Abstract

Metabolic Functions of Gut Microbes Associate With Efficacy of Tumor Necrosis Factor Antagonists in Patients with Inflammatory Bowel Diseases

Aden K1, Rehman A2, Waschina S3, Pan WH2, Walker A4, Lucio M4, Nunez AM2, Bharti R2, Zimmerman J3, Bethge J5, Schulte B5, Schulte D5, Franke A2, Nikolaus S5, Schroeder JO5, Vandeputte D6, Raes J6, Szymczak S7, Waetzig GH8, Zeuner R5, Schmitt-Kopplin P4, Kaleta C3, Schreiber S9, Rosenstiel P10. Gastroenterology. 2019 Jul 18. pii: S0016-5085(19)41118-9. doi: 10.1053/j.gastro.2019.07.025. [Epub ahead of print]

 
     

Author information

Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

Institute for Experimental Medicine, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

Research Unit Analytical BioGeoChemistry, Helmholtz ZentrumMünchen, German Research Centre for Environmental Health (GmbH), Neuherberg, Germany.

Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

VIB-KU Leuven Center for Microbiology, Campus Gasthuisberg, 3000 LEUVEN, Belgium.

Institute of Medical Informatics and Statistics, University of Kiel, Germany.

CONARIS Research Institute AG, Kiel, Germany.

Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Internal Medicine I., Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: s.schreiber@mucosa.de.

10 Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: p.rosenstiel@mucosa.de.

Abstract

BACKGROUND & AIMS: Altered interactions between the mucosal immune system and intestinal microbiota contribute to pathogenesis of inflammatory bowel diseases (IBD). It is not clear how inhibitors of cytokines, such as antagonists of tumor necrosis factor (anti-TNF), affect the intestinal microbiome. We investigated the effects of anti-TNF agents on gut microbe community structure and function in a longitudinal 2-step study of patients with IBD. We correlated our findings with outcomes of treatment and investigated patterns of metabolites in fecal samples before and after anti-TNF therapy.

METHODS: We performed a prospective study of 2 cohorts of patients in Germany; the discovery cohort comprised 12 patients with IBD, 17 patients with rheumatic disease, and 19 healthy individuals (controls); fecal samples were collected at baseline and 2, 6, and 30 weeks after induction of anti-TNF therapy. The validation cohort comprised 23 patients with IBD treated with anti-TNF or vedolizumab (anti-α4β7 integrin) and 99 healthy controls; fecal samples were collected at baseline and at weeks 2, 6, and 14. Fecal microbiota were analyzed by V3-V4 16S rRNA gene amplicon sequencing. Clinical response and remission were determined by clinical disease activity scores. Metabolic network reconstruction and associated fecal metabolite level inference was performed in silico using the AGORA resource. Metabolomic analyses of fecal samples from a subset of patients were performed to validate metabolites associated with treatment outcomes.

RESULTS: Anti-TNF therapy shifted the diversity of fecal microbiota in patients with IBD, but not with rheumatic disease, toward that of controls. Across timepoints, diversity indices did not vary significantly between patients with IBD who did or did not achieve clinical remission after therapy. In contrast, in silico modeling of metabolic interactions between gut microbes found metabolite exchange to be significantly reduced at baseline in fecal samples from patients with IBD and to be associated with later clinical remission. Predicted levels of butyrate and substrates involved in butyrate synthesis (ethanol or acetaldehyde) were significantly associated with clinical remission following anti-TNF therapy, verified by fecal metabolomic analyses.

CONCLUSIONS: Metabolic network reconstruction and assessment of metabolic profiles of fecal samples might be used to identify patients with IBD likely to achieve clinical remission following anti-TNF therapy and increase our understanding of the heterogeneity of IBD

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