Dataset Information

The role of in utero endotoxin exposure in the development of inflammatory bowel disease in mice.

ABSTRACT:

Problem

Although early environmental influences are thought to influence the development of inflammatory bowel disease (IBD), little is known about the role of the in utero environment on subsequent IBD risk. We hypothesized that prenatal exposure to bacterial lipopolysaccharide (LPS) could modify the subsequent development of dextran sulfate sodium (DSS)-induced ulcerative colitis in adulthood by influencing the associated cellular and immune response.

Method of study

To test this hypothesis, we exposed developing mice in utero to LPS or saline (PBS) at E17.5, and then induced colitis at 5 weeks. We then assessed colitis severity and effects on the microbiome. In order to define the developmental impact of any potential LPS effect, we also exposed 1-week-old mice to either LPS or saline before inducing colitis at 5 weeks.

Results

Mice that had been exposed to LPS but not saline in utero were protected from subsequent colitis development, and their intestinal barrier integrity and tight junction expression distribution were similar to that of control mice that were not exposed to DSS. By contrast, mice exposed to either LPS or saline at day 7 of life all developed severe colitis upon subsequent DSS exposure.

Conclusion

These results identify an informative time window during fetal development during which exposure to an otherwise pro-inflammatory agent like LPS protects against an inflammatory disease in adulthood.

SUBMITTER: Banfield E

PROVIDER: S-EPMC7722031 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPeroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR gamma in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD.MethodsPPAR gamma flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays.ResultsThe deficiency of PPAR gamma in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+ FoxP3+ regulatory T cells (Treg) and IL10+ CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR gamma in T cells.ConclusionsThe expression of PPAR gamma in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites.