Background: We recently showed that dietary butyrate reduces food intake and improves energy expenditure by activating brown adipose tissue (BAT) as dependent on vagus nerve signaling and related to the change of composition and diversity of gut microbiota (Li, Gut 2017). Since gut microbiota can induce vagus nerve activity, in the present study we aimed to investigate the role of gut microbiota in the beneficial effects of butyrate on energy metabolism.

Methods: Conventional or gut microbiota depleted APOE*3-Leiden.CETP mice, a well-established translational model for developing diet-induced human-like metabolic syndrome, were fed a high-fat diet (HFD) with or without sodium butyrate (5% w/w). After 7 weeks of intervention,  mice received triacylglycerol-rich lipoprotein (TRL)-like emulsion particles labelled with glycerol tri[³H]oleate by intravenous injection, and plasma clearance and organ uptake of [³H]oleate were determined.

Results: In conventional mice, butyrate reduced food intake and completely prevented the HFD-induced increase in body weight gain. Butyrate administration reduced BAT pad weight and intracellular lipid content within BAT pad, suggesting enhanced BAT thermogenic capacity. Accordingly, butyrate accelerated the clearance of glycerol tri[³H]oleate from plasma, accompanied by increased uptake specifically by BAT, confirming that butyrate enhances plasma triglyceride clearance by activating BAT. In contrast, depletion of gut microbiota by antibiotics completely abolished the satiety effects of butyrate. In addition, gut microbiota depletion also impaired the ability of butyrate to activate BAT, as the intracellular lipid content within BAT pad as well as the uptake of [³H]oleate by BAT were unaffected. As a result, butyrate only partially prevented HFD induced body weight gain in gut microbiota depleted mice.

Conclusion: Gut microbiota play a key role in the beneficial effects of butyrate on host energy metabolism with respect to reducing appetite, activating brown adipose tissue, and preventing HFD-induced obesity.