Maternal High-fat Diet Accelerates Development of Crohn's Disease-like Ileitis in TNFΔARE/WT Offspring

Gruber L1, Hemmerling J, Schüppel V, Müller M, Boekschoten MV, Haller D. Inflamm Bowel Dis. 2015 Sep;21(9):2016-25. doi: 10.1097/MIB.0000000000000465.
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1*Technische Universität München, Chair of Nutrition and Immunology, Munich, Germany; †ZIEL-Institute for Food & Health, Technische Universität München, Munich, Germany; ‡Norwich Medical School, University of East Anglia, Norwich, United Kingdom; and §Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.


BACKGROUND: Maternal high-fat diet (HFD) and obesity increases the risk of the offspring to develop inflammatory processes in various organs including the gut. We hypothesized that maternal diet-induced obesity programs the fetal gut towards inflammation in a mouse model of genetically-driven Crohn's disease (CD)-like ileitis.

METHODS: TNF (WT) and TNF (ARE) dams were fed an experimental control diet (CTRLD; 13 kJ% fat) or HFD (48 kJ%). Offspring mice were fed CTRLD or HFD at 4 weeks of age. Metabolic characteristics and severity of CD-like ileitis was assessed in 8- and 12-week old WT and ARE offspring measuring tissue histopathology and markers of inflammation in the distal ileum as well as plasma cytokine and LPS levels. To study prenatal effects, we laser microdissected fetal intestinal epithelial cells at 17.5 days postconception and performed microarray-based global gene expression analysis.

RESULTS: Maternal HFD significantly accelerated the severity of CD-like ileitis in HFD-fed ARE mice at early life stages associated with increased mucosal neutrophil infiltration, Il12p40 expression, and portal vein LPS levels. In contrast to WT mice, metabolic characteristics of ARE offspring were not affected by maternal HFD. Gene expression patterns in fetal intestinal epithelial cells of ARE mice remained largely unchanged under conditions of maternal diet-induced obesity suggesting that the positive association of intestinal inflammation, portal vein endotoxemia, and plasma TNF levels is independent of prenatal conditioning of the gut epithelium.

CONCLUSIONS: Maternal HFD promotes the early onset of severe CD-like ileitis in genetically susceptible offspring independent of metabolic alterations.

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