Ablation of liver Fxr results in an increased colonic mucus barrier in mice
| Autor: | Ijssennagger, Noortje, van Rooijen, Kristel S., Magnúsdóttir, Stefanía, Ramos Pittol, José M., Willemsen, Ellen C.L., de Zoete, Marcel R., Baars, Matthijs J.D., Stege, Paul B., Colliva, Carolina, Pellicciari, Roberto, Youssef, Sameh A., de Bruin, Alain, Vercoulen, Yvonne, Kuipers, Folkert, van Mil, Saskia W.C., dI&I I&I-2, Dep Biomolecular Health Sciences, Pathobiologie, dPB RMSC |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), dI&I I&I-2, Dep Biomolecular Health Sciences, Pathobiologie, dPB RMSC |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
fpkm fragments per kilobase of transcript per million mapped reads medicine.drug_class Colon HID high-iron diamine RC799-869 KEGG Kyoto Encyclopedia of Genes and Genomes Liver-specific Fxr-KO mouse Fxr-intKO intestine-specific Fxr knockout RT qPCR real-time quantitative PCR Liver–gut axis Farnesoid X receptor Internal medicine GO Gene Ontology Gene expression Internal Medicine medicine Immunology and Allergy Mucus layer DSS dextran sodium sulfate Fxr-livKO liver-specific Fxr knockout Microbiome Colitis Receptor Barrier function Gut microbiome IBD inflammatory bowel disease Hepatology Bile acid Chemistry BAs bile acids Fgfr4 fibroblast growth factor receptor 4 Gastroenterology Diseases of the digestive system. Gastroenterology medicine.disease Fxr-totKO whole body Fxr knockout Mucus Endocrinology Fxr farnesoid X receptor Intestine-specific Fxr-KO mouse FITC fluorescein isothiocyanate Liver-gut axis Research Article |
| Zdroj: | JHEP Reports, 3(5). Elsevier BV JHEP reports : innovation in hepatology, 3(5):100344. Elsevier JHEP Reports, Vol 3, Iss 5, Pp 100344-(2021) JHEP Reports |
| ISSN: | 2589-5559 |
| Popis: | Background & Aims The interorgan crosstalk between the liver and the intestine has been the focus of intense research. Key in this crosstalk are bile acids, which are secreted from the liver into the intestine, interact with the microbiome, and upon absorption reach back to the liver. The bile acid-activated farnesoid X receptor (Fxr) is involved in the gut-to-liver axis. However, liver-to-gut communication and the roles of bile acids and Fxr remain elusive. Herein, we aim to get a better understanding of Fxr-mediated liver-to-gut communication, particularly in colon functioning. Methods Fxr floxed/floxed mice were crossed with cre-expressing mice to yield Fxr ablation in the intestine (Fxr-intKO), liver (Fxr-livKO), or total body (Fxr-totKO). The effects on colonic gene expression (RNA sequencing), the microbiome (16S sequencing), and mucus barrier function by ex vivo imaging were analysed. Results Despite relatively small changes in biliary bile acid concentration and composition, more genes were differentially expressed in the colons of Fxr-livKO mice than in those of Fxr-intKO and Fxr-totKO mice (3272, 731, and 1824, respectively). The colons of Fxr-livKO showed increased expression of antimicrobial genes, Toll-like receptors, inflammasome-related genes and genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Fxr-livKO mice have a microbiome profile favourable for the protective capacity of the mucus barrier. The thickness of the inner sterile mucus layer was increased and colitis symptoms reduced in Fxr-livKO mice. Conclusions Targeting of FXR is at the forefront in the battle against metabolic diseases. We show that ablation of Fxr in the liver greatly impacts colonic gene expression and increased the colonic mucus barrier. Increasing the mucus barrier is of utmost importance to battle intestinal diseases such as inflammatory bowel disease, and we show that this might be done by antagonising FXR in the liver. Lay summary This study shows that the communication of the liver to the intestine is crucial for intestinal health. Bile acids are key players in this liver-to-gut communication, and when Fxr, the master regulator of bile acid homoeostasis, is ablated in the liver, colonic gene expression is largely affected, and the protective capacity of the mucus barrier is increased. Graphical abstract Highlights • Fxr ablation in the mouse liver has a major impact on colonic gene expression. • Fxr signalling is induced in the colons of liver Fxr knockout (Fxr-livKO) mice. • In Fxr-livKO colons, expression of antimicrobial and mucus genes is increased. • Microbiome of Fxr-livKO mice is indicative of enhanced mucus barrier function. • Fxr-livKO mice have an increased mucus barrier. |
| Databáze: | OpenAIRE |
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