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Bacterial colonization factors control specificity and stability of the gut microbiota

Lee, S. Melanie and Donaldson, Gregory P. and Mikulski, Zbigniew and Boyajian, Silva and Ley, Klaus and Mazmanian, Sarkis K. (2013) Bacterial colonization factors control specificity and stability of the gut microbiota. Nature, 501 (7467). pp. 426-429. ISSN 0028-0836. PMCID PMC3893107. doi:10.1038/nature12447.

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Mammals harbour a complex gut microbiome, comprising bacteria that confer immunological, metabolic and neurological benefits. 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 species, 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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Mazmanian, Sarkis K.0000-0003-2713-1513
Additional Information:© 2013 Macmillan Publishers Limited. Received 6 September 2012; accepted 11 July 2013. Published online 18 August 2013. 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-photonmicroscopy. 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. Author 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.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM007616
Crohn’s and Colitis Foundation of AmericaUNSPECIFIED
Issue or Number:7467
PubMed Central ID:PMC3893107
Record Number:CaltechAUTHORS:20130819-131238827
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:40720
Deposited By: Tony Diaz
Deposited On:19 Aug 2013 20:45
Last Modified:10 Nov 2021 00:07

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