Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity

Fei Li; Changtao Jiang; Kristopher W. Krausz; Yunfei Li; Istvan Albert; Haiping Hao; Kristin M. Fabre; James B. Mitchell; Andrew D. Patterson; Frank J. Gonzalez

doi:10.1038/ncomms3384

Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity

Fei Li, Changtao Jiang, Kristopher W. Krausz, Yunfei Li, Istvan Albert, Haiping Hao, Kristin M. Fabre, James B. Mitchell, Andrew D. Patterson, Frank J. Gonzalez

Research output: Contribution to journal › Article › peer-review

494 Citations (SciVal)

Abstract

The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (Fxr^ΔIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr^ΔIE mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.

Original language	English (US)
Article number	2384
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3384
State	Published - Sep 24 2013

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Access to Document

10.1038/ncomms3384

Cite this

@article{fed21c940b6b475bb12ef999b9a302d5,

title = "Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity",

abstract = "The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (FxrΔIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in FxrΔIE mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.",

author = "Fei Li and Changtao Jiang and Krausz, {Kristopher W.} and Yunfei Li and Istvan Albert and Haiping Hao and Fabre, {Kristin M.} and Mitchell, {James B.} and Patterson, {Andrew D.} and Gonzalez, {Frank J.}",

note = "Funding Information: We thank Grace L. Guo (Rutgers University) for providing the PGL4-Shp-TK firefly luciferase construct and human FXR expression plasmid and Paul A.Dawson (Wake Forest University School of Medicine) for providing the human ASBT expression plasmid. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Sequencing was provided by the Penn State Genomics Core Facility, University Park, PA. This project was funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. Publisher Copyright: {\textcopyright} 2013 Macmillan Publishers Limited. All rights reserved.",

year = "2013",

month = sep,

day = "24",

doi = "10.1038/ncomms3384",

language = "English (US)",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity

AU - Li, Fei

AU - Jiang, Changtao

AU - Krausz, Kristopher W.

AU - Li, Yunfei

AU - Albert, Istvan

AU - Hao, Haiping

AU - Fabre, Kristin M.

AU - Mitchell, James B.

AU - Patterson, Andrew D.

AU - Gonzalez, Frank J.

N1 - Funding Information: We thank Grace L. Guo (Rutgers University) for providing the PGL4-Shp-TK firefly luciferase construct and human FXR expression plasmid and Paul A.Dawson (Wake Forest University School of Medicine) for providing the human ASBT expression plasmid. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Sequencing was provided by the Penn State Genomics Core Facility, University Park, PA. This project was funded, in part, under a grant with the Pennsylvania Department of Health using Tobacco CURE Funds. Publisher Copyright: © 2013 Macmillan Publishers Limited. All rights reserved.

PY - 2013/9/24

Y1 - 2013/9/24

N2 - The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (FxrΔIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in FxrΔIE mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.

AB - The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (FxrΔIE) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in FxrΔIE mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.

UR - http://www.scopus.com/inward/record.url?scp=84887960056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887960056&partnerID=8YFLogxK

U2 - 10.1038/ncomms3384

DO - 10.1038/ncomms3384

M3 - Article

C2 - 24064762

AN - SCOPUS:84887960056

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

M1 - 2384

ER -

Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this