Fecal microbiota profiles in treatment-naïve pediatric inflammatory bowel disease – associations with disease phenotype, treatment, and outcome

Abstract

Purpose

Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naïve IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes.

Patients and methods

Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohn’s disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map^™ technology at diagnosis and after therapy in IBD patients.

Results

Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (P<0.001). Only Prevotella was more abundant in patients (P<0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (P<0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (P<0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (P<0.01), and nonmucosal healing (P<0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (P<0.03). After therapy, IBD patients had unchanged dysbiosis.

Conclusion

Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individualization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing.

Keywords:

• dysbiosis
• Crohn’s disease
• ulcerative colitis
• Proteobacteria
• biologic therapy
• Faecalibacterium prausnitzii

Supplementary material

Table S1 List of phyla and bacterial names of the GA-Map^™ technology markers

Acknowledgments

The authors thank Genetic Analysis AS, Oslo, Norway for conducting the analyses. A special thanks to all patients and parents who contributed to the study, to our colleagues and collaborators who were of assistance in collecting and analyzing the materials, and to the IBD Character Consortium for contributions in study conception and design: Jack Satsangi, Rahul Kalla, Alex T Adams, Elaine R Nimmo, Hazel E Drummond, Ray K Boyapati, Nicholas T Ventham, Nicholas A Kennedy, David C Wilson, Charles W Lees, Colin L Noble, Ian D Arnott, Gwo-Tzer Ho, Alan G Shand, Kate R O’Leary, Jørgen Jahnsen, Morten H Vatn, Tone M Tannæs, Aina EF Moen, Petr Ricanek, Simen Vatn, Christine Olbjørn, Trond Espen Detlie, Jonas C Lindstrom, Anna Frengen, Panpan You, Janne Sølvernes, Fredrik A Dahl, Gunn S Ekeland, Åsa V Keita, Johan D Söderholm, Henrik Hjortswang, Jonas Halfvarson, Daniel Bergemalm, Fernando Gomollón, Mauro D’Amato, Leif Törkvist, Christina Casén, Magdalena K Karlsson, Fredrik Hjelm, Mats Gullberg, Niklas Nordberg, Anette Ocklind, Erik Pettersson, Daniel Ekman, Mikael Sundell, Eddie Modig, Anne-Clémance Veillard, Renaud Schoemans, Dominique Poncelet, Céline Sabatel, Ivo G Gut, Marta Gut, Simon Heath, Monica Bayes, Angelika Merkel, and Ferdinando Bonfiglio. The study was partly funded by the EU FP7-Health-2012 project, IBD Character. Grant agreement no: 305676 (http://cordis.europa.eu/project/rcn/106191_en.html).

Author contributions

All authors have made substantial contributions in conception and study design, acquisition of data, or analysis and interpretation of data and taken part in drafting the article or revising it critically for important intellectual content. All authors have seen and approved the final version of the manuscript submitted to the journal and agree to be accountable for all aspects of the work. CO and GP contributed in planning the study, collecting data, analyzing, and interpreting the results and drafting the article. MCS, BN, ETE, and MHV contributed in planning the study, analyzing and interpreting the results, and drafting the article.

Disclosure

Christine Olbjørn is a member of the advisory board of AbbVie and has received speaker honoraria from AbbVie, Nutricia, Norgine, Tillotts Pharma, and Mead Johnson. Morten H Vatn has been an advisor for Genetic Analysis and organizer of the International Advisory Board of Genetic Analysis, a member of the advisory board for Tillotts Pharma, and has received speaker honoraria from AstraZeneca, AbbVie, MSD, and Falk. Gøri Perminow is a member of the advisory board of AbbVie and is a member of the steering committee in the IBSEN III study. The IBSEN III study has received an Investigator Initiated Research Grant from Takeda and nonrestricted research grants from Ferring Pharmaceuticals and Tillotts Pharma. Christina Casén and Magdalena K Karlsson are employed by Genetic Analysis. The authors report no other conflicts of interest in this work.