Rebuttal to: Melancholé: the Dark Side of Bile Acids and Its Cellular Consequences.

See Point-Counterpoint articles on pages 1474 and 1478.

Bile acids are ancient molecules that have been known to modern science for more than a century. However, the depth of their role in pathophysiology only recently has been recognized. Studies in the past 2 decades, especially after identification of various bile acid receptors, first Farnesoid X Receptor, and later others, including G Protein-Coupled Bile Acid Receptor 1, have revolutionized our understanding of how deeply bile acids affect human health. These studies also have highlighted the fact that maintaining a healthy bile acid level is critical. As elegantly pointed out by Zhou and Anakk in their Point-Counter Point article, an increase in total bile acids can be toxic, and a change in bile acid composition can affect hepatic physiology. However, depletion of bile acids also can affect multiple processes, from digestion to regeneration to regulation of lipid metabolism. The fact that bile acids are active signaling molecules that are absolutely necessary for cross-organ communication (eg, as part of the gut–liver axis) makes them unique among the endobiotics and puts them in the same class as hormones and immune mediators. Thus, the basic principle of toxicology, espoused by the 14th century monk-physician Paracelsus, that “dose determines the poison,” can be perfectly applied to the importance of bile acid maintenance.