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Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium

Nature Microbiology volume 2, Article number: 16215 (2017) Cite this article

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Abstract

Protection against enteric infections, also termed colonization resistance, results from mutualistic interactions of the host and its indigenous microbes. The gut microbiota of humans and mice is highly diverse and it is therefore challenging to assign specific properties to its individual members. Here, we have used a collection of murine bacterial strains and a modular design approach to create a minimal bacterial community that, once established in germ-free mice, provided colonization resistance against the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm). Initially, a community of 12 strains, termed Oligo-Mouse-Microbiota (Oligo-MM12), representing members of the major bacterial phyla in the murine gut, was selected. This community was stable over consecutive mouse generations and provided colonization resistance against S. Tm infection, albeit not to the degree of a conventional complex microbiota. Comparative (meta)genome analyses identified functions represented in a conventional microbiome but absent from the Oligo-MM12. By genome-informed design, we created an improved version of the Oligo-MM community harbouring three facultative anaerobic bacteria from the mouse intestinal bacterial collection (miBC) that provided conventional-like colonization resistance. In conclusion, we have established a highly versatile experimental system that showed efficacy in an enteric infection model. Thus, in combination with exhaustive bacterial strain collections and systems-based approaches, genome-guided design can be used to generate insights into microbe–microbe and microbe–host interactions for the investigation of ecological and disease-relevant mechanisms in the intestine.

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Figure 1: The Oligo-MM12 consortium stably colonizes mice and is vertically transmitted across filial generations.
Figure 2: Transplantation of the Oligo-MM12 consortium leads to increased CR against oral S. Tm infection.
Figure 3: Clustering analysis of KEGG modules represented in draft genomes of ASF and Oligo-MM strains.
Figure 4: Clustering analysis of KEGG modules represented in artificial metagenomes of ASF8 and Oligo-MM12 and conventional metagenomes (CON).
Figure 5: Transplantation of three facultative anaerobic bacteria restores CR of Oligo-MM12.
Figure 6: S. Tm infection in gnotobiotic mice colonized with different defined bacterial consortia.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

The authors thank W.-D. Hardt, J. Heesemann, O. Rossier and members of the Stecher laboratory for discussions. The authors also thank R. Robbiani for help with isolation of bacterial strains and K. Berer and G. Krishnamoorthy for providing mice. The work was supported by grants from the BMBF (Medizinische Infektionsgenomik), DFG Priority program SPP1656, research grants DFG STE 1971/4-1 and STE 1971/7-1, the German Center for Infection Research (DZIF), the Centre for Gastrointestinal Microbiome Research (CEGIMIR), the Austrian Science Fund (P26127-B20, P27831-B28, I2320-B22) and the Vienna Science and Technology Fund (LS12-001).

Author information

Author notes

  1. Markus Beutler, Carina Pfann and Debora Garzetti: These authors contributed equally to this work.

Authors and Affiliations

  1. Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany

    Sandrine Brugiroux, Markus Beutler, Debora Garzetti, Diana Ring, Manuel Diehl, Simone Herp, Saib Hussain, Philipp C. Münch & Bärbel Stecher

  2. Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Research Network Chemistry meets Microbiology, University of Vienna, A-1090 Vienna, Austria

    Carina Pfann, Alexander Loy & David Berry

  3. German Center for Infection Research (DZIF); Partner Site Munich,

    Debora Garzetti & Bärbel Stecher

  4. Partner Site Munich,

    Debora Garzetti & Bärbel Stecher

  5. Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany

    Hans-Joachim Ruscheweyh & Daniel H. Huson

  6. Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland

    Yvonne Lötscher

  7. DSMZ – German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany

    Boyke Bunk & Rüdiger Pukall

  8. Computational Biology of Infection Research, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany

    Philipp C. Münch & Alice C. McHardy

  9. Department of Algorithmic Bioinformatics, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany

    Alice C. McHardy

  10. Department of Clinical Research (DKF), Maurice Müller Laboratories, UVCM, University Hospital, 3010 Bern, Switzerland

    Kathy D. McCoy & Andrew J. Macpherson

  11. ZIEL Institute for Food and Health, Technische Universität München, 85354 Freising, Germany

    Thomas Clavel

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Contributions

B.S., S.B., T.C., A.L. and D.B. conceived and designed the experiments. B.S., S.B., M.B., D.G., D.R., M.D., S.He., Y.L., S.Hu., B.B., K.D.M. and D.B. performed the experiments. B.S., S.B., M.B., C.P., D.G., H.-J.R., S.H., B.B., R.P., D.H.H., P.C.M., A.C.M., T.C., A.L. and D.B. analysed the data. D.H.H., A.C.M., K.D.M., A.J.M., A.L., T.C. and D.B. contributed materials/analysis tools. B.S. coordinated the project, wrote the original draft, and all authors reviewed and edited the draft manuscript.

Corresponding author

Correspondence to Bärbel Stecher.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Figures 1-8, Supplementary Tables 1-4 and 11, legends for Supplementary Tables 5-10, Supplementary References (PDF 20447 kb)

Supplementary Table 5

Taxonomic composition of faecal microbiota expressed as relative abundances (Fig. 2c). (XLSX 24 kb)

Supplementary Table 6

Taxonomic composition of faecal microbiota expressed as relative abundances (Supplementary Fig. 4). (XLSX 15 kb)

Supplementary Table 7

KEGG module analysis for Oligo-MM12 and ASF8 26. (XLSX 39 kb)

Supplementary Table 8

KEGG module analysis for CON metagenomes and artificial metagenomes of Oligo-MM12 and ASF8 32. (XLSX 30 kb)

Supplementary Table 9

KEGG module analysis for Oligo-MM12, ASF8 and FA3 37. (XLSX 60 kb)

Supplementary Table 10

KEGG module analysis for CON metagenomes and artificial metagenomes of Oligo-MM12, FA3 and ASF8. (XLSX 33 kb)

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Brugiroux, S., Beutler, M., Pfann, C. et al. Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium. Nat Microbiol 2, 16215 (2017). https://doi.org/10.1038/nmicrobiol.2016.215

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