Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism

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

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere00070
JournalmSystems
Volume1
Issue number5
DOIs
StatePublished - Sep 1 2016

Fingerprint

Lipid Metabolism
intestinal microorganisms
lipid metabolism
Glycine
Receptor
obesity
Amino acids
High Fat Diet
Nutrition
Obesity
Oils and fats
metabolism
lipid
fat
high fat diet
liver
receptors
Acids
Liver
acid

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Physiology
  • Biochemistry
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Molecular Biology
  • Genetics
  • Computer Science Applications

Cite this

Zhang, Limin ; Xie, Cen ; Nichols, Robert G. ; Chan, Siu H.J. ; Jiang, Changtao ; Hao, Ruixin ; Smith, Philip B. ; Cai, Jingwei ; Simons, Margaret N. ; Hatzakis, Emmanuel ; Maranas, Costas D. ; Gonzalez, Frank J. ; Patterson, Andrew D. / Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. In: mSystems. 2016 ; Vol. 1, No. 5.
@article{2569fed8fca84b87abcf60c3b2ef229d,
title = "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 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.",
author = "Limin Zhang and Cen Xie and Nichols, {Robert G.} and Chan, {Siu H.J.} and Changtao Jiang and Ruixin Hao and Smith, {Philip B.} and Jingwei Cai and Simons, {Margaret N.} and Emmanuel Hatzakis and Maranas, {Costas D.} and Gonzalez, {Frank J.} and Patterson, {Andrew D.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1128/mSystems.00070-16",
language = "English (US)",
volume = "1",
journal = "mSystems",
issn = "2379-5077",
publisher = "American Society for Microbiology",
number = "5",

}

Zhang, L, Xie, C, Nichols, RG, Chan, SHJ, Jiang, C, Hao, R, Smith, PB, Cai, J, Simons, MN, Hatzakis, E, Maranas, CD, Gonzalez, FJ & Patterson, AD 2016, 'Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism', mSystems, vol. 1, no. 5, e00070. https://doi.org/10.1128/mSystems.00070-16

Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. / Zhang, Limin; Xie, Cen; Nichols, Robert G.; Chan, Siu H.J.; Jiang, Changtao; Hao, Ruixin; Smith, Philip B.; Cai, Jingwei; Simons, Margaret N.; Hatzakis, Emmanuel; Maranas, Costas D.; Gonzalez, Frank J.; Patterson, Andrew D.

In: mSystems, Vol. 1, No. 5, e00070, 01.09.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Farnesoid X receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism

AU - Zhang, Limin

AU - Xie, Cen

AU - Nichols, Robert G.

AU - Chan, Siu H.J.

AU - Jiang, Changtao

AU - Hao, Ruixin

AU - Smith, Philip B.

AU - Cai, Jingwei

AU - Simons, Margaret N.

AU - Hatzakis, Emmanuel

AU - Maranas, Costas D.

AU - Gonzalez, Frank J.

AU - Patterson, Andrew D.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85006765148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006765148&partnerID=8YFLogxK

U2 - 10.1128/mSystems.00070-16

DO - 10.1128/mSystems.00070-16

M3 - Article

AN - SCOPUS:85006765148

VL - 1

JO - mSystems

JF - mSystems

SN - 2379-5077

IS - 5

M1 - e00070

ER -