Browsing by Author "Rosh, Joel"

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    Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
    (Elsevier, 2018-10-10) Schirmer, Melanie; Denson, Lee; Vlamakis, Hera; Franzosa, Eric A.; Thomas, Sonia; Gotman, Nathan M.; Rufo, Paul; Baker, Susan S.; Sauer, Cary; Markowitz, James; Pfefferkorn, Marian; Oliva-Hemker, Maria; Rosh, Joel; Otley, Anthony; Boyle, Brendan; Mack, David; Baldassano, Robert; Keljo, David; LeLeiko, Neal; Heyman, Melvin; Griffiths, Anne; Patel, Ashish S.; Noe, Joshua; Kugathasan, Subra; Walters, Thomas; Huttenhower, Curtis; Hyams, Jeffrey; Xavier, Ramnik J.; Medicine, School of Medicine
    Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care
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    Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease
    (Oxford University Press, 2020-08-08) Haberman, Yael; Minar, Phillip; Karns, Rebekah; Dexheimer, Phillip J.; Ghandikota, Sudhir; Tegge, Samuel; Shapiro, Daniel; Shuler, Brianne; Venkateswaran, Suresh; Braun, Tzipi; Ta, Allison; Walters, Thomas D.; Baldassano, Robert N.; Noe, Joshua D.; Rosh, Joel; Markowitz, James; Dotson, Jennifer L.; Mack, David R.; Kellermayer, Richard; Griffiths, Anne M.; Heyman, Melvin B.; Baker, Susan S.; Moulton, Dedrick; Patel, Ashish S.; Gulati, Ajay S.; Steiner, Steven J.; LeLeiko, Neal; Otley, Anthony; Oliva-Hemker, Maria; Ziring, David; Gokhale, Ranjana; Kim, Sandra; Guthery, Stephen L.; Cohen, Stanley A.; Snapper, Scott; Aronow, Bruce J.; Stephens, Michael; Gibson, Greg; Dillman, Jonathan R.; Dubinsky, Marla; Hyams, Jeffrey S.; Kugathasan, Subra; Jegga, Anil G.; Denson, Lee A.; Pediatrics, School of Medicine
    Background and aims: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.