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Original research
Specific gut pathobionts escape antibody coating and are enriched during flares in patients with severe Crohn’s disease
  1. Carsten Eriksen1,2,
  2. Niels Banhos Danneskiold-Samsøe3,
  3. Janne Marie Moll1,
  4. Pernille Neve Myers1,
  5. Pi W Bondegaard1,
  6. Simone Vejrum1,
  7. Tine Brodka Hansen1,
  8. Lisbeth Buus Rosholm1,
  9. Philipp Rausch3,4,
  10. Kristine Højgaard Allin2,
  11. Tine Jess2,
  12. Karsten Kristiansen2,3,
  13. John Penders5,
  14. Daisy Jonkers6,
  15. Susanne Brix1
  1. 1Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
  2. 2Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
  3. 3Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark
  4. 4Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  5. 5Department of Medical Microbiology, Infectious Diseases and Infection Prevention, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands
  6. 6Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translation Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
  1. Correspondence to Prof Susanne Brix, Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark; sbrix{at}dtu.dk

Abstract

Objective Patients with Crohn’s disease (CD) exhibit great heterogeneity in disease presentation and treatment responses, where distinct gut bacteria and immune interactions may play part in the yet unresolved disease aetiology. Given the role of antibodies in the barrier defence against microbes, we hypothesised that gut bacterial antibody-coating patterns may influence underlying disease-mediated processes.

Design Absolute and relative single and multicoating of gut bacteria with IgA, IgG1, IgG2, IgG3 and IgG4 in patients with CD and healthy controls were characterised and compared with disease activity. IgG2-coated and non-coated taxa from patients with severe CD were identified, profiled for pathogenic characteristics and monitored for enrichment during active disease across cohorts.

Results Patients with severe CD exhibited higher gut bacterial IgG2-coating. Supervised clustering identified 25 bacteria to be enriched in CD patients with high IgG2-coating. Sorting, sequencing and in silico-based assessments of the virulent potential of IgG2-coated and bulk stool bacteria were performed to evaluate the nature and pathogenicity of IgG2-coated and non-coated bacteria. The analyses demonstrated IgG2-coating of both known pathogenic and non-pathogenic bacteria that co-occurred with two non-coated pathobionts, Campylobacter and Mannheimia. The two non-coated pathobionts exhibited low prevalence, rarely coincided and were strongly enriched during disease flares in patients with CD across independent and geographically distant cohorts.

Conclusion Distinct gut bacterial IgG2-coating was demonstrated in patients with severe CD and during disease flares. Co-occurrence of non-coated pathobionts with IgG2-coated bacteria points to an uncontrolled inflammatory condition in severe CD mediated via escape from antibody coating by two gut pathobionts.

  • Intestinal bowel disease
  • IgG-coating
  • IgA-coating
  • Gut Microbiota
  • Mucosal immunity

Data availability statement

Sequencing data are available in a public, open access repository. Personal individual-level data are not available according to the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR). Sequencing data are publicly available in NCBI Sequence Read Archive under BioProject: PRJNA418765. Analysis software including quality control, taxonomic and functional inference tools are publicly available and referenced as appropriate. Individual-level personally identifiable data from the subjects participating in the cohort cannot be made freely available, to protect the privacy of the participants, in accordance with the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR) that prohibit distribution even in pseudoanonymised form.

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Data availability statement

Sequencing data are available in a public, open access repository. Personal individual-level data are not available according to the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR). Sequencing data are publicly available in NCBI Sequence Read Archive under BioProject: PRJNA418765. Analysis software including quality control, taxonomic and functional inference tools are publicly available and referenced as appropriate. Individual-level personally identifiable data from the subjects participating in the cohort cannot be made freely available, to protect the privacy of the participants, in accordance with the Danish Data Protection Act and European Regulation 2016/679 of the European Parliament and of the Council (GDPR) that prohibit distribution even in pseudoanonymised form.

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Footnotes

  • Twitter @KristineAllin, @PREDICTIBD

  • Contributors Guarantor of the study: SB. Conceptual design of the study and method implementation: CE and SB. Responsible for the NL cohort and fecal 16S rRNA analysis: JP and DJ. Generation of Ig-coating profiles: PWB, SV, TBH and CE. Data analysis: CE supported by JMM, PNM and SB. Statistical support: PR. Sorting of coated bacteria: CE and LBR, supported by SB. Implementation of volume-based method and sequencing of IgG2-coated bacteria: CE supported by NBD-S, KK and SB. Writing of draft manuscript: CE and SB. Critical revision of manuscript: all authors.

  • Funding This research was supported by a scholarship from the Technical University of Denmark (DTU) to CE under supervision of SB, and the Danish National Research Foundation (grant number DNRF148) to TJ, SB is the incumbent of the FII institute Research Chair at DTU in Immune-based Prediction of Disease.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.