Enterobacteria-mediated deconjugation of taurocholic acid enhances ileal farnesoid X receptor signaling.
Enterobacteria are known to deconjugate amino acid-conjugated bile acids in the intestine. Administration of ampicillin (ABPC; 3 days, 100mg/kg) decreased the expression of ileal farnesoid X receptor (Fxr) target genes, and increased the levels of total bile acids in the intestinal lumen. The primary tauro-conjugates of cholic acid (TCA) and beta-muricholic acid (TβMCA) levels were increased, whereas the primary unconjugates, cholic acid (CA) and beta-muricholic acid (βMCA), levels decreased to below detectable levels (<0.01μmol) in ABPC-treated mice. The effects of individual bile acid on expression of the ileal farnesoid X receptor target genes were examined in ABPC-treated mice. The expression of ileal farnesoid X receptor target genes in ABPC-treated mice was clearly enhanced after CA (500mg/kg), but not TCA (500mg/kg) cotreatment. Their levels in control mice were enhanced after either CA or TCA-cotreatment. Unconjugated CA levels in the intestinal lumen and portal vein were increased in both ABPC-treated and control mice. Reduced ileal Fgf15 and Shp mRNA levels in ABPC-treated mice were also increased after CA (100mg/kg) cotreatment at which luminal CA levels was restored to the level in controls, but was unaffected by βMCA (100mg/kg) cotreatment. In addition, no increase in ileal Shp, Ibabp or Ostα mRNA levels was observed even after CA (500mg/kg) cotreatment in ABPC-treated farnesoid X receptor-null mice despite increased CA levels in the intestinal lumen. These results suggest the role of enterobacteria in bile acid-mediated enhancement of ileal farnesoid X receptor signaling by TCA deconjugation.
Tohoku University, Graduate School of Pharmaceitical Sciences, Division of Drug Metabolism and Molecular Toxicology, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Hideaki
H
Kuribayashi
Masaaki
M
Miyata
Hiroki
H
Yamakawa
Kouichi
K
Yoshinari
Yasushi
Y
Yamazoe
D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002793:Cholic Acids / Q000378:metabolism; D004755:Enterobacteriaceae / Q000187:drug effects / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D007082:Ileum / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D027981:Symporters / Q000235:genetics; D013656:Taurocholic Acid / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D000667:Ampicillin; D000900:Anti-Bacterial Agents; D002793:Cholic Acids; D005346:Fibroblast Growth Factors; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D013656:Taurocholic Acid; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C476576:organic solute transporter alpha, mouse; C476578:organic solute transporter beta, mouse; C071908:sodium-bile acid cotransporter; C004821:muricholic acid