title: Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10(-/-) mice.
abstract: OBJECTIVE
  Early-onset ulcerative colitis, which is considered severe colonic inflammation that develops in infants and young children, can be caused by alterations in interleukin (IL)-10 signaling, although other factors are involved in its pathogenesis. We investigated whether loss of phosphatase and tensin homologue (PTEN), which regulates many important cell functions such as cell proliferation, cell survival, and Toll-like receptor (TLR) signaling pathways, contributes to the development of colitis in Il10(-/-) mice.
  
  
  METHODS
  We generated Il10(-/-) mice (in C57BL/6 and C3H/HeJBir background strains) with disruption of Pten in the intestinal epithelium (Ints(ΔPten/ΔPten);Il10(-/-) mice) and Ints(ΔCont);Il10(-/-) (control) mice. Colon tissues were collected and histological, transmission electron microscopy, and gene expression analysis were performed. Fecal microbiota samples were analyzed by sequencing of 16S ribosomal RNA genes. We disrupted Tlr4 in Ints(ΔPten/ΔPten);Il10(-/-) mice. Lipopolysaccharide signaling via TLR4 was blocked by treating mice with polymyxin B.
  
  
  RESULTS
  Il10(-/-) mice developed colitis when they were 6 to 7 months old, whereas Ints(ΔPten/ΔPten);Il10(-/-) mice developed severe colitis and colon tumors by the time they were 36 days old. Within 3 months of birth, 80% of Ints(ΔPten/ΔPten);Il10(-/-) mice developed severe colitis and colonic malignancy, whereas none of the Ints(ΔCont);Il10(-/-) mice had these phenotypes. Ints(ΔPten/ΔPten);Il10(-/-) mice had alterations in fecal microbiota compared with controls, such as increased proportions of Bacteroides species, which are gram negative. Disruption of Tlr4 or treating Ints(ΔPten/ΔPten);Il10(-/-) mice with polymyxin B delayed the development of colitis and reduced disease severity.
  
  
  CONCLUSIONS
  Disruption of Pten in the intestinal epithelium of Il10(-/-) mice speeds the onset and increases the severity of colitis. Fecal microbiota from Ints(ΔPten/ΔPten);Il10(-/-) mice have increased proportions of Bacteroides species. Development of colitis is delayed and reduced by blocking TLR4 signaling. Ints(ΔPten/ΔPten);Il10(-/-) mice may be studied as a model for early-onset ulcerative colitis and used to identify new therapeutic targets.
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Korea.
authors.forename: Eunok
authors.initials: E
authors.lastname: Im
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Jane
authors.initials: J
authors.lastname: Jung
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address: shrhee@mednet.ucla.edu.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Rhee
mesh_terms: D000367:Age Factors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003092:Colitis / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D005786:Gene Expression Regulation; D005838:Genotype; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011112:Polymyxin B / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; C556062:IL10 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D011112:Polymyxin B
keywords: Inflammatory Bowel Disease; Innate Immunity; Intestinal Epithelial Cells; Pediatric