Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome

Mucosal Immunol. 2018 Sep;11(5):1466-1476. doi: 10.1038/s41385-018-0055-y. Epub 2018 Jul 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / metabolism
  • Colitis / microbiology
  • Collagen / metabolism
  • Crohn Disease / metabolism
  • Crohn Disease / microbiology
  • Fibroblasts / metabolism
  • Fibroblasts / microbiology
  • Fibrosis / metabolism*
  • Fibrosis / microbiology*
  • Gastrointestinal Microbiome / physiology*
  • Humans
  • Ileitis / metabolism
  • Ileitis / microbiology
  • Inflammation / metabolism*
  • Inflammation / microbiology
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / microbiology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestines / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / metabolism*

Substances

  • Tnfsf15 protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Collagen