title: Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice.
abstract: BACKGROUND
  Apolipoprotein E (ApoE) mediates potent antiinflammatory and immunomodulatory properties in addition to its roles in regulating cholesterol transport and metabolism. However, its role in the intestine, specifically during inflammation, is largely unknown.
  
  
  METHODS
  Mice (C57BL/6 or ApoE-deficient [ApoE-KO] mice) were administered either single or 4 injections (weekly) of anti-interleukin (IL)-10 receptor monoclonal antibody (1.0 mg/mouse; intraperitoneally) and euthanized 1 week after the last injection. 16S rRNA sequencing was performed in fecal samples to analyze the gut bacterial load and its composition. Microbiota was ablated by administration of broad-spectrum antibiotics in drinking water. IL-10KO mice were cohoused with ApoE-KO mice or their wild-type littermates to monitor the colitogenic potential of gut microbiota harbored in ApoE-KO mice.
  
  
  RESULTS
  ApoE-KO mice developed severe colitis upon neutralization of IL-10 signaling as assessed by every parameter analyzed. 16S rRNA sequencing revealed that the ApoE-KO mice display elevated and altered gut microbiota that were accompanied with impaired production of intestinal antimicrobial peptides. Interestingly, microbiota ablation ameliorates colitis development in ApoE-KO mice. Exacerbated and accelerated colitis was observed in IL-10KO mice when cohoused with ApoE-KO mice.
  
  
  CONCLUSIONS
  Our study highlights a novel interplay between ApoE and IL-10 in maintaining gut homeostasis and that such crosstalk may play a critical role in the pathogenesis of inflammatory bowel disease. Gut sterilization and the cohousing experiment suggest that microbiota play a pivotal role in the development of inflammatory bowel disease in mice lacking ApoE.
authors.affiliation: Departments of *Nutritional Sciences, and †Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania; and ‡Department of Medicine, The Pennsylvania State University Medical Center, Hershey, Pennsylvania.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.forename: Beng
authors.initials: B
authors.lastname: San Yeoh
authors.forename: Xia
authors.initials: X
authors.lastname: Xiao
authors.forename: Piu
authors.initials: P
authors.lastname: Saha
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D015153:Blotting, Western; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; C556062:IL10 protein, mouse; D012333:RNA, Messenger; D051198:Toll-Like Receptor 5; D016753:Interleukin-10