For IBD, Bugs and Genes Are the Name of the Game

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Science Translational Medicine  23 Jul 2014:
Vol. 6, Issue 246, pp. 246ec126
DOI: 10.1126/scitranslmed.3009812

Researchers working to understand inflammatory bowel disease (IBD) are like chess masters playing simultaneous games. Indeed, host genetic factors, microbial flora, and environmental cues are critical to the pathogenesis of IBD. However, studying these factors in isolation provides a fragmented snapshot because it ignores the cross-talk that occurs along the digestive tract. Now, Haberman et al. not only provide an elegant framework to collect, analyze, and interpret this type of multilevel data, they also offer novel insights into the biology of IBD that may have direct clinical implications.

The location and nature of IBD ulcerations are helpful to distinguish the two main forms of IBD. Whereas ulcerative colitis (UC) lesions are restricted to the mucosa of the colon/rectum, those of Crohn’s disease (CD) are not as superficial and occur anywhere along the digestive tract. The authors focused their efforts on the terminal ileum because it harbors the bulk of the mucosal immune system. Four types of pediatric patients were studied: those with CD with ileal lesions, those with CD or UC with colonic lesions, or asymptomatic controls. Ileal tissue obtained at biopsy was used for diagnostic pathology and RNA signatures. At the same time, the ileal microbial flora was sampled to establish patient-specific microorganism profiles. Because of the large sample size (n = 359), both discovery and validation cohorts were included by design.

Specific ileal gene expression and microbial profiles were identified that were shared by all CD patients (with or without ileal lesions). What’s more, several gene/microbe dyads were highly correlated when IBD samples were compared with controls. For example, decreased expression of apolipoprotein A1 (APOA1) was consistently noted in CD samples that were abnormally poor in bacteria of a specific phylum, the Firmicutes. Remarkably, a clinical prediction model based only on clinical parameters was substantially improved by inclusion of APOA1 gene expression and microbial flora data.

These results suggest that in CD, the terminal ileum plays a central role in modulating the pathologic immune system activation. Integration of these findings into clinical prediction algorithms may eventually also lead to improved clinical care. Further studies will, however, be necessary to substantiate whether the strong associations uncovered translate into a bona fide causal relationship.

Y. Haberman et al., Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest., published online 8 July 2014 (10.1172/JCI75436). [PubMed]

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