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Original research
Ranking microbiome variance in inflammatory bowel disease: a large longitudinal intercontinental study
  1. Adam G Clooney1,2,
  2. Julia Eckenberger1,2,
  3. Emilio Laserna-Mendieta1,2,
  4. Kathryn A Sexton3,
  5. Matthew T Bernstein3,
  6. Kathy Vagianos3,
  7. Michael Sargent3,4,
  8. Feargal J Ryan1,2,
  9. Carthage Moran1,5,
  10. Donal Sheehan1,5,
  11. Roy D Sleator1,6,
  12. Laura E Targownik3,4,
  13. Charles N Bernstein3,4,
  14. Fergus Shanahan1,5,
  15. Marcus J Claesson1,2
  1. 1APC Microbiome Ireland, University College Cork, Cork, Ireland
  2. 2School of Microbiology, University College Cork, Cork, Ireland
  3. 3The University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
  4. 4Section of Gastroenterology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
  5. 5Department of Medicine, University College, Cork, Ireland
  6. 6Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland
  1. Correspondence to Dr Marcus J Claesson, School of Microbiology, University College, Cork T12 YN60, Ireland; M.Claesson{at}


Objective The microbiome contributes to the pathogenesis of inflammatory bowel disease (IBD) but the relative contribution of different lifestyle and environmental factors to the compositional variability of the gut microbiota is unclear.

Design Here, we rank the size effect of disease activity, medications, diet and geographic location of the faecal microbiota composition (16S rRNA gene sequencing) in patients with Crohn’s disease (CD; n=303), ulcerative colitis (UC; n = 228) and controls (n=161), followed longitudinally (at three time points with 16 weeks intervals).

Results Reduced microbiota diversity but increased variability was confirmed in CD and UC compared with controls. Significant compositional differences between diseases, particularly CD, and controls were evident. Longitudinal analyses revealed reduced temporal microbiota stability in IBD, particularly in patients with changes in disease activity. Machine learning separated disease from controls, and active from inactive disease, when consecutive time points were modelled. Geographic location accounted for most of the microbiota variance, second to the presence or absence of CD, followed by history of surgical resection, alcohol consumption and UC diagnosis, medications and diet with most (90.3%) of the compositional variance stochastic or unexplained.

Conclusion The popular concept of precision medicine and rational design of any therapeutic manipulation of the microbiota will have to contend not only with the heterogeneity of the host response, but also with widely differing lifestyles and with much variance still unaccounted for.

  • Crohn's disease
  • ulcerative colitis
  • colonic microflora
  • diet

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  • AGC and JE contributed equally.

  • Contributors MJC, FS, LT and CNB designed and managed the project; AGC, JE and EL-M performed the analyses; FS, CNB, CM and DS provided clinical samples and expertise; AGC, JE, MJC and FS wrote the manuscript; MJC, RDS and FS secured funding. KAS and MTB created and managed the database for Canadian subjects, KV administered the FFQ to Canadian subjects, MS handled the stool samples and measured fCAL in Canadian subjects. AGC and JE contributed equally.

  • Funding This research was supported in part by Science Foundation Ireland (grant numbers SFI/12/RC/2273, 11/SIRG/B2162 and 17/CDA/4765) and European Crohn’s and Colitis Organisation (year 2014).

  • Disclaimer FS is a co-founder of Alimentary Health, Tucana Health (now 4D pharma Cork) and Atlantia Food Clinical Trials. MJC is a co-founder of SeqBiome.

  • Competing interests MTB reports grants and personal fees from AbbVie Canada, grants and personal fees from Janssen Canada, grants and personal fees from Pfizer Canada, grants from Shire Canada, grants and personal fees from Takeda Canada, personal fees from Mylan Pharmaceuticals, other from AbbVie, Janssen, Pfizer, Boerhinger Ingelheim, Celgene, outside the submitted work; FS reports other from Alimentary Health/Precision Biotics, other from 4D pharma, Cork, other from Atlantia Food Clinical Trials, personal fees from Kaleido Biosciences, outside the submitted work; MJC reports personal fees from Mars PetCare, other from Second Genome, outside the submitted work.

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

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Cork hospitals’ research ethics committee and the University of Manitoba Health Research Board.

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

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Sequence data are available at NCBI SRA PRJNA414072.

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