A high-fat diet (HFD) contributes to the increased incidence of colorectal cancer, but the mechanisms are unclear. We found that R-spondin 3 (Rspo3), a ligand for leucine-rich, repeat-containing GPCR 4 and 5 (LGR4 and LGR5), was the main subtype of R-spondins and was produced by myofibroblasts beneath the crypts in the intestine. HFD upregulated colonic Rspo3, LGR4, LGR5, and β-catenin gene expression in specific pathogen–free rodents, but not in germ-free mice, and the upregulations were prevented by the bile acid (BA) binder cholestyramine or antibiotic treatment, indicating mediation by both BA and gut microbiota. Cholestyramine or antibiotic treatments prevented HFD-induced enrichment of members of the Lachnospiraceae and Rumincoccaceae, which can transform primary BA into secondary BA. Oral administration of deoxycholic acid (DCA), or inoculation of a combination of the BA deconjugator Lactobacillus plantarum and 7α-dehydroxylase–containing Clostridium scindens with an HFD to germ-free mice increased serum DCA and colonic Rspo3 mRNA levels, indicating that formation of secondary BA by gut microbiota is responsible for HFD-induced upregulation of Rspo3. In primary myofibroblasts, DCA increased Rspo3 mRNA via TGR5. Finally, we showed that cholestyramine or conditional deletion of Rspo3 prevented HFD- or DCA-induced intestinal proliferation. We conclude that secondary BA is responsible for HFD-induced upregulation of Rspo3, which, in turn, mediates HFD-induced intestinal epithelial proliferation.
Ji-Yao Li, Merritt Gillilland III, Allen A. Lee, Xiaoyin Wu, Shi-Yi Zhou, Chung Owyang
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.