Cell Reports (Oct 2020)
Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content
- Lianmin Chen,
- Inge C.L. van den Munckhof,
- Kiki Schraa,
- Rob ter Horst,
- Martijn Koehorst,
- Martijn van Faassen,
- Claude van der Ley,
- Marwah Doestzada,
- Daria V. Zhernakova,
- Alexander Kurilshikov,
- Vincent W. Bloks,
- Albert K. Groen,
- Niels P. Riksen,
- Joost H.W. Rutten,
- Leo A.B. Joosten,
- Cisca Wijmenga,
- Alexandra Zhernakova,
- Mihai G. Netea,
- Jingyuan Fu,
- Folkert Kuipers
Affiliations
- Lianmin Chen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Inge C.L. van den Munckhof
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- Kiki Schraa
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- Rob ter Horst
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- Martijn Koehorst
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Martijn van Faassen
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Claude van der Ley
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Marwah Doestzada
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Daria V. Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg 197101, Russia
- Alexander Kurilshikov
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Vincent W. Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Albert K. Groen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Vascular Medicine, University of Amsterdam, Amsterdam University Medical Center, Amsterdam 1012WX, the Netherlands
- Niels P. Riksen
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- Joost H.W. Rutten
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands
- Leo A.B. Joosten
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400000, Romania
- Cisca Wijmenga
- University of Groningen, Groningen 9712CP, the Netherlands
- Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands
- Mihai G. Netea
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, the Netherlands; Department for Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn 53113, Germany; Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova 200349, Romania
- Jingyuan Fu
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Corresponding author
- Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Corresponding author
- Journal volume & issue
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Vol. 33,
no. 1
p. 108212
Abstract
Summary: Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10−8) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.
