Liver GPBAR1 Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4−/− Mice

Liver International, Год журнала: 2025, Номер 45(2)

Опубликована: Янв. 13, 2025

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to cirrhosis cholangiocarcinoma. GPBAR1 (TGR5) G protein-coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, selective agonist in PSC model. Single-cell analysis healthy human samples gene expression were conducted. vitro studies on cholangiocyte cell line (NHC), U937 hepatic stellate cells (hSteCs) performed. Additionally, Abcb4-/- mice treated with BAR501 12-24 weeks. demonstrated that expressed macrophages, NK cells, sinusoidal lesser extent cholangiocytes. Total increases patients compared controls positively correlates markers monocytes cytokeratin 19. treatment NHCs reversed acquisition pro-inflammatory phenotype downregulation promoted LPS an NF-κB-dependent manner. Treating reduced duct fibrosis prevented expression. also modulated acid pool composition dysbiosis-associated gut permeability, intestinal systemic inflammation. Ex vivo experiments using conditioned media from BAR501-treated cholangiocytes mitigated activation macrophages. Our study provides evidence agonists inflammation-associated cholestasis, warranting evaluation patients.

Язык: Английский

Phenotyping the Chemical Communications of the Intestinal Microbiota and the Host: Secondary Bile Acids as Postbiotics

Cells, Год журнала: 2025, Номер 14(8), С. 595 - 595

Опубликована: Апрель 15, 2025

The current definition of a postbiotic is “preparation inanimate microorganisms and/or their components that confers health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, intrinsic constituents microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic (LCA) are metabolites generated by enzymatic modifications primary enzymes. function receptor ligands modulating activity family bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) RORγT expressed various cell types within entire human body. integrate postbiotics, exerting potential beneficial effects given ability to regulate multiple biological processes such glucose metabolism, energy expenditure inflammation/immunity. Although there evidence might harmful intestine, most this does not account for dysbiosis. This review examines novel conceptual framework secondary postbiotics how these mediators participate in maintaining host health.

Язык: Английский

Fenofibrate as an Adjunct Therapy for Ulcerative Colitis: Targeting Inflammation via SIRT1, NLRP3, and AMPK Pathways: A Randomized Controlled Pilot Study

Drug Design Development and Therapy, Год журнала: 2024, Номер Volume 18, С. 5239 - 5253

Опубликована: Ноя. 1, 2024

Ulcerative colitis (UC) is an idiopathic chronic inflammation of colonic and rectal mucosa. The peroxisome proliferator-activated receptor α (PPARα) has been identified as having protective effects in UC.

Язык: Английский