Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

Abstract

Bile acids are the end product of cholesterol metabolism. Synthesized in the liver, primary bile acids are secreted by hepatocytes and are transformed by intestinal microbiota into secondary bile acids. In addition to their role in cholesterol and lipid absorption, bile acids act as signaling molecules activating a family of nuclear and G-protein-coupled receptors collectively known as bile acid activated receptors (BARs). These receptors are expressed at high density in enterohepatic tissues, but their expression occurs throughout the body and their activation mediates regulatory functions of bile acids on lipids and glucose metabolism and immunity. In the gastrointestinal tract, BARs maintain intestinal integrity, and their deletion makes the intestine more susceptible to the damage caused by acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Deficiency in farnesoid X receptor and G-protein-coupled bile acid receptor 1 genes alters the expression/activity of cystathione c-lyase and endothelial nitric oxide synthase, two genes involved in the synthesis of hydrogen sulfide and nitric oxide, i.e., two gaseous mediators that have been shown to be essential in maintaining the intestinal homeostasis. In addition, farnesoid X receptor regulates the expression of transporters required for secretion of phospholipid by hepatocytes. Because phospholids attenuate intestinal injury caused by acetylsalicylic acid and NSAIDs, BAR agonism could be exploited to protect the intestinal mucosa against injury caused by anti-inflammatory medications. This approach might be useful in the prevention of so-called NSAID enteropathy, a common clinical condition occurring in long-term users of NSAIDs, which is not effectively prevented either by cotreatment with proton pump inhibitors or by the use of coxibs.

Metabolic features of chronic fatigue syndrome

“…Decreased cholesterol flux can result in decreased substrate for bile acid synthesis needed for normal fat digestion and microbiome signaling (24). The absence of adequate bile acid delivery can lead to a loss in intestinal mucosal integrity and leaky gut via a cascade of events stemming in part from disrupted farnesoid X receptor signaling (25).…”

Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs

“…Furthermore, although primary and secondary bile acids have differential potential to cause damage to intestinal epithelial b cells, they also act as effector molecules that activate nuclear and G-proteinÀcoupled receptors; collectively known as bile acidÀactivated receptors, these help maintain intestinal integrity. 126 Bile therefore appears to have an important role in the pathogenesis of small bowel damage. It has been shown to maintain and disrupt intestinal integrity.…”

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

“…Because the above mentioned triterpenoids have been identified as natural ligands for two bile acid activated receptors, the Farnesoid-X-Receptor (FXR) and G protein Bile Acid Receptor (GPBAR)-1 (Sepe et al, 2015;De Marino et al, 2019;Fiorucci and Distrutti, 2019), we have further investigated whether mammalian ligands of these receptors were also endowed with the ability to bind the above mentioned RBD's pockets. More specifically, oleanolic, betulinic and ursolic acids have been proved to act as selective and potent GPBAR1 agonists (Sato et al, 2007;Genet et al, 2010;Lo et al, 2016), while glycyrrhetinic acid, the major metabolic component of licorice, and its corresponding saponin, glycyrrhizic acid, have been shown to act as dual FXR and GPBAR1 agonists in transactivation assay (Distrutti et al, 2015), also promoting GLP-1 secretion in type 1-like diabetic rats (Wang et al, 2017).…”