Antonopoulos Dionysios A.

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Antonopoulos
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Dionysios A.
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  • Article
    Patient-specific Bacteroides genome variants in pouchitis
    (American Society for Microbiology, 2016-11-15) Vineis, Joseph H. ; Ringus, Daina L. ; Morrison, Hilary G. ; Delmont, Tom O. ; Dalal, Sushila R. ; Raffals, Laura E. ; Antonopoulos, Dionysios A. ; Rubin, David T. ; Eren, A. Murat ; Chang, Eugene B. ; Sogin, Mitchell L.
    A 2-year longitudinal microbiome study of 22 patients who underwent colectomy with an ileal pouch anal anastomosis detected significant increases in distinct populations of Bacteroides during 9 of 11 patient visits that coincided with inflammation (pouchitis). Oligotyping and metagenomic short-read annotation identified Bacteroides populations that occurred in early samples, bloomed during inflammation, and reappeared after antibiotic treatment. Targeted cultivation of Bacteroides isolates from the same individual at multiple time points and from several patients detected subtle genomic changes, including the identification of rapidly evolving genomic elements that differentiate isogenic strains of Bacteroides fragilis from the mucosa versus lumen. Each patient harbored Bacteroides spp. that are closely related to commonly occurring clinical isolates, including Bacteroides ovatus, B. thetaiotaomicron, B. vulgatus, and B. fragilis, which contained unique loci in different patients for synthesis of capsular polysaccharides. The presence of unique Bacteroides capsular polysaccharide loci within different hosts and between the lumen and mucosa may represent adaptations to stimulate, suppress, and evade host-specific immune responses at different microsites of the ileal pouch.
  • Preprint
    Insights into the pathogenesis of ulcerative colitis from a murine model of stasis-induced dysbiosis, colonic metaplasia, and genetic susceptibility
    ( 2016-04) Ward, Marc A. ; Pierre, Joseph F. ; Leal, Raquel F. ; Huang, Yong ; Shogan, Benjamin ; Dalal, Sushila R. ; Weber, Christopher R. ; Leone, Vanessa A. ; Musch, Mark W. ; An, Gary C. ; Rao, Mrinalini C. ; Rubin, David ; Raffals, Laura E. ; Antonopoulos, Dionysios A. ; Sogin, Mitchell L. ; Hyman, Neil H. ; Alverdy, John C. ; Chang, Eugene B.
    Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis, offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self- emptying (SEL) ileal loops using wild-type (WT), IL-10 KO (IL10), and TLR4 KO (T4), and IL10/T4 double KO mice. After 5 weeks, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented towards the loop end, whereas SEL remain empty. In wild type mice, SFL, but not SEL, develop pouch-like microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-/- deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL- 10-/- required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL10-/- mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4- mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.
  • Article
    Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    (BioMed Central, 2017-05-04) Lee, Sonny T. M. ; Kahn, Stacy A. ; Delmont, Tom O. ; Shaiber, Alon ; Esen, Ozcan C. ; Hubert, Nathaniel A. ; Morrison, Hilary G. ; Antonopoulos, Dionysios A. ; Rubin, David T. ; Eren, A. Murat
    Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection and shows promise for treating other medical conditions associated with intestinal dysbioses. However, we lack a sufficient understanding of which microbial populations successfully colonize the recipient gut, and the widely used approaches to study the microbial ecology of FMT experiments fail to provide enough resolution to identify populations that are likely responsible for FMT-derived benefits. We used shotgun metagenomics together with assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from fecal samples of a single FMT donor. We then used metagenomic mapping to track the occurrence and distribution patterns of donor MAGs in two FMT recipients. Our analyses revealed that 22% of the 92 highly complete bacterial MAGs that we identified from the donor successfully colonized and remained abundant in two recipients for at least 8 weeks. Most MAGs with a high colonization rate belonged to the order Bacteroidales. The vast majority of those that lacked evidence of colonization belonged to the order Clostridiales, and colonization success was negatively correlated with the number of genes related to sporulation. Our analysis of 151 publicly available gut metagenomes showed that the donor MAGs that colonized both recipients were prevalent, and the ones that colonized neither were rare across the participants of the Human Microbiome Project. Although our dataset showed a link between taxonomy and the colonization ability of a given MAG, we also identified MAGs that belong to the same taxon with different colonization properties, highlighting the importance of an appropriate level of resolution to explore the functional basis of colonization and to identify targets for cultivation, hypothesis generation, and testing in model systems. The analytical strategy adopted in our study can provide genomic insights into bacterial populations that may be critical to the efficacy of FMT due to their success in gut colonization and metabolic properties, and guide cultivation efforts to investigate mechanistic underpinnings of this procedure beyond associations.
  • Preprint
    Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation
    ( 2009-03-13) Antonopoulos, Dionysios A. ; Huse, Susan M. ; Morrison, Hilary G. ; Schmidt, Thomas M. ; Sogin, Mitchell L. ; Young, Vincent B.
    Shifts in microbial communities are implicated in the pathogenesis of a number of gastrointestinal diseases, but we have limited understanding of the mechanisms that lead to altered community structures. One difficulty with studying these mechanisms in human subjects is the inherent baseline variability of the microbiota in different individuals that arise due to varying life histories. To try and overcome this baseline variability we employed a mouse model to control host genotype, diet and other possible influences on the microbiota. This allowed us to determine if the indigenous microbiota in such mice had a stable baseline community structure and whether this community exhibited a consistent response following antibiotic administration. We employed a tag sequencing strategy targeting the V6 hypervariable region of the bacterial small-subunit (16S) ribosomal RNA combined with massively parallel sequencing to determine the community structure of the gut microbiota. Inbred mice in a controlled environment harbored a reproducible baseline community that was significantly impacted by antibiotic administration. The ability of the gut microbial community to recover to baseline following cessation of antibiotic administration varied according to the antibiotic regimen administered. Severe antibiotic pressure resulted in reproducible long-lasting alterations in the gut microbial community including a decrease in overall diversity. The finding of stereotypic responses of the indigenous microbiota to ecologic stress implies that a better understanding of the factors that govern community structure could lead to strategies for the intentional manipulation of this ecosystem to preserve or restore a healthy microbiota.
  • Article
    A novel conjugative transposon carrying an autonomously amplified plasmid
    (American Society for Microbiology, 2024-01-23) Vineis, Joseph H. ; Reznikoff, William S. ; Antonopoulos, Dionysios A. ; Koval, Jason ; Chang, Eugene B. ; Fallon, Bailey R. ; Paul, Blair G. ; Morrison, Hilary G. ; Sogin, Mitchell L.
    Tetracyclines serve as broad-spectrum antibiotics to treat bacterial infections. The discovery of new tetracycline resistance genes has led to new questions about the underlying mechanisms of resistance, gene transfer, and their relevance to human health. We tracked changes in the abundance of a 55-kbp conjugative transposon (CTn214) carrying tetQ, a tetracycline resistance gene, within a Bacteroides fragilis metagenome-assembled genome derived from shotgun sequencing of microbial DNA extracted from the ileal pouch of a patient with ulcerative colitis. The mapping of metagenomic reads to CTn214 revealed the multi-copy nature of a 17,044-nt region containing tetQ in samples collected during inflammation and uninflamed visits. B. fragilis cultivars isolated from the same patient during periods of inflammation harbored CTn214 integrated into the chromosome or both a circular, multi-copy, extrachromosomal region of the CTn214 containing tetQ and the corresponding integrated form. The tetracycline-dependent mechanism for the transmission of CTn214 is nearly identical to a common conjugative transposon found in the genome of B. fragilis (CTnDOT), but the autonomously amplified nature of a circular 17,044-nt region of CTn214 that codes for tetQ and the integration of the same sequence in the linear chromosome within the same cell is a novel observation. Genome and transcriptome sequencing of B. fragilis cultivars grown under different concentrations of tetracycline and ciprofloxacin indicates that tetQ in strains containing the circular form remains actively expressed regardless of treatment, while the expression of tetQ in strains containing the linear form increases only in the presence of tetracycline.