Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

ABSTRACT 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 obesit...

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Autores principales:	Limin Zhang, Cen Xie, Robert G. Nichols, Siu H. J. Chan, Changtao Jiang, Ruixin Hao, Philip B. Smith, Jingwei Cai, Margaret N. Simons, Emmanuel Hatzakis, Costas D. Maranas, Frank J. Gonzalez, Andrew D. Patterson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	bile acid farnesoid X receptor genome-scale metabolic models gut microbiota metabolomics nonalcoholic fatty liver disease Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e83188a77784a3c912625c3860b0e97
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spelling	oai:doaj.org-article:0e83188a77784a3c912625c3860b0e972021-12-02T18:39:46ZFarnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism10.1128/mSystems.00070-162379-5077https://doaj.org/article/0e83188a77784a3c912625c3860b0e972016-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00070-16https://doaj.org/toc/2379-5077ABSTRACT 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 (phylogenetic investigation of communities by reconstruction of unobserved states), then validated using 1H 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 of Firmicutes to Bacteroidetes and its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis and de novo lipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specific Fxr-null (FxrΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link between Lactobacillus and Clostridia bile 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. IMPORTANCE The 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 of Fxr in 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.Limin ZhangCen XieRobert G. NicholsSiu H. J. ChanChangtao JiangRuixin HaoPhilip B. SmithJingwei CaiMargaret N. SimonsEmmanuel HatzakisCostas D. MaranasFrank J. GonzalezAndrew D. PattersonAmerican Society for Microbiologyarticlebile acidfarnesoid X receptorgenome-scale metabolic modelsgut microbiotametabolomicsnonalcoholic fatty liver diseaseMicrobiologyQR1-502ENmSystems, Vol 1, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	bile acid farnesoid X receptor genome-scale metabolic models gut microbiota metabolomics nonalcoholic fatty liver disease Microbiology QR1-502
spellingShingle	bile acid farnesoid X receptor genome-scale metabolic models gut microbiota metabolomics nonalcoholic fatty liver disease Microbiology QR1-502 Limin Zhang Cen Xie Robert G. Nichols Siu H. J. Chan Changtao Jiang Ruixin Hao Philip B. Smith Jingwei Cai Margaret N. Simons Emmanuel Hatzakis Costas D. Maranas Frank J. Gonzalez Andrew D. Patterson Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
description	ABSTRACT 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 (phylogenetic investigation of communities by reconstruction of unobserved states), then validated using 1H 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 of Firmicutes to Bacteroidetes and its PICRUSt-predicted metabolic function, including reduced production of short-chain fatty acids (substrates for hepatic gluconeogenesis and de novo lipogenesis) in the ceca of HFD-fed mice. Metabolic improvement was intestinal FXR dependent, as revealed by the lack of changes in HFD-fed intestine-specific Fxr-null (FxrΔIE) mice treated with Gly-MCA. Integrative analyses based on genome-scale metabolic models demonstrated an important link between Lactobacillus and Clostridia bile 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. IMPORTANCE The 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 of Fxr in 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.
format	article
author	Limin Zhang Cen Xie Robert G. Nichols Siu H. J. Chan Changtao Jiang Ruixin Hao Philip B. Smith Jingwei Cai Margaret N. Simons Emmanuel Hatzakis Costas D. Maranas Frank J. Gonzalez Andrew D. Patterson
author_facet	Limin Zhang Cen Xie Robert G. Nichols Siu H. J. Chan Changtao Jiang Ruixin Hao Philip B. Smith Jingwei Cai Margaret N. Simons Emmanuel Hatzakis Costas D. Maranas Frank J. Gonzalez Andrew D. Patterson
author_sort	Limin Zhang
title	Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
title_short	Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
title_full	Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
title_fullStr	Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
title_full_unstemmed	Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism
title_sort	farnesoid x receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0e83188a77784a3c912625c3860b0e97
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Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism

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