Abstract
BACKGROUND: Hemorrhagic shock (HS) is a severe condition involving stress proteins, inflammation, and gut microbiota dysbiosis. Understanding whether regulatory proteins influence HS through microbial pathways is crucial for improving therapeutic strategies. METHODS: We used Mendelian randomization (MR) combined with animal experiments to investigate the role of regulatory proteins in HS. Two-sample MR was performed to assess the impact of various stress-related proteins. Additionally, 16 S rRNA sequencing was conducted in a rat HS model to analyze gut microbiota diversity and composition at baseline, 24 h, and 72 h after hemorrhage. RESULTS: Two-sample MR identified HSPB1 and HIF1A as protective proteins, while APAF1, F7, and F10 increased susceptibility to HS. In the rat model, microbiota alpha diversity decreased at 24 h but partially recovered by 72 h, with significant shifts in beta diversity. Genus-level analysis revealed transient expansion of Lactobacillus, followed by dominance of Blautia and Romboutsia. Stage-specific predictions from PICRUSt2 suggested enrichment of amino acid metabolism and protein synthesis, particularly at 72 h, implicating microbial regulation in cellular recovery and stress adaptation. CONCLUSIONS: Our findings support a “protein-microbiota-HS” regulatory framework, highlighting the gut microbiota as key mediators of host stress responses. This integrative approach provides mechanistic insights into HS pathogenesis and suggests potential microbiome-targeted therapeutic strategies. We propose that targeting specific microbial communities, such as Blautia and Lactobacillus, could enhance recovery from HS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07364-8.