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Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

Xochitl C Morgan1, Timothy L Tickle12, Harry Sokol345, Dirk Gevers2, Kathryn L Devaney34, Doyle V Ward2, Joshua A Reyes1, Samir A Shah6, Neal LeLeiko6, Scott B Snapper7, Athos Bousvaros7, Joshua Korzenik37, Bruce E Sands8, Ramnik J Xavier234 and Curtis Huttenhower12*

Author Affiliations

1 Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA

2 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA

3 Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

4 Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

5 Current address: Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine and UPMC University of Paris, Paris, 75012, France

6 Division of Pediatric Gastroenterology, Hasbro Children's Hospital, The Warren Alpert School of Medicine at Brown University, Providence, RI 02903, USA

7 Gastrointestinal Unit, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA

8 Department of Gastroenterology, Mount Sinai School of Medicine, New York, NY 10029, USA

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Genome Biology 2012, 13:R79  doi:10.1186/gb-2012-13-9-r79

Published: 26 September 2012

Abstract

Background

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.

Results

Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways.

Conclusions

This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.