Portal Vein Metabolomic Profiling Highlights One-Carbon Metabolism As A Key Pathway Affected By Roux-En-Y Gastric Bypass Surgery

After Roux-en-Y gastric bypass (RYGB) surgery, the intestine undergoes structural and metabolic reprogramming and appears to enhance utilization of energetic fuels including glucose and amino acids (AAs), changes that may be related to the surgery’s remarkable metabolic effects. Consistently, RYGB alters serum levels of AAs and other metabolites, changes hypothesized to underlie these benefits. To home in on the intestinal contribution, we performed metabolomic profiling in portal vein (PV) blood from lean, Long Evans rats after RYGB versus sham surgery. After RYGB, systemic blood (SB) metabolomic fingerprinting reflected changes in AA metabolism including serine/glycine/threonine metabolism, an important mechanism of one-carbon donation for folate metabolism. Principal component analysis (PCA) confirmed, among the metabolites most influential to the post-RYGB SB metabolome (PC1, P=0.0008), enrichment for these pathways as well as for sphingolipid and glycerophospholipid metabolism. PV profiling largely mirrored that of SB; using PCA to identify the PV metabolites most affected after RYGB (PC2, P=0.016), we found one-carbon metabolism (OCM) to be enriched. Among those metabolites significantly altered in PV versus SB, 15 were uniquely affected in sham-operated animals and 33 in RYGB-operated animals. Pathway analysis of the latter revealed overrepresentation of nitrogen, serine/glycine/threonine, and sphingolipid metabolism as well as ubiquinone biosynthesis. Together, our data provide novel insight into RYGB’s effects on the gut-liver axis and highlight a role for OCM as a key metabolic pathway affected by RYGB. OCM links cellular nutrient status to homeostatic mechanisms including purine biosynthesis, AA homeostasis, and epigenetic maintenance, and we hypothesize that in the intestine and liver, it might serve as a key fuel sensing pathway to mediate local changes in glucose metabolism, perhaps via epigenetic reprogramming. Disclosure M.A. Stefater: None. J. Avila: None. C.B. Clish: None. N. Stylopoulos: None. Funding National Institutes of Health