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Link to original content: http://dx.doi.org/10.1038/nature12447
Bacterial colonization factors control specificity and stability of the gut microbiota | Nature
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Bacterial colonization factors control specificity and stability of the gut microbiota

Nature volume 501, pages 426–429 (2013)Cite this article

Abstract

Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits1. Despite advances in sequence-based microbial profiling and myriad studies defining microbiome composition during health and disease, little is known about the molecular processes used by symbiotic bacteria to stably colonize the gastrointestinal tract. We sought to define how mammals assemble and maintain the Bacteroides, one of the most numerically prominent genera of the human microbiome. Here we find that, whereas the gut normally contains hundreds of bacterial species2,3, germ-free mice mono-associated with a single Bacteroides species are resistant to colonization by the same, but not different, species. To identify bacterial mechanisms for species-specific saturable colonization, we devised an in vivo genetic screen and discovered a unique class of polysaccharide utilization loci that is conserved among intestinal Bacteroides. We named this genetic locus the commensal colonization factors (ccf). Deletion of the ccf genes in the model symbiont, Bacteroides fragilis, results in colonization defects in mice and reduced horizontal transmission. The ccf genes of B. fragilis are upregulated during gut colonization, preferentially at the colonic surface. When we visualize microbial biogeography within the colon, B. fragilis penetrates the colonic mucus and resides deep within crypt channels, whereas ccf mutants are defective in crypt association. Notably, the CCF system is required for B. fragilis colonization following microbiome disruption with Citrobacter rodentium infection or antibiotic treatment, suggesting that the niche within colonic crypts represents a reservoir for bacteria to maintain long-term colonization. These findings reveal that intestinal Bacteroides have evolved species-specific physical interactions with the host that mediate stable and resilient gut colonization, and the CCF system represents a novel molecular mechanism for symbiosis.

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Figure 1: Bacteroides species occupy species-specific niches in the gut via an evolutionarily conserved genetic locus.
Figure 2: B.fragilis colonization of the colonic crypts is mediated by the CCF system.
Figure 3: B.fragilis requires the ccf genes for stable and resilient colonization of mice.

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Acknowledgements

We thank T. Thron and S. McBride for the maintenance of germ-free animals, J. Selicha for assisting with the experimental procedures and G. Chodaczek for help with confocal and two-photon microscopy. We are grateful to E. C. Martens and members of the Mazmanian laboratory for critical review of the manuscript. S.M.L. and G.P.D. were supported by a pre-doctoral training grant (GM007616). This work was supported by grants from the National Institutes of Health (GM099535 and DK078938) and the Crohn’s and Colitis Foundation of America to S.K.M.

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Author notes

  1. Gregory P. Donaldson and Zbigniew Mikulski: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, 91125, California, USA

    S. Melanie Lee, Gregory P. Donaldson, Silva Boyajian & Sarkis K. Mazmanian

  2. Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Zbigniew Mikulski & Klaus Ley

Authors
  1. S. Melanie Lee
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  2. Gregory P. Donaldson
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  6. Sarkis K. Mazmanian
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Contributions

S.M.L. and S.K.M. conceived the project. S.M.L. performed most of the experiments; G.P.D., Z.M. and S.B. contributed data. S.M.L., G.P.D., Z.M., K.L. and S.K.M. interpreted the data. K.L. and S.K.M. secured funding. S.M.L. and S.K.M. wrote the manuscript. G.P.D., Z.M. and K.L. edited the manuscript.

Corresponding author

Correspondence to Sarkis K. Mazmanian.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-13, Supplementary Equation 1, Supplementary References and Supplementary Tables 1-2. (PDF 10885 kb)

Wild-type B. fragilis within the central channel of colonic crypt

Travel through a confocal Z stack from the apical portion of the colonic mucosa down the length of the crypt of a B. fragilis mono-colonized mouse. F-actin is visualized with fluorescently labeled phalloidin (Alexa Fluor 546) to distinguish cell boundaries and crypt structures (green). Cell nuclei are stained with DAPI (blue). Bacteria are detected using chicken antibody directed to B. fragilis and Alexa Fluor 488-conjugated anti-chicken secondary antibody (red). Note the presence of a central channel that is bifurcating in the lower portion of the stack in the three-dimensional visualization of F-actin morphology using iso-surface rendering. Bacteria are found near the apical part of the epithelium and in the crypt space. (MOV 3036 kb)

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Lee, S., Donaldson, G., Mikulski, Z. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013). https://doi.org/10.1038/nature12447

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