Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism.
The gut microbiota modulates obesity and associated metabolic phenotypes in part through intestinal farnesoid X receptor (FXR) signaling. Glycine-β-muricholic acid (Gly-MCA), an intestinal FXR antagonist, has been reported to prevent or reverse high-fat diet (HFD)-induced and genetic obesity, insulin resistance, and fatty liver; however, the mechanism by which these phenotypes are improved is not fully understood. The current study investigated the influence of FXR activity on the gut microbiota community structure and function and its impact on hepatic lipid metabolism. Predictions about the metabolic contribution of the gut microbiota to the host were made using 16S rRNA-based PICRUSt (phylogeneticinvestigation ofcommunities byreconstruction ofunobservedstates), then validated using1H nuclear magnetic resonance-based metabolomics, and results were summarized by using genome-scale metabolic models. Oral Gly-MCA administration altered the gut microbial community structure, notably reducing the ratio ofFirmicutestoBacteroidetesand its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis andde novolipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specificFxr-null (FxrΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link betweenLactobacillusandClostridiabile salt hydrolase activity and bacterial fermentation. Hepatic metabolite levels after Gly-MCA treatment correlated with altered levels of gut bacterial species. In conclusion, modulation of the gut microbiota by inhibition of intestinal FXR signaling alters host liver lipid metabolism and improves obesity-related metabolic dysfunction.IMPORTANCEThe farnesoid X receptor (FXR) plays an important role in mediating the dialog between the host and gut microbiota, particularly through modulation of enterohepatic circulation of bile acids. Mounting evidence suggests that genetic ablation ofFxrin the gut or gut-restricted chemical antagonism of the FXR promotes beneficial health effects, including the prevention of nonalcoholic fatty liver disease in rodent models. However, questions remain unanswered, including whether modulation of FXR activity plays a role in shaping the gut microbiota community structure and function and what metabolic pathways of the gut microbiota contribute in an FXR-dependent manner to the host phenotype. In this report, new insights are gained into the metabolic contribution of the gut microbiota to the metabolic phenotypes, including establishing a link between FXR antagonism, bacterial bile salt hydrolase activity, and fermentation. Multiple approaches, including unique mouse models as well as metabolomics and genome-scale metabolic models, were employed to confirm these results.
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA; CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
Limin
L
Zhang
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Cen
C
Xie
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Robert G
RG
Nichols
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.
Siu H J
SH
Chan
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
Changtao
C
Jiang
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Ruixin
R
Hao
Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Philip B
PB
Smith
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Jingwei
J
Cai
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.
Margaret N
MN
Simons
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania, USA; Department of Food Science and Technology, The Ohio State University, Columbus, Ohio, USA.
Emmanuel
E
Hatzakis
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania, USA.
Costas D
CD
Maranas
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Frank J
FJ
Gonzalez
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Andrew D
0000-0003-2073-0070
AD
Patterson
bile acid; farnesoid X receptor; genome-scale metabolic models; gut microbiota; metabolomics; nonalcoholic fatty liver disease