Integrated multi-tissue transcriptome and serum metabolome analysis reveals brain–gut–liver regulatory axes of residual feed intake in ducks

Residual feed intake (RFI) is a key indicator of feed efficiency in poultry. Although regulatory links such as the hypothalamus-gut and gut-liver axes have been implicated, most studies remain restricted to single axes or fragmented analyses, and systematic multi-organ integration is lacking. Here, we measured feed efficiency in 1,000 Nonghua ducks and selected 12 individuals with divergent RFI for transcriptomic profiling of the hypothalamus, pituitary, liver, duodenum, jejunum, ileum, and cecum, combined with serum metabolomics. We identified 769 differentially expressed genes (DEGs), with the hypothalamus, liver, and cecum as major contributors, and 28 differential serum metabolites enriched in lipid and amino acid metabolism. Beyond tissue-specific functions, enrichment analysis highlighted several pathways that were repeatedly shared across central and peripheral tissues, including neuroactive ligand-receptor interaction, hormone signaling, steroid hormone biosynthesis, and insulin signaling, suggesting a coordinated regulation of feed efficiency between the brain, gut, and liver. To clarify their relevance, we integrated gene modules with metabolites and identified two candidate cross-organ association frameworks: the MEblack-6-Oxopiperidine-2-carboxylic acid (gut-liver) networks, enriched for liver genes CNTNAP1, SHC3, and RAB36, and cecal genes DCC and CCDC60. The MEblue-LysoPE(18:2(9Z,12Z)/0:0) (gut-brain) networks, enriched for cecal genes FABP6, KCNJ11, and the pituitary gene TRPA1, in which these genes and metabolites may contribute to RFI regulation. Together, these findings provide new insights into cross-organ molecular networks underlying feed efficiency in ducks and establish a valuable resource for future functional studies and breeding strategies.