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Genomic variation and strain-specific functional adaptation in the human gut microbiome during early life

Nature Microbiology volume 4, pages 470–479 (2019)Cite this article

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A Publisher Correction to this article was published on 05 February 2019

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Abstract

The human gut microbiome matures towards the adult composition during the first years of life and is implicated in early immune development. Here, we investigate the effects of microbial genomic diversity on gut microbiome development using integrated early childhood data sets collected in the DIABIMMUNE study in Finland, Estonia and Russian Karelia. We show that gut microbial diversity is associated with household location and linear growth of children. Single nucleotide polymorphism- and metagenomic assembly-based strain tracking revealed large and highly dynamic microbial pangenomes, especially in the genus Bacteroides, in which we identified evidence of variability deriving from Bacteroides-targeting bacteriophages. Our analyses revealed functional consequences of strain diversity; only 10% of Finnish infants harboured Bifidobacterium longum subsp. infantis, a subspecies specialized in human milk metabolism, whereas Russian infants commonly maintained a probiotic Bifidobacterium bifidum strain in infancy. Groups of bacteria contributing to diverse, characterized metabolic pathways converged to highly subject-specific configurations over the first two years of life. This longitudinal study extends the current view of early gut microbial community assembly based on strain-level genomic variation.

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Fig. 1: Strain diversity across species in early gut metagenomes.
Fig. 2: Bifidobacterium strains in DIABIMMUNE children.
Fig. 3: Contributional diversity of microbial pathways.

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Data availability

All 16S rRNA and metagenomic sequencing data are available in the NCBI Sequence Read Archive under BioProject PRJNA497734 and through the DIABIMMUNE microbiome website at https://pubs.broadinstitute.org/diabimmune/.

Change history

  • 05 February 2019

    In the version of this Article originally published, in the first sentence of the second paragraph of the Discussion section, the word “operingrationally” should have read “operationally”. This has now been amended in all versions of the Article.

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Acknowledgements

The authors thank T. Poon and S. Steelman (Broad Institute) for help with sequence production and sample management, A. Rahnavard for help with HMP SNP haplotype analysis, D. Shungin for discussions and connections regarding the use of infant milk products in Russia, K. Koski and M. Koski (University of Helsinki) for the coordination and database work in the DIABIMMUNE study and T. Reimels for editorial help with writing and figure generation. T.V. was supported by funding from the Juvenile Diabetes Research Foundation (JDRF). A.B.H. is a Merck Fellow of the Helen Hay Whitney Foundation. P.C.M. received funding from the German Research Foundation (grant no. 315980449). C.H. was supported by funding from the JDRF (3-SRA-2016–141-Q-R) and the National Institutes of Health (R24DK110499). M.K. was supported by the European Union Seventh Framework Programme FP7/2007–2013 (202063) and the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (250114). R.J.X. was supported by funding from JDRF (2-SRA-2016–247-S-B and 2-SRA-2018–548-S-B), the National Institutes of Health (DK43351 and AI110498) and the Center for Microbiome Informatics and Therapeutics.

Author information

Authors and Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Tommi Vatanen, Damian R. Plichta, Timothy D. Arthur, Andrew Brantley Hall, Xiaobo Ke, Raivo Kolde, Moran Yassour, Hera Vlamakis, Curtis Huttenhower & Ramnik J. Xavier

  2. Department of Computer Science, Aalto University, Espoo, Finland

    Juhi Somani & Harri Lähdesmäki

  3. Department for Computational Biology of Infection Research, Helmholtz Center for Infection Research, Brunswick, Germany

    Philipp C. Münch & Alice C. McHardy

  4. Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig-Maximilian University of Munich, Munich, Germany

    Philipp C. Münch

  5. Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, Basel, Switzerland

    Sabine Rudolf

  6. Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Edward J. Oakeley, Xiaobo Ke, Rachel A. Young, Henry J. Haiser & Jeffrey A. Porter

  7. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Moran Yassour & Ramnik J. Xavier

  8. Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Kristiina Luopajärvi, Heli Siljander & Mikael Knip

  9. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland

    Kristiina Luopajärvi, Heli Siljander & Mikael Knip

  10. Department of Pediatrics, Tampere University Hospital, Tampere, Finland

    Heli Siljander & Mikael Knip

  11. Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland

    Suvi M. Virtanen

  12. Faculty of Social Sciences/Health Sciences, University of Tampere, Tampere, Finland

    Suvi M. Virtanen

  13. Science Centre, Pirkanmaa Hospital District and Research Center for Child Health, University Hospital, Tampere, Finland

    Suvi M. Virtanen

  14. Immunogenetics Laboratory, University of Turku, Turku, Finland

    Jorma Ilonen

  15. Clinical Microbiology, Turku University Hospital, Turku, Finland

    Jorma Ilonen

  16. Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

    Raivo Uibo

  17. Department of Pediatrics, University of Tartu and Tartu University Hospital, Tartu, Estonia

    Vallo Tillmann

  18. Ministry of Health and Social Development, Karelian Republic of the Russian Federation, Petrozavodsk, Russia

    Sergei Mokurov

  19. Petrozavodsk State University, Department of Family Medicine, Petrozavodsk, Russia

    Natalya Dorshakova

  20. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Curtis Huttenhower

  21. Folkhälsan Research Center, Helsinki, Finland

    Mikael Knip

  22. Gastrointestinal Unit, and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Ramnik J. Xavier

  23. Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA

    Ramnik J. Xavier

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  1. Tommi Vatanen
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Contributions

T.V., D.R.P., J.S. and P.C.M. analysed the sequencing data. T.D.A., S.R., E.J.O., X.K., R.A.Y., H.J.H. and J.A.P. contributed to B. dorei isolate sequencing. A.B.H. and R.K. contributed to bioinformatic analysis. M.Y., K.L. and H.S. contributed to study design. J.I., S.M.V., R.U., V.T., S.M. and N.D. collected clinical samples. A.C.M., H.L., H.V., C.H., M.K. and R.J.X. served as principal investigators. T.V., D.R.P., J.S., P.C.M., H.V., C.H., M.K. and R.J.X. drafted the manuscript. All authors discussed the results, contributed to critical revisions and approved the final manuscript.

Corresponding author

Correspondence to Ramnik J. Xavier.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Notes, Supplementary References.

Reporting Summary

Supplementary Table 1

Cohort metadata.

Supplementary Table 2

PERMANOVA results.

Supplementary Table 3

Microbial alpha-diversity.

Supplementary Table 4

Taxonomic associations.

Supplementary Table 5

Strain diversity of gut microbial species.

Supplementary Table 6

Extended B. dorei pangenome.

Supplementary Table 7

Tentative circular genomic elements in the sequenced B. dorei isolates.

Supplementary Table 8

CRISPR Spacer mapping to virome contigs and DIABIMMUNE assembly.

Supplementary Table 9

Most frequent taxa assigned to CRISPR spacer carrier contigs with matches to virome contigs of the DIABIMMUNE assembly.

Supplementary Table 10

Bacterial species by body site.

Supplementary Table 11

Contributional diversities of biological process GO terms.

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Vatanen, T., Plichta, D.R., Somani, J. et al. Genomic variation and strain-specific functional adaptation in the human gut microbiome during early life. Nat Microbiol 4, 470–479 (2019). https://doi.org/10.1038/s41564-018-0321-5

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