title: Dynamics of the microbiota in response to host infection.
abstract: Longitudinal studies of the microbiota are important for discovering changes in microbial communities that affect the host. The complexity of these ecosystems requires rigorous integrated experimental and computational methods to identify temporal signatures that promote physiologic or pathophysiologic responses in vivo. Employing a murine model of infectious colitis with the pathogen Citrobacter rodentium, we generated a 2-month time-series of 16S rDNA gene profiles, and quantitatively cultured commensals, from multiple intestinal sites in infected and uninfected mice. We developed a computational framework to discover time-varying signatures for individual taxa, and to automatically group signatures to identify microbial sub-communities within the larger gut ecosystem that demonstrate common behaviors. Application of this model to the 16S rDNA dataset revealed dynamic alterations in the microbiota at multiple levels of resolution, from effects on systems-level metrics to changes across anatomic sites for individual taxa and species. These analyses revealed unique, time-dependent microbial signatures associated with host responses at different stages of colitis. Signatures included a Mucispirillum OTU associated with early disruption of the colonic surface mucus layer, prior to the onset of symptomatic colitis, and members of the Clostridiales and Lactobacillales that increased with successful resolution of inflammation, after clearance of the pathogen. Quantitative culture data validated findings for predominant species, further refining and strengthening model predictions. These findings provide new insights into the complex behaviors found within host ecosystems, and define several time-dependent microbial signatures that may be leveraged in studies of other infectious or inflammatory conditions.
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Clara
authors.initials: C
authors.lastname: Belzer
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Georg K
authors.initials: GK
authors.lastname: Gerber
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Guus
authors.initials: G
authors.lastname: Roeselers
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Delaney
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: DuBois
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vera
authors.initials: V
authors.lastname: Belavusava
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yeliseyev
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Andres
authors.initials: A
authors.lastname: Houseman
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Onderdonk
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Colleen
authors.initials: C
authors.lastname: Cavanaugh
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Clinical and Translational Metagenomics, Brigham & Women's Hospital, Harvard Digestive Diseases Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
mesh_terms: D000818:Animals; D058491:Bacterial Load; D044082:Citrobacter rodentium / Q000235:genetics* / Q000254:growth & development; D003092:Colitis / Q000382:microbiology*; D004754:Enterobacter / Q000235:genetics / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000382:microbiology*; D005798:Genes, Bacterial; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000382:microbiology; D007422:Intestines / Q000382:microbiology; D007778:Lactobacillus / Q000235:genetics / Q000302:isolation & purification; D054892:Metagenome; D051379:Mice; D064307:Microbiota / Q000235:genetics*; D058977:Molecular Sequence Annotation; D010802:Phylogeny; D011514:Proteus vulgaris / Q000235:genetics / Q000302:isolation & purification; D012336:RNA, Ribosomal, 16S / Q000145:classification / Q000235:genetics*
chemical_list: D012336:RNA, Ribosomal, 16S