Linking microbial genes to plasma and stool metabolites uncovers host-microbial interactions underlying ulcerative colitis disease course.

Veillonella parvula culturomics metabolomics metagenomics microbiome multiomics data integration nitrate respiration thiopurines tryptophan metabolism ulcerative colitis

Journal

Cell host & microbe
ISSN: 1934-6069
Titre abrégé: Cell Host Microbe
Pays: United States
ID NLM: 101302316

Informations de publication

Date de publication:
04 Jan 2024
Historique:
received: 13 03 2023
revised: 08 11 2023
accepted: 15 12 2023
medline: 13 1 2024
pubmed: 13 1 2024
entrez: 12 1 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.chom.2023.12.013 PMID: 38215740
pubmed: 38215740
pii: S1931-3128(23)00508-5
doi: 10.1016/j.chom.2023.12.013
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests R.J.X. is a co-founder of Celsius Therapeutics and Jnana Therapeutics, board director at MoonLake Immunotherapeutics, and consultant to Nestlé. D.R.M. is a co-founder of MedBiome Inc.

Auteurs

Melanie 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 address: melanie.schirmer@tum.de.

Martin Stražar (M)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Julian Avila-Pacheco (J)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Daniel F Rojas-Tapias (DF)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Eric M 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.

Emily Temple (E)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Amy Deik (A)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Kevin Bullock (K)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Sarah Jeanfavre (S)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Kerry Pierce (K)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Shen Jin (S)

Translational Microbiome Data Integration, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.

Rachele Invernizzi (R)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Marie-Madlen 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.

Zach Costliow (Z)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

David R Mack (DR)

Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, ON K1H 8L1, Canada.

Anne M Griffiths (AM)

Division of Gastroenterology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Thomas Walters (T)

Division of Gastroenterology, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Brendan M Boyle (BM)

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Subra Kugathasan (S)

Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.

Hera Vlamakis (H)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Jeffrey Hyams (J)

Connecticut Children's Medical Center, Division of Digestive Diseases, Hartford, CT 06106, USA.

Lee Denson (L)

Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

Clary B Clish (CB)

The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Ramnik J 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 Institute of Technology, Cambridge, MA 02139, USA. Electronic address: rxavier@broadinstitute.org.

Classifications MeSH