Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases

Abstract

Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline. Obeticholic acid has been approved by regulatory agencies for use in patients with primary biliary cholangitis.

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducers

“…We began by investigating the effects of CBAs on canonical bile acid receptors farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (Takeda G protein-coupled receptor 5, TGR5) and their reported downstream mediators ( Figure 6A and refs. 30,31), which are increased by bile acid stimulation in various tissues (e.g., liver and kidney) (32,33). We found that lung transcript levels of Gpbar1 (TGR5) and downstream mediators Nos3 and Dio2, as well as transcript levels of Nr1h4 (FXR) and downstream mediators Abcb4, Abcc2, and Nr0b2, were not elevated in HDM plus TUDCA-treated mice compared with both the PBS and HDM control groups ( Figure 6B).…”

Fecal microbiota transplantation in cancer management: Current status and perspectives

“…The liver is exposed to intestinal microbiota through the portal vein which delivers gut‐derived bacterial products or toxins, such as lipopolysaccharide and deoxycholic acid . The close structural and functional interaction between the gut and the liver is defined as the gut‐liver axis.…”

“…The liver is exposed to intestinal microbiota through the portal vein which delivers gut-derived bacterial products or toxins, such as lipopolysaccharide and deoxycholic acid. 6,92 The close structural and functional interaction between the gut and the liver is defined as the gut-liver axis. Liver diseases are often associated with intestinal dysbiosis, and it has been shown that gut bacterial metabolites could promote the development of chronic liver disease and HCC through gut-liver axis.…”

Obesity and nonalcoholic fatty liver disease: current perspectives

“…It not only inhibits bile acid formation from cholesterol by blocking CYP7a1 enzyme but also improves insulin sensitization and is believed to have favorable metabolic effects. 49 It has been studied in a recent phase IIa, randomized, placebo-controlled trial by enrolling 82 patients with biopsy-confirmed NASH (NAS ≥4 with one point in each component, fibrosis stage 1–3), with 8% liver fat content by MRI-PDFF and abnormal ALT. Subjects were randomized to 3 mg, 6 mg of NGM282, or placebo as a daily subcutaneous injection for 12 weeks.…”