Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease
Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-micr...
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002217 |
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| author | Maxime Deslande Francesc Puig-Castellvi Inés Castro-Dionicio Romina Pacheco-Tapia Violeta Raverdy Robert Caiazzo Guillaume Lassailly Audrey Leloire Petros Andrikopoulos Yasmina Kahoul Nawel Zaïbi Bénédicte Toussaint Frédérik Oger Nicolas Gambardella Philippe Lefebvre Mehdi Derhourhi Souhila Amanzougarene Bart Staels François Pattou Philippe Froguel Amélie Bonnefond Marc-Emmanuel Dumas |
| author_facet | Maxime Deslande Francesc Puig-Castellvi Inés Castro-Dionicio Romina Pacheco-Tapia Violeta Raverdy Robert Caiazzo Guillaume Lassailly Audrey Leloire Petros Andrikopoulos Yasmina Kahoul Nawel Zaïbi Bénédicte Toussaint Frédérik Oger Nicolas Gambardella Philippe Lefebvre Mehdi Derhourhi Souhila Amanzougarene Bart Staels François Pattou Philippe Froguel Amélie Bonnefond Marc-Emmanuel Dumas |
| author_sort | Maxime Deslande |
| collection | DOAJ |
| description | Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-microbial co-metabolite has been associated with human gut microbial gene richness and with metabolic health. However, its role on liver metabolism and homeostasis is poorly understood. Methods: We characterised liver biospies from 318 patients with obesity using RNAseq and metabolomics in liver and plasma to derive associations among hepatic hippurate, hepatic gene expression and MASLD and phenotypes. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profile the metabolome of (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24 h insulin exposure. Results: We first report significant associations among MASLD traits, plasma and hepatic hippurate. Further analysis of the hepatic transcriptome shows that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. Hippurate treatment inhibits lipid accumulation and rescues insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improves hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis that are depleted by chronic insulin treatment while decreasing those involved in inflammation. Conclusions: Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate. |
| format | Article |
| id | doaj-art-643e1174719c467c874cb8889490441e |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Molecular Metabolism |
| spelling | doaj-art-643e1174719c467c874cb8889490441e2025-02-01T04:11:58ZengElsevierMolecular Metabolism2212-87782025-02-0192102090Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver diseaseMaxime Deslande0Francesc Puig-Castellvi1Inés Castro-Dionicio2Romina Pacheco-Tapia3Violeta Raverdy4Robert Caiazzo5Guillaume Lassailly6Audrey Leloire7Petros Andrikopoulos8Yasmina Kahoul9Nawel Zaïbi10Bénédicte Toussaint11Frédérik Oger12Nicolas Gambardella13Philippe Lefebvre14Mehdi Derhourhi15Souhila Amanzougarene16Bart Staels17François Pattou18Philippe Froguel19Amélie Bonnefond20Marc-Emmanuel Dumas21University of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomINSERM U1190, Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceINSERM U1190, Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceINSERM U1011 Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceDivision of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceINSERM U1011 Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, FranceINSERM U1011 Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceINSERM U1190, Institut Pasteur de Lille, University of Lille, Lille University Hospital, 59045, Lille, FranceUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United KingdomUniversity of Lille, Lille University hospital, 59045, Lille, France; INSERM U1283, CNRS UMR 8199, Institut Pasteur de Lille, 59045, Lille, France; Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, W12 0NN, United Kingdom; The Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University, Montréal, H3A 0G1, Canada; Corresponding author. University of Lille, Lille University hospital, 59045, Lille, France.Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player in liver metabolism and health. Hippurate, a host-microbial co-metabolite has been associated with human gut microbial gene richness and with metabolic health. However, its role on liver metabolism and homeostasis is poorly understood. Methods: We characterised liver biospies from 318 patients with obesity using RNAseq and metabolomics in liver and plasma to derive associations among hepatic hippurate, hepatic gene expression and MASLD and phenotypes. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profile the metabolome of (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24 h insulin exposure. Results: We first report significant associations among MASLD traits, plasma and hepatic hippurate. Further analysis of the hepatic transcriptome shows that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. Hippurate treatment inhibits lipid accumulation and rescues insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improves hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis that are depleted by chronic insulin treatment while decreasing those involved in inflammation. Conclusions: Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate.http://www.sciencedirect.com/science/article/pii/S2212877824002217MASLDMetabolic diseasesMetabolomeMicrobiomeHepatocyteRNAseq |
| spellingShingle | Maxime Deslande Francesc Puig-Castellvi Inés Castro-Dionicio Romina Pacheco-Tapia Violeta Raverdy Robert Caiazzo Guillaume Lassailly Audrey Leloire Petros Andrikopoulos Yasmina Kahoul Nawel Zaïbi Bénédicte Toussaint Frédérik Oger Nicolas Gambardella Philippe Lefebvre Mehdi Derhourhi Souhila Amanzougarene Bart Staels François Pattou Philippe Froguel Amélie Bonnefond Marc-Emmanuel Dumas Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease Molecular Metabolism MASLD Metabolic diseases Metabolome Microbiome Hepatocyte RNAseq |
| title | Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease |
| title_full | Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease |
| title_short | Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease |
| title_sort | intrahepatic levels of microbiome derived hippurate associates with improved metabolic dysfunction associated steatotic liver disease |
| topic | MASLD Metabolic diseases Metabolome Microbiome Hepatocyte RNAseq |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002217 |
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