Role of Bile Acids in Metabolic Control

Bile acids are endocrine signaling molecules that affect host physiology via activation of bile acid receptors such as FXR and TGR5. Microbes in the gut are responsible for the intestinal modification of bile acids and for the regulation of several hepatic key enzymes involved in bile acid synthesis. Alterations in bile acid homeostasis are often associated with metabolic disease. Bile acid and microbiota interactions via FXR and TGR5 are fundamental for host metabolism and bile acid signaling regulate metabolic pathways in a tissue specific manner. Modulation of intestinal microbiota and consequently of bile acid profiles might affect the treatment of metabolic diseases and the outcome of bariatric surgery, indicating new possible therapeutic avenues. Pre/probiotics and fecal transplantation are tools available to manipulate microbiota and bile acid composition in the host. This has been shown to have a profound effect on host physiology. Improving these techniques could be a reasonable approach to treat metabolic disease. 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 signaling actions of bile acids are mediated through specific bile-acid-activated nuclear and membrane-bound receptors. These receptors are not only expressed by tissues within the enterohepatic circulation such as the liver and the intestine, but also in other organs where bile acids mediate their systemic actions. In this review, we discuss bile acid signaling and the interplay with the gut microbiota in the pathophysiology of obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and the role of surgical and pharmacological interventions on bile acid profiles and metabolism. 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 signaling actions of bile acids are mediated through specific bile-acid-activated nuclear and membrane-bound receptors. These receptors are not only expressed by tissues within the enterohepatic circulation such as the liver and the intestine, but also in other organs where bile acids mediate their systemic actions. In this review, we discuss bile acid signaling and the interplay with the gut microbiota in the pathophysiology of obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and the role of surgical and pharmacological interventions on bile acid profiles and metabolism. primary bile acids are synthesized in the liver from cholesterol and conjugated with glycine or taurine before excretion. Gut microbes deconjugate primary bile acids and transform these into secondary bile acids. About 95% of bile acids are reabsorbed from the intestine, returned to the liver in the portal blood, then re-secreted in a process known as the enterohepatic recirculation. a combined restrictive/malabsorptive bariatric surgery. A small stomach pouch is created and the distal part of the small intestine is connected to the stomach pouch. The bypassed small intestine, which carries the bile and pancreatic enzymes, is reconnected to the last portion of the small intestine. Bile acids can mix with the food after bypassing ∼80% of the small intestine. a family of heme-containing enzymes that catalyze a wide range of enzymatic reactions a number of which are involved in the BA formation. CYP7A1 is the rate limiting enzyme in BA synthesis and CYP8B1 is responsible for the synthesis of 12-hydroxylated BAs. a nuclear receptor for bile acids, also known as NR1H4 . When activated by certain bile acids (CDCA and CA, and to a smaller extent also DCA and LCA) FXR initiates the expression of a wide range of target genes. In the distal ileum activated FXR induces the expression and secretion of Fgf19 (Fgf15 in mice), which regulates bile acids synthesis in the liver. a restrictive bariatric surgery. An inflatable band is placed around the upper portion of the stomach creating a small adjustable gastric pouch. In this procedure, there is no bypass of food, gastric secretion, and bile acids. community of microbial species that live in a given environment. a complex disease spanning from simple steatosis to NASH, characterized by steatosis and various degrees of fibrosis that may progress to cirrhosis, and ultimately liver failure and liver cancer. About 25% of the global, and 30% of the US population is affected by NAFLD; 30% of which are estimated to develop NASH. a combined restrictive/malabsorptive bariatric surgery. The jejunum is divided in two portions where the bottom one is connected to a small newly made pouch of the stomach (30–50 ml volume). The top portion of the jejunum is connected to the small intestine further down. The food will enter a small gastric pouch and then bypassed directly to the lower part of the small intestine for further digestion. Thus, the stomach secretions from the remaining and bypassed stomach as well as BAs first contact food in the mid-part of the small intestine. a plasma membrane-bound G protein-coupled receptor for bile acids. It is highly expressed in gallbladder, spleen, intestine, liver, placenta, lung, brown and white adipose tissue, skeletal muscle, and bone marrow. TGR5 is activated by certain bile acids (LCA and DCA), especially in muscle and brown adipose tissue (BAT) where it promotes the conversion of inactive thyroxine into active thyroid hormone inducing thermogenesis. TGR5 activation in L cells in the intestine promotes the secretion of GLP-1. restrictive bariatric surgery. A minor stomach pouch is created by a vertical longitudinal resection from the antrum to the fundus. The remaining size of the stomach is ∼150 ml. In this procedure, there is no bypass of food, gastric secretion, and BAs.