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Linking microbial genes to plasma and stool metabolites uncovers host-microbial interactions underlying ulcerative colitis disease course.
Schirmer, Melanie; Strazar, Martin; Avila-Pacheco, Julian; Rojas-Tapias, Daniel F; Brown, Eric M; Temple, Emily; Deik, Amy; Bullock, Kevin; Jeanfavre, Sarah; Pierce, Kerry; Jin, Shen; Invernizzi, Rachele; Pust, Marie-Madlen; Costliow, Zach; Mack, David R; Griffiths, Anne M; Walters, Thomas; Boyle, Brendan M; Kugathasan, Subra; Vlamakis, Hera; Hyams, Jeffrey; Denson, Lee; Clish, Clary B; Xavier, Ramnik J.
Affiliation
  • Schirmer M; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Microbiome Data Integration, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany; ZIEL - Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany. Electronic a
  • Strazar M; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Avila-Pacheco J; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Rojas-Tapias DF; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Brown EM; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Temple E; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Deik A; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Bullock K; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Jeanfavre S; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pierce K; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Jin S; Translational Microbiome Data Integration, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
  • Invernizzi R; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pust MM; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • Costliow Z; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Mack DR; Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • Griffiths AM; Division of Gastroenterology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Walters T; Division of Gastroenterology, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
  • Boyle BM; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH 43205, USA.
  • Kugathasan S; Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
  • Vlamakis H; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Hyams J; Connecticut Children's Medical Center, Division of Digestive Diseases, Hartford, CT 06106, USA.
  • Denson L; Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • Clish CB; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Xavier RJ; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts
Cell Host Microbe ; 32(2): 209-226.e7, 2024 Feb 14.
Article in En | MEDLINE | ID: mdl-38215740
ABSTRACT
Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colitis, Ulcerative / Gastrointestinal Microbiome Type of study: Prognostic_studies Limits: Child / Humans Language: En Journal: Cell Host Microbe Journal subject: MICROBIOLOGIA Year: 2024 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colitis, Ulcerative / Gastrointestinal Microbiome Type of study: Prognostic_studies Limits: Child / Humans Language: En Journal: Cell Host Microbe Journal subject: MICROBIOLOGIA Year: 2024 Document type: Article