Unknown,Transcriptomics,Genomics,Proteomics

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Differential early pathogenic changes in human ileal gene expression in Crohn's disease and ulcerative colitis

ABSTRACT: The aim of this study is to identify early pathogenic changes in ileal gene expression that precede the development of macroscopic disease in inflammatory bowel diseases (IBDs). We focused on two IBD phenotypes that were unlikely to overlap: 1) ileal Crohn‚Äôs disease (CD) patients undergoing initial ileocolic resection of diseased ileum; and 2) ulcerative colitis (UC) patients undergoing total colectomy. The Control patients were those patients without IBD undergoing initial right hemicolectomy or total colectomy. In order to identify early pathogenic changes in the human ileum in inflammatory bowel diseases, we analyzed 99 two-color whole human genome expression profiles (Agilent 4410A) of a test human ileal cRNA probe vs. a common reference human ileal RNA from a Control patient (N17). A minimum of four biopsies were taken from the macroscopically disease-unaffected proximal ileal margin of freshly resected specimens from 47 ileal Crohn's disease patients undergoing initial ileocolic resection, 27 ulcerative colitis patients undergoing total colectomy and 25 Control patients undergoing either right hemicolectomy or total colectomy. The test and common reference probes were synthesized using the Agilent Low Input Linear Amplification Kit. Hybridization was carried out in DNA hybridization chambers, washed and scanned on an Axon GenePix 4000B scanner. The preprocessing, filtering and normalization of the array data was carried out using the R package LIMMA.

ORGANISM(S): Homo sapiens

SUBMITTER: Tianyi Zhang

PROVIDER: E-GEOD-24287 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition.

Zhang Tianyi T DeSimone Robert A RA Jiao Xiangmin X Rohlf F James FJ Zhu Wei W Gong Qing Qing QQ Hunt Steven R SR Dassopoulos Themistocles T Newberry Rodney D RD Sodergren Erica E Weinstock George G Robertson Charles E CE Frank Daniel N DN Li Ellen E

PloS one 20120613 6

The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn's disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial i ...[more]

PMID: 22719822

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Project description:Gut dysbiosis and host genetics are implicated as causative factors in inflammatory bowel disease, yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis, offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically-created blind self-filling (SFL) and self-emptying (SEL) ileal loops. SFL exhibit fecal stasis due to directional peristalsis motility oriented towards away from the loop end, whereas SEL remain empty. In wild type mice, SFL, but not SEL, develop pouch-like microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-/- deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. Germ-free IL10-/- mice conventionalized with wild type SFL, but not SEL, microbiota, develop severe colitis. These data demonstrate an essential role for fecal stasis, gut dysbiosis, and genetic susceptibility and offer insights into human pouchitis and ulcerative colitis. All animal protocols were approved by IACUC at the University of Chicago. All animals were C57Bl/6 mice that were bred and housed under standard 12:12 light/dark conditions at the University of Chicago. Female mice aged 6-8 weeks were fed ad libitum gel diet 76A (Cat# 72-07-5022, Clear H20, Portland, ME) for 5-days prior to surgery to prevent obstruction at the anastomosis. Animals were anesthetized with ketamine/xylazine. Aseptic surgery was performed to resect 2.5cm of ileum 3cm proximal to the ileal-cecal value with anastomosis to the ileum using 8-0 suture (Figure 1a). The abdominal wall was closed with interrupted 4-0 silk suture and skin was closed with staples. Analgesics (betanorphine mg/kg BW) were provided post-operatively. After 5 weeks, mice were humanely euthanized. Intestinal loops were collected for RNA, protein, and histology. Loop, sham ileum, and sham colon contents were collected and snap frozen at −80°C for microbiota analysis. Human biopsies and stool samples were obtained under IRB approval and privacy protocols were followed. Our initial work demonstrated up regulation of TLR4 signaling in the mucosa of self-filling ileal loops. We hypothesized that TLR4 may be in-part responsible for mediating the metaplasia and inflammatory responses observed. Therefore, TLR4 KO mice were used to test this hypothesis and subsequently demonstrated attenuated responses in these parameters.

Dataset Information

Differential early pathogenic changes in human ileal gene expression in Crohn's disease and ulcerative colitis

Publications

Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition.

Similar Datasets

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