Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor

EBioMedicine. 2020 Apr:54:102719. doi: 10.1016/j.ebiom.2020.102719. Epub 2020 Apr 5.

Abstract

Background: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation.

Methods: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis.

Findings: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease.

Interpretation: Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis.

Funding: A. Moschetta is funded by MIUR-PRIN 2017 <- 2017J3E2W2; Italian Association for Cancer Research (AIRC, IG 23239); Interreg V-A Greece-Italy 2014-2020-SILVER WELLBEING, MIS5003627; HDHL-INTIMIC EuJPI-FATMAL; MIUR PON "R&I" 2014-2020-ARS01_01220. No money has been paid by NGM Biopharmaceuticals or any other agency to write this article.

Keywords: Bile acids; DSS-colitis; Enterokine; Intestinal inflammation; Nuclear receptors.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Bile Acids and Salts / metabolism
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / microbiology*
  • Crohn Disease / drug therapy
  • Crohn Disease / metabolism
  • Crohn Disease / microbiology*
  • Female
  • Fibroblast Growth Factors / chemistry
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gastrointestinal Microbiome*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptides / genetics
  • Peptides / therapeutic use*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / therapeutic use

Substances

  • Anti-Inflammatory Agents
  • Bile Acids and Salts
  • Peptides
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • Fibroblast Growth Factors