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Ablation of liver Fxr results in an increased colonic mucus barrier in mice

ABSTRACT: The inter-organ cross talk between liver and intestine has been focus of intense research. Key in this cross-talk are bile acids, which are secreted from the liver into the intestine and, via the enterohepatic circulation, reach back to the liver. Important new insights have been gained in the Farnesoid X receptor (Fxr)-mediated communication from intestine-to-liver in health and disease. However, liver-to-intestine communication and the role of bile acids and FXR in this cross talk remain elusive. Here, we analyse Fxr-mediated liver-to-gut communication, and its consequences in the colon. Mice in which Fxr was selectively ablated in intestine (Fxr-intKO), the liver (Fxr-livKO), or in the full body (Fxr-totKO) were engineered. The effects on colonic gene expression (RNA sequencing), on the microbiome (16S rRNA Gene Sequencing) and on mucus barrier were analyzed. Compared to Fxr-intKO and Fxr-totKO mice, more genes were differentially expressed in the colons of Fxr-livKO mice relative to control mice (731, 1824 and 3272 respectively), suggestive of a strong role of hepatic Fxr in liver-to-gut communication. The colons of Fxr-livKO showed increased expression of anti-microbial genes, such as Regenerating islet-derived 3 beta and gamma (Reg3β and Reg3γ), Toll-like receptors (Tlrs), inflammasome related genes and differential expression of genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Compared to control mice, Fxr-livKO mice have decreased levels of the predicted mucin degrading bacterium Turicibacter and a concomitant increase in the thickness of the inner sterile mucus layer. In conclusion, ablation of Fxr in the liver has a major effect on colonic gene expression, the gut microbiome and on the permeability of the mucus layer. This stresses the importance of the Fxr-mediated liver-to-gut signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE163157 | GEO | 2021/09/29

REPOSITORIES: GEO

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Project description:The transcription factor farnesoid X receptor (FXR) governs bile acid and energy homeostasis, is involved in inflammation, and has protective functions in the liver. In the present study we investigated the effect of Fxr deficiency in mouse precision cut liver slices (PCLS) exposed to a model hepatotoxicant cyclosporin A (CsA). It was anticipated that Fxr deficiency could aggravate toxicity of CsA in PCLS and pinpoint to novel genes/processes regulated by FXR. To test this hypothesis, PCLS obtained from livers of wild type mice (WT-PCLS) and Fxr-knockout mice (FXRKO-PCLS) were treated with 40µM CsA for 24h and 48h. ATP and histological assays were applied to assess the viability of PCLS. DNA microarrays combined with bioinformatics analysis were used to identify genes and processes that were affected by CsA in WT-PCLS and/or FXRKO-PCLS. In addition, WT-PCLS and FXRKO-PCLS were exposed to the endogenous FXR ligand chenodeoxycholic acid (CDCA) and subjected to q-PCR to determine whether subsets of known FXR-targets and the identified genes were regulated upon FXR activation in an FXR-dependent manner. No difference in viability was observed between WT-PCLS and FXRKO-PCLS upon CsA treatment. Transcriptomics data analysis revealed that CsA significantly upregulated stress-response and inflammation and significantly downregulated processes involved in lipid and glucose metabolism in both WT-PCLS and FXRKO-PCLS. However, only in FXRKO-PCLS, CsA upregulated additional pro-inflammatory genes and downregulated genes related to mitochondrial functions. Furthermore, only in WT-PCLS, CDCA upregulated a subset of known FXR-target genes as well as the regulator of inflammation and mitochondrial functions peroxisome proliferator- activated receptor delta (Ppar delta). Although FXR governs energy metabolism, no major differences in response to CsA could be observed between WT-PCLS and FXRKO-PCLS in regulation of processes involved in lipid and glucose metabolism. This finding indicates that CsA does not directly affect FXR functions in relation to the above mentioned processes. However, the more pronounced induction of pro-inflammatory genes and the downregulation of genes involved in mitochondrial functions only in FXRKO-PCLS suggest that FXR deficiency aggravates CsA-induced inflammation and impairs mitochondrial functions. Therefore, FXR can exert its hepatoprotective functions by controlling inflammation and mitochondrial functions, possibly involving an FXR-PPAR delta cross-talk. Precision cut liver slices (PCLS) obtained from livers of wild type (WT) and farnesoid X receptor knockout (FXRKO) mice were exposed for 24 hours to 40uM of CyclosporinA (CsA).

Project description:Mardinoglu2015 - Curated tissue-specific genome-scale metabolic model - Small intestine This model is described in the article: The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mardinoglu A, Shoaie S, Bergentall M, Ghaffari P, Zhang C, Larsson E, Bäckhed F, Nielsen J. Mol. Syst. Biol. 2015; 11(10): 834 Abstract: The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice. This model is hosted on BioModels Database and identified by: MODEL1509220032. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Ablation of liver Fxr results in an increased colonic mucus barrier in mice

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