BACKGROUND: Nutrient-sensing studies in humans frequently use intragastric intubation. A non-invasive alternative would be the use of freeze-dried lipids (FDL) capsules. We proposed to validate this method in pigs by (i) demonstrating that low-dose FDL can increase vagal activity, gastric compliance (GC), and delay gastric emptying time (GET); (ii) evaluating the release kinetics of encapsulated FDL. METHODS: Nine conscious pigs fitted with duodenal catheter and gastric cannula were administered FDL (3-mL freeze-dried Intralipid((R)) ). Vagal tone was estimated via heart rate variability (HRV) measurements, GC was measured via the barostatic method, and GET after a test meal was evaluated via scintigraphy. FDL vs placebo (methylcellulose [MC]) capsules release kinetics were also evaluated via scintigraphy. KEY RESULTS: Duodenal FDL infusion increased GC in 2/8 trials only, but systematically delayed GET compared to saline (96 vs 70 min; p = 0.018). The presence of FDL in the duodenum decreased heart rate, increased vagal tone, and HRV. FDL capsules released their content in the duodenum before MC capsules (41 vs 67 min; p = 0.013), and MC induced ECG data quite similar to FDL except for HRV (p = 0.011). CONCLUSIONS & INFERENCES: Low-dose FDL was a potent signal to induce vagal reflex and increase GET. FDL capsules released their content in the duodenum and activated the vagal pathway after approximately 40 min, which is an important data for designing future paradigms in humans. MC was not a good placebo because of its stickiness and ability to activate the vagal pathway too.