TY - JOUR
T1 - Bacterial colonization factors control specificity and stability of the gut microbiota
AU - Lee, S. Melanie
AU - Donaldson, Gregory P.
AU - Mikulski, Zbigniew
AU - Boyajian, Silva
AU - Ley, Klaus
AU - Mazmanian, Sarkis K.
N1 - Funding Information:
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.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84884411052&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884411052&partnerID=8YFLogxK
U2 - 10.1038/nature12447
DO - 10.1038/nature12447
M3 - Article
C2 - 23955152
AN - SCOPUS:84884411052
SN - 0028-0836
VL - 501
SP - 426
EP - 429
JO - Nature
JF - Nature
IS - 7467
ER -