Abstract
BackgroundInappropriate responses to normal intestinal bacteria may be involved in the development of Inflammatory Bowel Diseases (IBD, e.g. Crohn's Disease (CD), Ulcerative Colitis (UC)) and variations in the host genome may mediate this process. IL-10 gene-deficient (Il10-/-) mice develop CD-like colitis mainly in the colon, in part due to inappropriate responses to normal intestinal bacteria including Enterococcus strains, and have therefore been used as an animal model of CD. Comprehensive characterization of changes in cecum gene expression levels associated with inflammation in the Il10-/- mouse model has recently been reported. Our aim was to characterize changes in colonic gene expression levels in Il10-/- and C57BL/6J (C57; control) mice resulting from oral bacterial inoculation with 12 Enterococcus faecalis and faecium (EF) strains isolated from calves or poultry, complex intestinal flora (CIF) collected from healthy control mice, or a mixture of the two (EF·CIF). We investigated two hypotheses: (1) that oral inoculation of Il10-/- mice would result in greater and more consistent intestinal inflammation than that observed in Il10-/- mice not receiving this inoculation, and (2) that this inflammation would be associated with changes in colon gene expression levels similar to those previously observed in human studies, and these mice would therefore be an appropriate model for human CD.ResultsAt 12 weeks of age, total RNA extracted from intact colon was hybridized to Agilent 44 k mouse arrays. Differentially expressed genes were identified using linear models for microarray analysis (Bioconductor), and these genes were clustered using GeneSpring GX and Ingenuity Pathways Analysis software. Intestinal inflammation was increased in Il10-/- mice as a result of inoculation, with the strongest effect being in the EF and EF·CIF groups. Genes differentially expressed in Il10-/- mice as a result of EF or EF·CIF inoculation were associated with the following pathways: inflammatory disease (111 genes differentially expressed), immune response (209 genes), antigen presentation (11 genes, particularly major histocompatability complex Class II), fatty acid metabolism (30 genes) and detoxification (31 genes).ConclusionsOur results suggest that colonic inflammation in Il10-/- mice inoculated with solutions containing Enterococcus strains is associated with gene expression changes similar to those of human IBD, specifically CD, and that with the EF·CIF inoculum in particular this is an appropriate model to investigate food-gene interactions relevant to human CD.
Highlights
Inappropriate responses to normal intestinal bacteria may be involved in the development of Inflammatory Bowel Diseases (IBD, e.g. Crohn's Disease (CD), Ulcerative Colitis (UC)) and variations in the host genome may mediate this process
We tested two hypotheses: (1) that oral inoculation of Il10-/- mice with a mixture of pure Enterococcus isolates, alone or combined with conventional intestinal flora derived from healthy and conventionally raised C57 mice, would result in greater and more consistent intestinal inflammation than that observed in Il10-/- mice not receiving this inoculation, and (2) that this inflammation would be associated with changes in colon gene expression levels in key pathways similar to those previously observed in human studies, and these mice would be an appropriate model for human CD [32,33]
While the lack of a significant between-strain difference in mice inoculated with Enterococcus faecalis and faecium (EF)·complex intestinal flora (CIF) seems to be due to the presence of two outliers, there is no data from any other observations which would justify the removal of these values
Summary
Inappropriate responses to normal intestinal bacteria may be involved in the development of Inflammatory Bowel Diseases (IBD, e.g. Crohn's Disease (CD), Ulcerative Colitis (UC)) and variations in the host genome may mediate this process. IL-10 gene-deficient (Il10-/-) mice develop CD-like colitis mainly in the colon, in part due to inappropriate responses to normal intestinal bacteria including Enterococcus strains, and have been used as an animal model of CD. Our aim was to characterize changes in colonic gene expression levels in Il10-/- and C57BL/6J (C57; control) mice resulting from oral bacterial inoculation with 12 Enterococcus faecalis and faecium (EF) strains isolated from calves or poultry, complex intestinal flora (CIF) collected from healthy control mice, or a mixture of the two (EF·CIF). The term 'Inflammatory Bowel Disease' (IBD) refers to a heterogeneous collection of conditions characterized by chronic inflammation of the gastrointestinal tract, and includes Crohn's Disease (CD) and Ulcerative Colitis (UC) [1]. Several candidate genes for IBD susceptibility have been identified, including nucleotide-binding oligomerization domain containing 2 (NOD2) [3,4,5], tumour necrosis factor (TNF) [6], members of the toll-like receptor (TLR) family [7], IL-4 [8] and IL-18 [9], and a number of genes encoding transporter molecules, such as the ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) [10,11] and solute carrier family 22 (organic cation/ergothioneine transporter), member 4 (SLC22A4) genes [12,13]
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