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Semisynthetic Diet Ameliorates Crohn’s Disease–Like Ileitis in TNFΔARE/WT Mice Through Antigen-Independent Mechanisms of Gluten

Wagner, Stefan J. MSc*; Schmidt, Annemarie MSc*; Effenberger, Manuel J. P. BSc*; Gruber, Lisa MSc*; Danier, Jürgen MSc; Haller, Dirk PhD*

doi: 10.1097/MIB.0b013e318281f573
Original Basic Science Article

Background: Enteral nutrition is used to treat a subset of patients with inflammatory bowel diseases. Because dietary factors may contribute to an aggressive immune response toward the intestinal microbiota in the disease susceptible host, we used TNFΔARE/WT mice to study the therapeutic effect of a semisynthetic experimental diet in the pathogenesis of Crohn’s disease (CD)–like inflammation in the ileum.

Methods: TNFΔARE/WT mice were fed chow and experimental diets partially fortified with gluten in a dose and time-dependent manner. Histopathology, markers of inflammation, intraepithelial lymphocytes phenotypes, and antigen-specific reactivation of CD4+ T cells were determined.

Results: TNFΔARE/WT mice being transferred to an experimental diet with 7 but not with 10 or 14 weeks of age were protected from development of Crohn’s disease–like ileitis. Although disease-related CD8αβ+ intraepithelial lymphocytes were increased irrespective of dietary intervention, the protective effect of experimental diet was associated with decreased expression of inflammation markers in ileal tissues. In addition, CD4+ T-cell reactivation in bacterial antigen-primed dendritic cell cocultures was not altered between semisynthetic and chow diet-fed TNFΔARE/WT mice, suggesting bacteria-independent mechanisms. Most importantly, gluten-fortified experimental diet induced chronic ileitis in TNFΔARE/WT mice, despite the fact that gluten-derived peptides failed to induce CD4+ T-cell activation. Reduced occludin expression levels suggest a negative role of gluten-fortified experimental diet on intestinal barrier integrity.

Conclusions: Crohn’s disease–like ileitis can be prevented at early stages of disease development using a semisynthetic experimental diet. Gluten was identified as antigen-independent dietary factor relevant for the induction of chronic inflammation in the small intestine of TNFΔARE/WT mice.

Article first published online 4 April 2013Supplemental Digital Content is Available in the Text.

*ZIEL Research Center for Nutrition and Food Science, CDD Center for Diet and Disease, Technische Universität München, Freising-Weihenstephan, Germany; and

BIOANALYTIK Weihenstephan, ZIEL Research Center for Nutrition and Food Science, Technische Universität München, Freising-Weihenstephan, Germany.

Reprints: Dirk Haller, PhD, Technische Universität München, Gregor-Mendel-Str. 2, 85350 Freising-Weihenstephan, Germany (e-mail:

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received October 01, 2012

Accepted October 16, 2012

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