BACKGROUND: Short-chain fatty acids (SCFAs), fermentation products of undigested fibers, are considered beneficial for colonic health. High plasma concentrations are potentially harmful; therefore, information about systemic SCFA clearance is needed before therapeutic use of prebiotics or colonic SCFA administration. OBJECTIVE: The aim of this study was to investigate the effect of rectal butyrate administration on SCFA interorgan exchange. METHODS: Twelve patients (7 men; age: 66.4 +/- 2.0 y; BMI 24.5 +/- 1.4 kg/m(2)) undergoing upper abdominal surgery participated in this randomized placebo-controlled trial. During surgery, 1 group received a butyrate enema (100 mmol sodium butyrate/L; 60 mL; n = 7), and the other group a placebo (140 mmol 0.9% NaCl/L; 60 mL; n = 5). Before and 5, 15, and 30 min after administration, blood samples were taken from the radial artery, hepatic vein, and portal vein. Plasma SCFA concentrations were analyzed, and fluxes from portal-drained viscera, liver, and splanchnic area were calculated and used for the calculation of the incremental area under the curve (iAUC) over a 30-min period. RESULTS: Rectal butyrate administration led to higher portal butyrate concentrations at 5 min compared with placebo (92.2 +/- 27.0 mumol/L vs. 14.3 +/- 3.4 mumol/L, respectively; P < 0.01). In the butyrate-treated group, iAUCs of gut release (282.8 +/- 133.8 mumol/kg BW . 0.5 h) and liver uptake (-293.7 +/- 136.0 mumol/kg BW . 0.5 h) of butyrate were greater than in the placebo group [-16.6 +/- 13.4 mumol/kg BW . 0.5 h (gut release) and 16.0 +/- 13.8 mumol/kg BW . 0.5 h (liver uptake); P = 0.01 and P < 0.05, respectively]. As a result, splanchnic butyrate release did not differ between groups. CONCLUSION: After colonic butyrate administration, splanchnic butyrate release was prevented in patients undergoing upper abdominal surgery. These observations imply that therapeutic colonic SCFA administration at this dose is safe. The trial was registered at clinicaltrials.gov as NCT02271802.