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Parenteral and Enteral Nutrition in Critical Illness
Published in Michael M. Rothkopf, Jennifer C. Johnson, Optimizing Metabolic Status for the Hospitalized Patient, 2023
Michael M. Rothkopf, Jennifer C. Johnson
The lack of luminal flow also alters the balance of trophic signaling and biliary secretion. The normal enterohepatic circulation is disrupted, which may affect signals to the hepatic nuclear farnesoid X receptor (FXR). This may have a direct influence on the gut regulatory hormone FGF-19, which may further impact the liver (Jain and Teckman 2014).
Bile Acids in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Most BA reclamation occurs in the distal ileum via the apical sodium-dependent bile acid transporter (ASBT) (10). The intestinal bile acid–binding protein (IBABP, aka FABP6) is thought to shuttle internalized BAs to the basolateral surface of enterocytes (11, 12), where the heteromeric organic solute transporter (OSTα-OSTβ) effluxes BAs into portal circulation (13). On hepatocytes, the sodium-dependent taurocholate-transporting polypeptide (NTCP) and members of the organic anion-transporting polypeptide (OATP) family mediate the completion of enterohepatic circulation. The farnesoid X receptor (FXR) is a nuclear receptor for which BAs are endogenous ligands (14, 15). When BAs bind to FXR in the liver, a cascade of events occurs, eventually leading to suppression of CYP7A1 and NTCP with up-regulation of BSEP. In the intestine, activation of FXR by BAs down-regulates ASBT and up-regulates IBABP and OSTα-OSTβ (16, 17). Binding of BAs to FXR also activates fibroblast growth factor 19 (FGF19) in humans and FGF15 in mice. FGF15/19, an intestinal hormone, is secreted into portal circulation and in the liver and suppresses CYP7A1 and BA synthesis after binding to FGF receptor 4 (FGFR4) complexed with β-Klotho (18). This highly regulated process provides an effective mechanism for recycling BAs and preventing toxic accumulation in enterocytes and hepatocytes (19, 20).
Impact of Probiotics on Human Gut Microbiota and the Relationship with Obesity
Published in Marcela Albuquerque Cavalcanti de Albuquerque, Alejandra de Moreno de LeBlanc, Jean Guy LeBlanc, Raquel Bedani, Lactic Acid Bacteria, 2020
Fernanda Bianchi, Katia Sivieri
The gut microbiota modulates bile acid metabolism by influencing the nuclear bile acid receptor farnesoid X (FXR)/G protein-coupled receptor (TGR5) signalling that indirectly contribute to obesity development (Dahiya et al. 2017). FXR is a receptor that negatively regulates the expression of the gene cholesterol 7α-hydroxylase (CYP7A1), which encodes the enzyme cholesterol 7α-hydroxylase. The enzyme cholesterol 7α-hydroxylase catalyses the initial step of cholesterol catabolism and bile acid synthesis in liver (Chiang 2009). In the intestine, FXR induces fibroblast growth factor 15/19 (FGF15/FGF19), which will indirectly signal to inhibit CYP7A1 gene transcription and, consequently, the initial step of cholesterol catabolism and bile acid synthesis in liver. Decreasing BSH activity in gut microbiota increases tauro-β-muricholic acid (TβMCA), which antagonizes FXR activity, reducing FGF15/19 and stimulating CYP7A1, which will consequently stimulate bile acid synthesis in hepatocytes (Figure 5) (Chiang et al. 2017). The G protein-coupled receptor (TGR5) is a membrane receptor sensitive to the presence of bile acids expressed in the ileum and colon. This receptor promotes an intracellular elevation of cyclic Adenosine MonoPhosphate (cAMP). When cAMP is elevated in the adipose and muscle tissue cells, it triggers mechanisms of energy expenditure and stimulates insulin secretion in pancreatic β cells to improve insulin sensitivity (Figure 5) (de Fabiani et al. 2003, Watanabe et al. 2006, Chiang et al. 2017). Because of these facts, it is possible to state that the gut-liver axis has an important role in metabolic homeostasis regulation and bile acid synthesis (Chiang et al. 2017).
Current trends of benzothiazoles in drug discovery: a patent review (2015–2020)
Published in Expert Opinion on Therapeutic Patents, 2022
Christine Shing Wei Law, Keng Yoon Yeong
Among all, compound 1 (Tropifexor) is regarded as one of the most promising compounds having high nanomolar in vivo potency. Findings from its phase II/III clinical trials have demonstrated its potential as a potent FXR agonist against primary biliary cholangitis (PBC) and nonalcoholic steatophepatitis (NASH). In the phase II study, topifexor has shown to improve serum markers of patients with liver diseases, besides reducing pruritus, a common side effect associated with cholestasis [100]. In recent years, FXR agonism has been extensively studied [101]. This is apparent as four out of the seven inventions targeting metabolic diseases reported in this review are FXR agonists. Combinatorial therapy between FXR agonist and a complementary drug has also been explored for NASH. Combination of tropifexor with licogliflozin, a sodium-glucose co-transporter 1/2 inhibitor is one of the few combination therapies which are currently being tested in clinical trial [102].
Advances in the pharmacological management of bacterial peritonitis
Published in Expert Opinion on Pharmacotherapy, 2021
Daniel Pörner, Sibylle Von Vietinghoff, Jacob Nattermann, Christian P Strassburg, Philipp Lutz
A better understanding of the immunology of the peritoneal cavity may become helpful in the prevention and medical management of bacterial peritonitis in the future. Research for the optimal PD solution to avoid damage to the peritoneal membrane and to prevent peritonitis is ongoing. In addition, it is important to note that the anti-bacterial peritoneal immune response is tightly balanced to protect the host from bacterial infection on one side and to avoid over-reaction on the other side, which finally would lead into a deleterious systemic cytokine storm. Drugs to correct a disbalance in the peritoneal immune system might be helpful to decrease the mortality associated with bacterial peritonitis. The farnesoid X receptor (FXR) is a nuclear bile acid receptor expressed mainly in the liver and the small intestine which is essential for the maintenance of the gut barrier [102,103]. In addition, FXR is involved in the modulation of immune response [104]. Experimental knock-out or genetic polymorphisms leading to lack of FXR function increase the risk for bacterial translocation and peritonitis [105,106]. Based on these findings, FXR agonists, which have been developed to treat liver disease such as primary biliary cholangitis or nonalcoholic steatohepatitis (NASH), may become examples that pharmacological modulation of the physical and functional response to intestinal microbiome may prevent peritonitis [107].
Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health
Published in Gut Microbes, 2020
Baolei Jia, Dongbin Park, Yoonsoo Hahn, Che Ok Jeon
Fatty liver diseases are strongly associated with obesity and T2D, and may develop to nonalcoholic steatohepatitis, cirrhosis, and eventually, liver cancer.36 In patients with NAFLD, total fecal BA concentrations are elevated;37 in contrast, cirrhosis is associated with a decrease in total fecal BA concentration.38,39 Our analysis showed that the majority of BSH clusters were less abundant in patients with liver diseases than in control subjects. The decrease of bacteria with BSH activity was also observed in piglet model of short bowel syndrome-associated liver disease, which was regulated by altered farnesoid X receptor (FXR) signaling.40 Zhang et al. reported that FXR plays important roles in shaping the gut microbiota of mice and treatment with FXR antagonist can decrease both the abundance of bacteria encoding BSHs and BSH activity.41 Interestingly, the expression of FXR is downregulated during the development of liver diseases.42 On the basis of this background, we proposed that the decrease of BSH abundance in patients with liver diseases is associated with the host FXR expression level; however, further experiments need to be performed to elucidate the related underlying mechanisms.