Bile Acid Receptors in Cholangiocyte

Bile acids are known to play a role in helping the digestion of lipid and maintenance of the bile flow. However, since the first bile acid receptor was discovered in 1999, it has been found that various bile acid receptors are present. Bile acid receptors are involved in bile acid physiology, energy metabolism, and inflammatory response. G-protein bile acid-activated receptor 1 (GPBAR1) and Sphingosine-1-phosphate receptor 2 (S1PR2) are representative bile acid receptors in cholangiocyte. They are involved in proliferation and secretion of cholangiocyte, which seem to protect cholangiocyte from the toxicity of bile acids. GPBAR1 and S1PR2 are also associated with the progression of cholangiocarcinoma.

Role of bile acids in inflammatory liver diseases

Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .

Cholecystocardial syndrome in real clinical practice

Cholecystocardial syndrome is a complex symptom complex, manifested by various disorders in the heart, the development of which is facilitated by the presence of gallstone disease and other diseases of the biliary tract in the patient. For many years, clinicians around the world have been studying the relationship between acute and chronic diseases of the biliary tract and the cardiovascular system. Often these disorders are detected during an attack of biliary colic, in which painful sensations in the region of the heart often occur, and in some cases they are equivalent to an attack of biliary colic. In real clinical practice, cholecystocardial syndrome is an actual syndrome of interest to therapists, cardiologists, gastroenterologists and surgeons. The review presents data on its prevalence, causes and mechanism of development, clinical manifestations. Data on the incidence of cholecystocardial syndrome in real clinical practice vary significantly, which depends on the interpretation of the concept of cholecystocardial syndrome. With the introduction of ultrasound into the widespread practice, the diagnosis of cholelithiasis was significantly simplified, therefore, cholecystocardial syndrome in the classical version described by S.P. Botkin, has been found less and less recently. With a broader consideration of the concept of cholecystocardial syndrome as a complex of clinical symptoms indicating the possibility of changes on the part of the cardiovascular system, in patients with a diagnosed pathology of the biliary tract, its occurrence is quite high. The analysis of domestic data on the problem of cholecystocardial syndrome in real clinical practice, combined with data obtained as a result of a search of foreign literature on electronic biomedical databases (PubMed, MEDLINE, Scopus, Google Scholar) suggests the allocation of another mechanism of its development, associated with cholestasis, high levels of circulating bile acids and activation of bile acid receptors, and allows us to consider its cholecystocardial syndrome not only as a diagnostic syndrome during differential diagnosis, but also as a syndrome reflecting the comorbidity of the pathology of CVS and the biliary tract.

Functional and Phylogenetic Diversity of BSH and PVA Enzymes

Bile salt hydrolase (BSH) and penicillin V acylase (PVA) are related enzymes that are classified as choloylglycine hydrolases (CGH). BSH enzymes have attracted significant interest for their ability to modulate the composition of the bile acid pool, alter bile acid signaling events mediated by the host bile acid receptors FXR and TGR5 and influence cholesterol homeostasis in the host, while PVA enzymes have been widely utilised in an industrial capacity in the production of semi-synthetic antibiotics. The similarities between BSH and PVA enzymes suggest common evolution of these enzymes and shared mechanisms for substrate binding and catalysis. Here, we compare BSH and PVA through analysis of the distribution, phylogeny and biochemistry of these microbial enzymes. The development of new annotation approaches based upon functional enzyme analyses and the potential implications of BSH enzymes for host health are discussed.

Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

Background. Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. Methods. C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. Results. The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. Conclusion. Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.