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Impaired Innate Immune Function Associated with Fecal Supernatant from Crohn's Disease Patients: Insights into Potential Pathogenic Role of the Microbiome

Meelu, Parool PhD*; Marin, Romela BS*; Clish, Clary PhD; Zella, Garret MD; Cox, Stephen PhD§; Yajnik, Vijay MD*; Nguyen, Deanna D. MD*; Korzenik, Joshua R. MD

doi: 10.1097/MIB.0000000000000081
Original Basic Science Articles

Background: Although a dysbiosis of the intestinal microbiome plays a role in the pathogenesis of Crohn's disease (CD), the functional implication is unclear. We sought to determine the influence of fecal supernatant from patients with CD on innate immune function in neutrophil, macrophage, and epithelial cells. Metabolomic analysis was subsequently performed in an attempt to identify potential compounds responsible for the effects identified.

Methods: In the fecal samples from 11 pediatric patients with CD and 10 healthy controls, 16S ribosomal and metabolomic analyses were performed. We evaluated the effect of preincubation with fecal supernatant on neutrophil, macrophage, epithelial cell survival, superoxide production, bacterial invasion, and/or bactericidal function using gentamicin protection assay. Ten substances identified as most elevated in CD compared with control samples by metabolomic analysis were similarly tested for effect on bactericidal function.

Results: There were no statistically significant differences in microbial membership in fecal samples from patients with CD compared with healthy controls. However, bactericidal function was impaired in neutrophils and monocytes preincubated with supernatant from fecal samples from patients with CD. Although levels of many metabolites were noted to be altered in samples from patients with CD, the combination of the 10 most elevated compounds failed to demonstrate any effect on neutrophil bactericidal capacity.

Conclusions: Fecal supernatant from patients with CD impairs intracellular bactericidal activity in neutrophils and macrophages. The functional consequences of the intestinal microbiome and its associated secreted products on innate immune function may be more critical than microbial membership in understanding the pathophysiology of CD.

Article first published online 2 June 2014.

*Gastrointestinal Unit, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts;

Broad Institute, Cambridge, Massachusetts;

Division of Gastroenterology and Nutrition, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts;

§Research and Testing Laboratory, Lubbock, Texas; and

Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts.

Reprints: Joshua R. Korzenik, MD, BWH Crohn's and Colitis Center, 75 Francis Street, Boston, MA 02115 (e-mail: jkorzenik@partners.org).

Funding was generously supported by the Benedict Foundation.

The authors has no conflicts of interest to disclose.

Received March 19, 2014

Accepted April 17, 2014

© Crohn's & Colitis Foundation of America, Inc.
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