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Maternal High-fat Diet Accelerates Development of Crohn's Disease-like Ileitis in TNFΔARE/WT Offspring
Lisa Gruber1, Jana Hemmerling, Valentina Schüppel
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.
Insights
Maternal high-fat diet (HFD) exacerbates Crohn's disease-like ileitis in genetically susceptible offspring. This effect occurs early in life and is independent of metabolic changes, highlighting the impact of prenatal nutrition on inflammatory conditions.
Area of Science:
- Gastroenterology
- Immunology
- Nutritional Science
Background:
- Maternal high-fat diet (HFD) and obesity are linked to increased offspring risk of inflammatory conditions, particularly in the gut.
- Genetically driven Crohn's disease (CD)-like ileitis models are crucial for understanding disease pathogenesis.
- Prenatal exposure to maternal obesity may program the fetal gut for inflammation.
Purpose of the Study:
- To investigate if maternal diet-induced obesity programs the fetal gut towards inflammation.
- To assess the impact of maternal HFD on the development of CD-like ileitis in offspring.
- To determine the role of prenatal gene expression in the offspring's susceptibility to inflammation.
Main Methods:
- Utilized TNF(WT/WT) and TNF(ΔARE/WT) mouse models, feeding dams control or HFD.
- Assessed offspring ileitis severity, histopathology, inflammation markers, and plasma cytokines/LPS.
- Analyzed fetal intestinal epithelial cell gene expression via microarrays.
Main Results:
- Maternal HFD accelerated CD-like ileitis in HFD-fed ARE offspring, marked by increased neutrophil infiltration and LPS levels.
- Offspring metabolic characteristics were unaffected by maternal HFD in contrast to WT mice.
- Fetal gene expression in ARE mice showed minimal changes, indicating inflammation onset is independent of prenatal gut programming.
Conclusions:
- Maternal HFD promotes early-onset, severe CD-like ileitis in genetically susceptible offspring.
- The observed inflammation is independent of metabolic alterations in the offspring.
- Prenatal nutritional environment significantly influences the development of inflammatory bowel disease phenotypes.
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/WT) and TNF(ΔARE/WT) 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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