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 and Frank J. Gonzalez ()
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Fei Li: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Changtao Jiang: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Kristopher W. Krausz: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Yunfei Li: Bioinformatics Consulting Center, The Pennsylvania State University
Istvan Albert: Bioinformatics Consulting Center, The Pennsylvania State University
Haiping Hao: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Kristin M. Fabre: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
James B. Mitchell: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Andrew D. Patterson: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health
Frank J. Gonzalez: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3384

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