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Microbiota Separation and C-reactive Protein Elevation in Treatment-naïve Pediatric Granulomatous Crohn Disease

Kellermayer, Richard*; Mir, Sabina A.V.*; Nagy-Szakal, Dorottya*; Cox, Stephen B.; Dowd, Scot E.; Kaplan, Jess L.§; Sun, Yan; Reddy, Sahna*; Bronsky, Jiri||; Winter, Harland S.§

Journal of Pediatric Gastroenterology & Nutrition: September 2012 - Volume 55 - Issue 3 - p 243–250
doi: 10.1097/MPG.0b013e3182617c16
Rapid Communications

Objectives: In patients with inflammatory bowel diseases (IBDs), the presence of noncaseating mucosal granuloma is sufficient for diagnosing Crohn disease (CD) and may represent a specific immune response or microbial-host interaction. The cause of granulomas in CD is unknown and their association with the intestinal microbiota has not been addressed with high-throughput methodologies.

Methods: The mucosal microbiota from 3 different pediatric centers was studied with 454 pyrosequencing of the bacterial 16S rRNA gene and the fungal small subunit (SSU) ribosomal region in transverse colonic biopsy specimens from 26 controls and 15 treatment-naïve pediatric CD cases. Mycobacterium avium subspecies paratuberculosis (MAP) was tested with real-time polymerase chain reaction. The correlation of granulomatous inflammation with C-reactive protein was expanded to 86 treatment-naïve CD cases.

Results: The CD microbiota separated from controls by distance-based redundancy analysis (P = 0.035). Mucosal granulomata found in any portion of the intestinal tract associated with an augmented colonic bacterial microbiota divergence (P = 0.013). The granuloma-based microbiota separation persisted even when research center bias was eliminated (P = 0.04). Decreased Roseburia and Ruminococcus in granulomatous CD were important in this separation; however, principal coordinates analysis did not reveal partitioning of the groups. CRP levels >1 mg/dL predicted the presence of mucosal granulomata (odds ratio 28 [6–134.32]; 73% sensitivity, 91% specificity).

Conclusions: Granulomatous CD associates with microbiota separation and C-reactive protein elevation in treatment-naïve children; however, overall dysbiosis in pediatric CD appears rather limited. Geographical/center bias should be accounted for in future multicenter microbiota studies.

*Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Texas Children's Hospital, Houston

Research and Testing Laboratory, Lubbock

Molecular Research (MR DNA), Shallowater, TX

§Department of Pediatrics, MassGeneral Hospital for Children, Boston, MA

||Department of Pediatrics, Second Medical Faculty, Charles University and University Hospital Motol, Prague, Czech Republic.

Address correspondence and reprint requests to Richard Kellermayer, MD, PhD, Section of Pediatric Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, 6621 Fannin St, CC1010.00, Houston, TX 77030-2399 (e-mail:

Received 2 March, 2012

Accepted 25 May, 2012

Microbial sequences were uploaded to the EMBL Nucleotide Sequence Database under the accession number SRA048320.1

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R.K. was supported in part by the Broad Medical Research Program, the Broad Foundation (IBD-0252), the Child Health Research Career Development Agency of the Baylor College of Medicine (NIH # 5K12 HD041648), and Public Health Service grant DK56338, funding the Texas Medical Center Digestive Diseases Center, which supported the Baylor biorepository as well. The biorepository of MassGeneral Hospital was supported by the Pediatric IBD Foundation, and H.W. was supported in part by philanthropic support from Martin Schlaff. The other authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN