Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2^−/− mice by modulating composition, signalling and excretion of faecal bile acids

Abstract

Background and aimsInterruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis.MethodsMdr2−/− mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2−/− mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis.ResultsColesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus.ConclusionColesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2−/− mice.

Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice

“…Obeticholic acid, a derivative of CDCA with high FXR activation potency, has been used in several clinical trials for the treatment of PBC and PSC, and it is used clinically for patients with PBC who are intolerant or poorly responsive to UDCA. Recent studies suggest that intestinal microbiota play an important role in the pathophysiology of cholestatic liver disease . Targeting microbiota may offer treatment options for cholestatic liver disease.…”

Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities

“…Toxic effects of bile upon cholangiocytes [32,45], due to cholestasis, or primary or secondary changes in bile composition as part of disease processes in the bile ducts or colon [46][47][48][49][50], or impairment of protective means (e.g. the so-called ''bicarbonate umbrella'') [51], may contribute to biliary inflammatory and fibrotic processes.…”

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

“…Bile acid sequestrants (BAS) are large polymers that bind negatively charged bile acids in the small intestine, which can prevent reabsorption of bile acids in the gut, increase their fecal excretion, Page 13 of 30 and finally disrupt enterohepatic circulation [25]. BAS is efficient to reduce TBA pool, however, evidence also shown that it can consequently inhibit ileal FXR and reduce expression of FGF15 in mice [26] and FGF19 in human [19]. To determine the impact of enterohepatic TBA on autophagy-deficient livers, mice were given cholestyramine resin treatment (Fig.…”

“…FGF15/19 is required for the efficiency of SHP-mediated CYP7A1 repression and plays a critical role in repressing BA synthesis [18]. Conversely, decrease of intestinal level of BA by BA sequestrants can reduce ileal FGF15 expression in mice [26] and serum FGF19 levels in healthy humans [42]. Animal experiments have shown that FGF15 is essential for hepatic homeostasis, and overexpression of FGF15/19 in the liver has beneficial effects on multiple liver diseases, including sclerosing cholangitis Page 20 of 30 [20], alcoholic fatty liver [22], and NAFLD [21,29].…”