Weaning stress reprograms immune translation through GC biased codon usage in piglets with gut microbiota dysbiosis

Weaning stress constitutes a critical early-life challenge that disrupts immune homeostasis and reshapes gut microbiota composition. Here, we integrate ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) to characterize transcriptional and translational responses in peripheral blood mononuclear cells (PBMCs) from healthy and weaning piglets. We show that weaning stress induces widespread translational reprogramming, with pronounced effects on immune genes, including significantly increased translation efficiency of key inflammatory mediators CD82, CCL25, and TNFSF13. These changes are accompanied by distinct shifts in codon usage patterns, with genes exhibiting enhanced translation in the weaning group displaying enrichment of GC-ending codons (GC3), including those encoding leucine, glutamate, and lysine. Integrative analysis further suggests a coordinated relationship between translational remodeling and gut microbiota dysbiosis. Genera enriched in healthy piglets, including Romboutsia, Lactobacillus, and Turicibacter, were associated with AT-rich codon usage patterns, whereas genera expanded under weaning stress, such as Fusobacterium and Streptococcus, were linked to GC-enriched codon profiles, concomitant with increased GC3 content and codon adaptation index. Collectively, these findings identify a previously unrecognized association between microbiota composition and codon-usage-linked translational regulation during stress-induced immune responses, providing a framework for understanding microbiome-host interactions at the level of translational control.