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Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome.
Jacob, Noam; Jacobs, Jonathan P; Kumagai, Kotaro; Ha, Connie W Y; Kanazawa, Yoshitake; Lagishetty, Venu; Altmayer, Katherine; Hamill, Ariel M; Von Arx, Aimee; Sartor, R Balfour; Devkota, Suzanne; Braun, Jonathan; Michelsen, Kathrin S; Targan, Stephan R; Shih, David Q.
Affiliation
  • Jacob N; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. njacob@mednet.ucla.edu.
  • Jacobs JP; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. njacob@mednet.ucla.edu.
  • Kumagai K; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Ha CWY; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Kanazawa Y; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Lagishetty V; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Altmayer K; Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Hamill AM; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Von Arx A; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Sartor RB; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Devkota S; Departments of Medicine, Microbiology and Immunology and National Gnotobiotic Rodent Resource Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • Braun J; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Michelsen KS; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
  • Targan SR; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
  • Shih DQ; F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Mucosal Immunol ; 11(5): 1466-1476, 2018 09.
Article in En | MEDLINE | ID: mdl-29988118
Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Fibrosis / Tumor Necrosis Factor Ligand Superfamily Member 15 / Gastrointestinal Microbiome / Inflammation / Intestines Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Mucosal Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2018 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Fibrosis / Tumor Necrosis Factor Ligand Superfamily Member 15 / Gastrointestinal Microbiome / Inflammation / Intestines Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Mucosal Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2018 Document type: Article Affiliation country: United States Country of publication: United States