metabolic pathway among a microbial consortium enhances production of natural products. Nat. Biotechnol. 33, 377–383 (2015).

    Article  Google Scholar 

  22. Mee, M. T., Collins, J. J., Church, G. M. & Wang, H. H. Syntrophic exchange in synthetic microbial communities. Proc. Natl Acad. Sci. USA 111, E2149–E2156 (2014).

    Article  Google Scholar 

  23. Mukherjee, S. & Bassler, B. L. Bacterial quorum sensing in complex and dynamically changing environments. Nat. Rev. Microbiol. 17, 371–382 (2019).

    Article  Google Scholar 

  24. Scott, S. R. & Hasty, J. Quorum sensing communication modules for microbial consortia. ACS Synth. Biol. 5, 969–977 (2016).

    Article  Google Scholar 

  25. Jagmann, N. & Philipp, B. Design of synthetic microbial communities for biotechnological production processes. J. Biotechnol. 184, 209–218 (2014).

    Article  Google Scholar 

  26. McCarty, N. S. & Ledesma-Amaro, R. Synthetic biology tools to engineer microbial communities for biotechnology. Trends Biotechnol. 37, 181–197 (2019).

    Article  Google Scholar 

  27. Vázquez-Castellanos, J. F., Biclot, A., Vrancken, G., Huys, G. R. & Raes, J. Design of synthetic microbial consortia for gut microbiota modulation. Curr. Opin. Pharmacol. 49, 52–59 (2019).

    Article  Google Scholar 

  28. Meyer, A. et al. Optimization of a whole-cell biocatalyst by employing genetically encoded product sensors inside nanolitre reactors. Nat. Chem. 7, 673–678 (2015).

    Article  Google Scholar 

  29. Widder, S. et al. Challenges in microbial ecology: building predictive understanding of community function and dynamics. ISME J. 10, 2557–2568 (2016).

    Article  MathSciNet  Google Scholar 

  30. Friedman, J., Higgins, L. M. & Gore, J. Community structure follows simple assembly rules in microbial microcosms. Nat. Ecol. Evol. 1, 0109 (2017).

    Article  Google Scholar 

  31. Goldford, J. E. et al. Emergent simplicity in microbial community assembly. Science 361, 469–474 (2018).

    Article  Google Scholar 

  32. Xiao, Y. et al. Mapping the ecological networks of microbial communities. Nat. Commun. 8, 2042 (2017).

    Article  Google Scholar 

  33. Machado, D. et al. Polarization of microbial communities between competitive and cooperative metabolism. Nat. Ecol. Evol. 5, 195–203 (2021).

    Article  Google Scholar 

  34. Pacheco, A. R., Moel, M. & Segrè, D. Costless metabolic secretions as drivers of interspecies interactions in microbial ecosystems. Nat. Commun. 10, 103–103 (2019).

    Article  Google Scholar 

  35. Pacheco, A. R., Osborne, M. L. & Segrè, D. Non-additive microbial community responses to environmental complexity. Nat. Commun. 12, 2365 (2021).

    Article  Google Scholar 

  36. Gould, A. L. et al. Microbiome interactions shape host fitness. Proc. Natl Acad. Sci. USA 115, E11951–E11960 (2018).

    Article  Google Scholar 

  37. Ansari, A. F. et al. High-order interactions can eclipse pairwise interactions in shaping the structure of microbial communities. Ind. Eng. Chem. Res. 58, 23508–23518 (2019).

    Article  Google Scholar 

  38. Bairey, E., Kelsic, E. D. & Kishony, R. High-order species interactions shape ecosystem diversity. Nat. Commun. 7, 12285 (2016).

    Article  Google Scholar 

  39. Grilli, J., Barabás, G., Michalska-Smith, M. J. & Allesina, S. Higher-order interactions stabilize dynamics in competitive network models. Nature 548, 210–213 (2017).

    Article  Google Scholar 

  40. Biggs, M. B., Medlock, G. L., Kolling, G. L. & Papin, J. A. Metabolic network modeling of microbial communities. WIRES Syst. Biol. Med. 7, 317–334 (2015).

    Article  Google Scholar 

  41. Harcombe, W. R. et al. Metabolic resource allocation in individual microbes determines ecosystem interactions and spatial dynamics. Cell Rep. 7, 1104–1115 (2014).

    Article  Google Scholar 

  42. Levy, R. & Borenstein, E. Metabolic modeling of species interaction in the human microbiome elucidates community-level assembly rules. Proc. Natl Acad. Sci. USA 110, 12804–12809 (2013).

    Article  Google Scholar 

  43. Ravikrishnan, A. & Raman, K. Systems-Level Modelling of Microbial Communities (CRC, 2018); https://doi.org/10.1201/9780429487484

  44. Cammarota, G. et al. Gut microbiome, big data and machine learning to promote precision medicine for cancer. Nat. Rev. Gastroenterol. Hepatol. 17, 635–648 (2020).

    Article  Google Scholar 

  45. Faust, K. & Raes, J. Microbial interactions: from networks to models. Nat. Rev. Microbiol. 10, 538–550 (2012).

    Article  Google Scholar 

  46. Guo, X. & Boedicker, J. Q. The contribution of high-order metabolic interactions to the global activity of a four-species microbial community. PLoS Comput. Biol. 12, e1005079 (2016).

    Article  Google Scholar 

  47. Sanchez-Gorostiaga, A., Bajić, D., Osborne, M., Poyatos, J. & Sanchez, A. High-order interactions distort the functional landscape of microbial consortia. PLoS Biol. 17, e3000550 (2019).

    Article  Google Scholar 

  48. Leventhal, G. E. et al. Strain-level diversity drives alternative community types in millimetre-scale granular biofilms. Nat. Microbiol. 3, 1295–1303 (2018).

    Article  Google Scholar 

  49. Bosi, E., Bacci, G., Mengoni, A. & Fondi, M. Perspectives and challenges in microbial communities metabolic modeling. Front. Genet. 8, 88 (2017).

    Article  Google Scholar 

  50. Babaei, P., Shoaie, S., Ji, B. & Nielsen, J. Challenges in modeling the human gut microbiome. Nat. Biotechnol. 36, 682–686 (2018).

    Article  Google Scholar 

  51. Großkopf, T. & Soyer, O. S. Synthetic microbial communities. Curr. Opin. Microbiol. 18, 72–77 (2014).

    Article  Google Scholar 

  52. Johns, N. I., Blazejewski, T., Gomes, A. L. C. & Wang, H. H. Principles for designing synthetic microbial communities. Curr. Opin. Microbiol. 31, 146–153 (2016).

    Article  Google Scholar 

  53. De Roy, K., Marzorati, M., Van den Abbeele, P., Van de Wiele, T. & Boon, N. Synthetic microbial ecosystems: an exciting tool to understand and apply microbial communities. Environ. Microbiol. 16, 1472–1481 (2014).

    Article  Google Scholar 

  54. Venturelli, O. S. et al. Deciphering microbial interactions in synthetic human gut microbiome communities. Mol. Syst. Biol. 14, e8157 (2018).

    Article  Google Scholar 

  55. Zomorrodi, A. R. & Segrè, D. Synthetic ecology of microbes: mathematical models and applications. J. Mol. Biol. 428, 837–861 (2016).

    Article  Google Scholar 

  56. Kuntal, B. K., Gadgil, C. & Mande, S. S. Web-gLV: a web based platform for Lotka–Volterra based modeling and simulation of microbial populations. Front. Microbiol. 10, 288 (2019).

    Article  Google Scholar 

  57. Marino, S., Baxter, N. T., Huffnagle, G. B., Petrosino, J. F. & Schloss, P. D. Mathematical modeling of primary succession of murine intestinal microbiota. Proc. Natl Acad. Sci. USA 111, 439–444 (2014).

    Article  Google Scholar 

  58. Vos, M. G. J. de, Zagorski, M., McNally, A. & Bollenbach, T. Interaction networks, ecological stability, and collective antibiotic tolerance in polymicrobial infections. Proc. Natl Acad. Sci. USA 114, 10666–10671 (2017).

    Article  Google Scholar 

  59. Opper, M. & Diederich, S. Replicator dynamics. Comput. Phys. Commun. 121, 141–144 (1999).

    Article  Google Scholar 

  60. Bolnick, D. I. et al. Individuals’ diet diversity influences gut microbial diversity in two freshwater fish (threespine stickleback and Eurasian perch). Ecol. Lett. 17, 979–987 (2014).

    Article  Google Scholar 

  61. Momeni, B., Xie, L. & Shou, W. Lotka–Volterra pairwise modeling fails to capture diverse pairwise microbial interactions. eLife 6, e25051 (2017).

    Article  Google Scholar 

  62. Ansari, A. F., Reddy, Y. B. S., Raut, J. & Dixit. N. M. EPICS Version v1 (Zenodo, 2021); https://doi.org/10.5281/zenodo.5156236

Download references

Acknowledgements

We thank K. Raman and S. Jhunjhunwala for insightful comments.

Author information

Authors and Affiliations

Authors

Contributions

A.F.A. and N.M.D. developed the theory. A.F.A. performed the numerical simulations and analyzed the empirical data. Y.B.S.R. and J.R. performed the experiments. All authors interpreted the results and wrote the manuscript.

Corresponding author

Correspondence to Narendra M. Dixit.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Computational Science thanks Boyang Ji and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement Handling editor: Ananya Rastogi, in collaboration with the Nature Computational Science team.

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

Extended data

Extended Data Fig. 1 Consistency of effective pairwise interactions from leave-one-out and leave-two-out subcommunities.

The RMS relative error between the interactions estimated using n − 1 species subcommunities and n − 2 species subcommunities for different n using parameter settings corresponding to the first four points in the 3D diagonal in Fig. 3A, indicated as 1, 2, 3, and 4 above.

Source data

Extended Data Fig. 2 Exactness of EPICS with purely pairwise interactions.

Comparisons between effective pairwise interactions estimated using EPICS and true pairwise interactions underlying in silico 5-species communities following the GLV model (see Methods). The interaction strengths are depicted in the panels. (A) Pairwise interactions alone are present. (B) Pairwise and ternary interactions present; (C) Pairwise and quaternary interactions present; (D) All three interaction types present. Each dot represents one pairwise interaction in one realization. The red dashed line represents y=x.

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2, and Figs. 1–15.

Reporting Summary

Source data

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Source Data Fig. 6

Statistical source data.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 2

Statistical source data.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ansari, A.F., Reddy, Y.B.S., Raut, J. et al. An efficient and scalable top-down method for predicting structures of microbial communities. Nat Comput Sci 1, 619–628 (2021). https://doi.org/10.1038/s43588-021-00131-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43588-021-00131-x

This article is cited by

Search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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