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-12α-
OH BAs, namely, β-
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 α, and organic solute transporter β) 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-12α-
OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and
GLP-1.