Endocrine Abstracts

Bile acids are endocrine molecules that in addition to facilitating the absorption of fat-soluble nutrients regulate numerous metabolic processes, including glucose, lipid, and energy homeostasis. The actions of bile acids are mediated through specific bile acid-activated nuclear and membrane bound receptors such as farnesoid X receptor (FXR) and G protein-coupled receptor 5 (TGR5). Bile acid signaling is modified by interactions with gut bacteria which metabolize primary bile acids into secondary bile acids and thereby changes their affinity for their receptors. FXR and TGR5 have become major targets for studies of metabolic diseases and it is clear that the microbiota can modulate signaling through both FXR and TGR5 via modifications of bile acids. Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of their receptors. To study the influence of microbiota and bile acid interactions on host metabolism we use germ-free mice that can be colonized with specific communities of bacteria. These mice are important tools but the interpretation and translation of results from mouse models must be done carefully since mice and humans have substantial differences in bile acid composition. The major primary bile acid in germ-free mice, TβMCA, is absent in adult humans and this bile acid function as an FXR antagonist. It has been shown that mice treated with antibiotics or Tempol have increased levels of TβMCA and are protected against diet- induced obesity and it was suggested that intestinal-specific inhibition of FXR was responsible for the beneficial effects. It has also been shown that a glycine-conjugated form of βMCA (GβMCA) improved metabolic phenotypes in obesity mouse models. On the other hand, it has also been shown that intestinal-specific activation of FXR with fexaramine protects against the development of obesity and was associated with increased thermogenesis and browning of adipose tissue. Furthermore, it has been suggested that some of the beneficial effects following bariatric surgery may be mediated by changes in gut microbiota, bile acid profile and FXR activation. Thus, targeting the interplay between microbiota, bile acids and FXR and/or TGR5 signaling seems to evolve as a promising avenue for the treatment of metabolic diseases but much more research is needed especially in humans.