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.