FXR Regulates Intestinal Cancer Stem Cell Proliferation

Cell. 2019 Feb 21;176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.


Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Keywords: BA-FXR axis; Lgr5(+) intestinal stem cells; colon cancer progression; genetic and dietary risk factors.

Publication types

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

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Cell Line
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / metabolism
  • Deoxycholic Acid / metabolism
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism*
  • Intestines
  • Liver
  • Mice
  • Mice, Inbred C57BL
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / physiology
  • Organoids / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Risk Factors
  • Signal Transduction
  • Taurocholic Acid / analogs & derivatives
  • Taurocholic Acid / metabolism
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology


  • Bile Acids and Salts
  • Receptors, Cytoplasmic and Nuclear
  • Deoxycholic Acid
  • farnesoid X-activated receptor
  • tauromuricholic acid
  • Taurocholic Acid