Integrated culturing, modeling and transcriptomics uncovers complex interactions and emergent behavior in a three-species synthetic gut community

  1. Kevin D'hoe
  2. Stefan Vet
  3. Karoline Faust  Is a corresponding author
  4. Frédéric Moens
  5. Gwen Falony
  6. Didier Gonze
  7. Verónica Lloréns-Rico
  8. Lendert Gelens
  9. Jan Danckaert
  10. Luc De Vuyst
  11. Jeroen Raes  Is a corresponding author
  1. KU Leuven, Belgium
  2. Vrije Universiteit Brussel, Belgium
  3. Université Libre de Bruxelles, Belgium

Abstract

Whereas the composition of the human gut microbiome is well resolved, predictive understanding is still lacking. Here, we followed a bottom-up strategy to explore human gut community dynamics: we established a synthetic community composed of three representative human gut isolates (Roseburia intestinalis L1-82, Faecalibacterium prausnitzii A2-165 and Blautia hydrogenotrophica S5a33) and explored their interactions under well-controlled conditions in vitro. Systematic mono- and pair-wise fermentation experiments confirmed competition for fructose and cross-feeding of formate. We quantified with a mechanistic model how well tri-culture dynamics was predicted from mono-culture data. With the model as reference, we demonstrated that strains grown in co-culture behaved differently than in mono-culture and confirmed their altered behavior at the transcriptional level. In addition, we showed with replicate tri-cultures and simulations that dominance in tri-culture sensitively depended on initial conditions. Our work has important implications for gut microbial community modeling as well as ecological interaction detection from batch cultures.

Data availability

RNA-seq results have been deposited to the Short Read Archive under the study identifier SRP136465 (https://www.ncbi.nlm.nih.gov/sra/SRP136465). Fermentation data have been submitted to Dryad (doi:10.5061/dryad.g83f29f). Source data has been provided for Figures 3 to 6.

The following data sets were generated

Article and author information

Author details

  1. Kevin D'hoe

    Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Stefan Vet

    Applied Physics Research Group, Vrije Universiteit Brussel, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Karoline Faust

    Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    For correspondence
    karoline.faust@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7129-2803
  4. Frédéric Moens

    Research Group of Industrial Microbiology and Food Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Gwen Falony

    Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Didier Gonze

    Unité de Chronobiologie Théorique, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Verónica Lloréns-Rico

    Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  8. Lendert Gelens

    Laboratory of Dynamics in Biological Systems, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  9. Jan Danckaert

    Applied Physics Research Group, Vrije Universiteit Brussel, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  10. Luc De Vuyst

    Research Group of Industrial Microbiology and Food Biotechnology, Vrije Universiteit Brussel, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  11. Jeroen Raes

    Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
    For correspondence
    jeroen.raes@kuleuven.vib.be
    Competing interests
    The authors declare that no competing interests exist.

Funding

Vrije Universiteit Brussel

  • Kevin D'hoe

Fonds Wetenschappelijk Onderzoek

  • Kevin D'hoe
  • Karoline Faust
  • Frédéric Moens
  • Verónica Lloréns-Rico

Interuniversity Institute of Bioinformatics in Brussels

  • Stefan Vet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Xochitl Morgan, University of Otago, New Zealand

Version history

  1. Received: March 29, 2018
  2. Accepted: October 4, 2018
  3. Accepted Manuscript published: October 16, 2018 (version 1)
  4. Version of Record published: November 15, 2018 (version 2)
  5. Version of Record updated: November 4, 2019 (version 3)

Copyright

© 2018, D'hoe et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,548
    views
  • 954
    downloads
  • 72
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kevin D'hoe
  2. Stefan Vet
  3. Karoline Faust
  4. Frédéric Moens
  5. Gwen Falony
  6. Didier Gonze
  7. Verónica Lloréns-Rico
  8. Lendert Gelens
  9. Jan Danckaert
  10. Luc De Vuyst
  11. Jeroen Raes
(2018)
Integrated culturing, modeling and transcriptomics uncovers complex interactions and emergent behavior in a three-species synthetic gut community
eLife 7:e37090.
https://doi.org/10.7554/eLife.37090

Share this article

https://doi.org/10.7554/eLife.37090

Further reading

    1. Cell Biology
    2. Computational and Systems Biology
    Trine Line Hauge Okholm, Andreas Bjerregaard Kamstrup ... Christian Kroun Damgaard
    Research Article

    Circular RNAs represent a class of endogenous RNAs that regulate gene expression and influence cell biological decisions with implications for the pathogenesis of several diseases. Here, we disclose a novel gene-regulatory role of circHIPK3 by combining analyses of large genomics datasets and mechanistic cell biological follow-up experiments. Using time-course depletion of circHIPK3 and specific candidate RNA-binding proteins, we identify several perturbed genes by RNA sequencing analyses. Expression-coupled motif analyses identify an 11-mer motif within circHIPK3, which also becomes enriched in genes that are downregulated upon circHIPK3 depletion. By mining eCLIP datasets and combined with RNA immunoprecipitation assays, we demonstrate that the 11-mer motif constitutes a strong binding site for IGF2BP2 in bladder cancer cell lines. Our results suggest that circHIPK3 can sequester IGF2BP2 as a competing endogenous RNA (ceRNA), leading to target mRNA stabilization. As an example of a circHIPK3-regulated gene, we focus on the STAT3 mRNA as a specific substrate of IGF2BP2 and validate that manipulation of circHIPK3 regulates IGF2BP2-STAT3 mRNA binding and, thereby, STAT3 mRNA levels. Surprisingly, absolute copy number quantifications demonstrate that IGF2BP2 outnumbers circHIPK3 by orders of magnitude, which is inconsistent with a simple 1:1 ceRNA hypothesis. Instead, we show that circHIPK3 can nucleate multiple copies of IGF2BP2, potentially via phase separation, to produce IGF2BP2 condensates. Our results support a model where a few cellular circHIPK3 molecules can induce IGF2BP2 condensation, thereby regulating key factors for cell proliferation.