Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity.
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.
1] Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
Fei
F
Li
Changtao
C
Jiang
Kristopher W
KW
Krausz
Yunfei
Y
Li
Istvan
I
Albert
Haiping
H
Hao
Kristin M
KM
Fabre
James B
JB
Mitchell
Andrew D
AD
Patterson
Frank J
FJ
Gonzalez
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003497:Cyclic N-Oxides / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D007778:Lactobacillus / Q000187:drug effects* / Q000201:enzymology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota / Q000187:drug effects* / Q000502:physiology; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000382:microbiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013113:Spin Labels; D013656:Taurocholic Acid / Q000819:agonists / Q000031:analogs & derivatives* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D000581:Amidohydrolases; D019440:Anti-Obesity Agents; D000975:Antioxidants; D001426:Bacterial Proteins; D003497:Cyclic N-Oxides; D005947:Glucose; D018160:Receptors, Cytoplasmic and Nuclear; D013113:Spin Labels; D013656:Taurocholic Acid; D000099150:Receptor, Farnesoid X-Activated; C037351:tauromuricholic acid; C023154:choloylglycine hydrolase; C001803:tempol