Association between Circulating Vitamin D Metabolites and Fecal Bile Acid Concentrations

Abstract

Although hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Using a cross-sectional design, we sought to determine whether baseline circulating concentrations of the vitamin D metabolites 25(OH)D and 1,25(OH)2D were associated with baseline fecal bile acid concentrations in a trial of UDCA for the prevention of colorectal adenoma recurrence. We also prospectively evaluated whether vitamin D metabolite concentrations modified the effect of UDCA on adenoma recurrence. After adjustment for age, sex, BMI, physical activity, and calcium intake, adequate concentrations of 25(OH)D (≥30 ng/mL) were statistically significantly associated with reduced odds for high levels of total [OR, 0.61; 95% confidence interval (CI), 0.38-0.97], and primary (OR, 0.61; 95% CI, 0.38-0.96) bile acids, as well as individually with chenodeoxycholic acid (OR, 0.39; 95% CI, 0.24-0.63) and cholic acid (OR, 0.56; 95% CI, 0.36-0.90). No significant associations were observed for 1,25(OH)2D and high versus low fecal bile acid concentrations. In addition, neither 25(OH)D nor 1,25(OH)2D modified the effect of UDCA on colorectal adenoma recurrence. In conclusion, this is the first study to demonstrate an inverse relationship between circulating levels of 25(OH)D and primary fecal bile acid concentrations. These results support prior data demonstrating that vitamin D plays a key role in bile acid metabolism, and suggest a potential mechanism of action for 25(OH)D in colorectal cancer prevention. Cancer Prev Res; 9(7); 589-97. ©2016 AACR.

Figure 1

Regulation of cholesterol, bile acid, and vitamin D metabolism. An integrative model illustrating the interplay between vitamin D and bile acid metabolism, as mediated by nuclear receptors/transcription factors, and the potential mechanisms that may drive colon carcinogenesis. The first committed/rate-limiting step in the synthesis of bile acids from cholesterol is the introduction of a hydroxyl group at carbon #7 of the sterol ring by the enzyme cholesterol 7α-hydroxylase (encoded by CYP7A1). Catabolism of cholesterol to bile acids is regulated by: 1) oxysterols that induce the expression of CYP7A1 via the liganding of LXRα in cooperation with LRH-1 to feed-forward enhance bile acid synthesis, and 2) bile acids that repress the expression of CYP7A1 via binding to FXR to induce SHP, which in turn neutralizes LRH-1, ultimately inhibiting bile acid synthesis. Other transcription factors/nuclear receptors, besides LXRα and FXR, that regulate the expression of CYP7A1 are: LRH-1, SHP, VDR, RXR, and FOXO1. FOXO1 is phosphorylated in response to FGF19 and insulin signaling, and removed from the nucleus to abolish its induction of CYP7A1. Thus, feedback repression of CYP7A1 is regulated by a trio of nuclear receptors: FXR, SHP, LRH-1, plus phosphorylation/dephosphorylation of FOXO1. The sequence of molecular events is as follows: Bile acids bind to FXR, the primary bile acid sensor, inducing the transcription of SHP in liver, and FGF19 in small intestine. Elevated SHP protein inactivates LRH-1 by forming heteromeric complex to elicit promoter-specific repression of CYP7A1 and SHP. In the intestine, FGF19 signals that the gut is processing large amounts of bile acids, and FGF19 circulates to the liver to signal the activation of a kinase that phosphorylates FOXO1 (thereby excluding it from the nucleus) to suppress hepatobiliary CYP7A1 expression. Insulin similarly signals the activation of phosphorylation of FOXO1 in liver to repress CYP7A1; thus insulin increases cholesterol levels. Vitamin D is converted to 25(OH)D by CYP2R1 in the liver, and circulating 25(OH)D is metabolized to the 1,25(OH)₂D hormone by CYP27B1 in kidney and extra-renal tissues such as colon. VDR is also a bile acid sensor that, when liganded, represses CYP7A1 in liver to reduce cholesterol catabolism, as well as triggers LCA detoxification in colon by inducing CYP3A4 and SULT2A when VDR is liganded with either lithocholic acid or 1,25(OH)₂D. In bone (osteocytes), 1,25(OH)₂D induces FGF23, a phosphaturic hormone that induces CYP24A1 in colon to initiate catabolism of 1,25(OH)₂D to inactive metabolites. This latter action of FGF23 tempers the ability of 1,25(OH)₂D to reduce colon carcinogenesis through induction of CYP3A4/SULT2A, and FGF23 may have additional independent tumor promoting actions in the colon(41). VDR, vitamin D receptor; LXR, liver X receptor; FXR, farnesoid X (bile acid) receptor; LCA, lithocholic acid; BAs, bile acids; ABC, ATP-binding cassette transporters; 1,25D, 1,25-dihydroxyvitamin D; 25D, 25-hydroxyvitamin D.