Chang Eugene B.

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Chang
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Eugene B.
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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
    Bile acid fitness determinants of a Bacteroides fragilis isolate from a human pouchitis patient
    (American Society for Microbiology, 2023-12-08) Fiebi, Aretha ; Schnizlein, Matthew K. ; Pena-Rivera, Selymar ; Trigodet, Florian ; Dubey, Abhishek Anil ; Hennessy, Miette K. ; Basu, Anindita ; Pott, Sebastian ; Dalal, Sushila R. ; Rubin, David ; Sogin, Mitchell L. ; Eren, A. Murat ; Chang, Eugene B. ; Crosson, Sean
    Bacteroides fragilis comprises 1%–5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated a B. fragilis strain from a UC patient with pouch inflammation (i.e., pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impact B. fragilis fitness in DC and crude bile. Treatment of B. fragilis with a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems, and down-regulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further defined B. fragilis genes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of a B. fragilis bile response and genetic determinants of its fitness in DC and crude bile.
  • Article
    Microbially catalyzed conjugation of GABA and tyramine to bile acids
    (American Society for Microbiology, 2024-01-04) Mullowney, Michael W. ; Fiebig, Aretha ; Schnizlein, Matthew K. ; McMillin, Mary ; Rose, Amber R. ; Koval, Jason ; Rubin, David T. ; Dalal, Sushila R. ; Sogin, Mitchell L. ; Chang, Eugene B. ; Sidebottom, Ashley M. ; Crosson, Sean
    Bile acids (BAs) are cholesterol-derived molecules that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence physiology of the gut microbiota. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate BAs to other amine classes. Here, we show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended this analysis to other human gut isolates and identified species that are competent to conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and BA-tyramine amides in human stool. A longitudinal metabolomic analysis of J-pouch contents of the patient from whom B. fragilis P207 was isolated revealed highly reduced levels of secondary bile acids and a shifting BA amide profile before, during, and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to GABA and tyramine and demonstrates that these molecules are present in the human gut.
  • Article
    A cryptic plasmid is among the most numerous genetic elements in the human gut
    (Elsevier, 2024-02-29) Fogarty, Emily C. ; Schechter, Matthew S. ; Lolans, Karen ; Sheahan, Madeline L. ; Veseli, Iva A. ; Moore, Ryan M. ; Kiefl, Evan ; Moody, Thomas ; Rice, Phoebe A. ; Yu, Michael K. ; Mimee, Mark ; Chang, Eugene B. ; Ruscheweyh, Hans-Joachim ; Sunagawa, Shinichi ; McLellan, Sandra L. ; Willis, Amy D. ; Comstock, Laurie E. ; Eren, A. Murat
    Plasmids are extrachromosomal genetic elements that often encode fitness-enhancing features. However, many bacteria carry “cryptic” plasmids that do not confer clear beneficial functions. We identified one such cryptic plasmid, pBI143, which is ubiquitous across industrialized gut microbiomes and is 14 times as numerous as crAssphage, currently established as the most abundant extrachromosomal genetic element in the human gut. The majority of mutations in pBI143 accumulate in specific positions across thousands of metagenomes, indicating strong purifying selection. pBI143 is monoclonal in most individuals, likely due to the priority effect of the version first acquired, often from one’s mother. pBI143 can transfer between Bacteroidales, and although it does not appear to impact bacterial host fitness in vivo, it can transiently acquire additional genetic content. We identified important practical applications of pBI143, including its use in identifying human fecal contamination and its potential as an alternative approach to track human colonic inflammatory states.
  • 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.