Technical Abstract: Methionine (Met) is an indispensable, sulfur amino acid that functions as a key precursor for the synthesis of homocysteine and cysteine via transmethylation (TM) and transsulfuration (TS), respectively. We previously showed that significant metabolism of indispensable amino acids occurs in the gut. Our aim was to first quantify the first-pass splanchnic metabolism of dietary methionine and secondly to quantify the metabolic fate of methionine utilized by the gastrointestinal tract, defined as the portal-drained viscera (PDV). Four-week-old, formula fed piglets (n=16) were implanted with catheters in the carotid artery, jugular vein, and portal vein and an ultrasonic flow probe on the portal vein. Piglets were given an intravenous (IV) and intraduodenal (ID) infusion of [1-13C] methionine and [2H3] methionine on two separate days, in a cross-over design. The diet supplied a daily intake of 0.25g methionine and 0.31g cystine per kg body weight. Plasma arterial and portal concentrations and isotopic enrichments of methionine, homocysteine and 13CO2 were measured by HPLC and GC-(IR)MS. There was no significant first-pass splanchnic utilization of dietary methionine and TM and TS represented 25% and 18% of whole body Met flux, respectively. The net intestinal absorption of dietary methionine was 80% and 20% was utilized by the PDV. However, the PDV preferentially metabolized systemic arterial methionine rather than dietary methionine. PDV homocysteine release (TM) was 12 +/- 2% of PDV methionine uptake and 4% of whole body TM. PDV 13CO2 release (TS) was 15+/- 2% of PDV methionine uptake and 7% of whole body TS. We conclude that first-pass metabolism of dietary Met is limited, but that PDV metabolism of systemic arterial Met consumes 20% of the dietary intake. Our results also demonstrate that the neonatal PDV tissues are capable of TM and TS of methionine, but this represents a relative minor contribution of whole body Met metabolism.