Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice

Abstract

It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2-to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12a-OH BAs, namely, b-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter a, and organic solute transporter b) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12a-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

Remote Sensing Between Liver and Intestine: Importance of Microbial Metabolites

“…Perturbation of intestinal bacteria affects the ratio of conjugated and unconjugated BAs and the ratio of primary and secondary BA, which have differential effects on BA receptors. As expected, an altered BA profile has been observed in gnotobiotic animals (37, 38). …”

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

“…Previous studies have shown that in mice, colonization with gut bacteria can directly regulate signaling of the FXR in the gut and, in this manner, modify bile acid metabolism and potentially lipid and glucose homeostasis (Sayin et al, 2013). In this issue, Selwyn et al (2015a) provide evidence that the gut microbiome may contribute to the generation of bile acids that are capable of acting as agonists of TGR5 in concentrations sufficient for increasing ileac secretion of the TGR5 target, GLP-1.…”

Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism

“…In humans, UDCA is a secondary bile acid, and MCAs are generally not detected. We and others have shown that in the absence of bacteria (as in GF or antibiotic-treated mice or rats), the bile acid pool consists of mainly primary conjugated bile acids (Kellogg et al, 1970;Kellogg and Wostmann, 1969;Koopman et al, 1986;Sayin et al, 2013;Selwyn et al, 2015;Wostmann, 1973). Early experiments in GF rats indicated that MCAs are synthesized in the liver from CDCA (Gustafsson et al, 1981); however, the enzyme(s) involved in this process are still not defined.…”

“…A minor part of deconjugated secondary bile acids is also absorbed from the gut through passive diffusion and gets enriched in the enterohepatic circulation and may then act as signaling molecules in the host. Levels of uMCA, MDCA, and HDCA detected in the feces of mice can vary substantially among different mouse facilities (Degirolamo et al, 2014;Sayin et al, 2013;Selwyn et al, 2015), and this could be attributed to differences in gut microbiota composition that shifts the microbial modification of the bile acids. Importantly, it has been suggested that the human gut microbiota is unable to metabolize bMCA (Martin et al, 2007(Martin et al, , 2008Sacquet et al, 1984Sacquet et al, , 1985.…”