Host stress proteins shape hemorrhagic shock via gut microbiota: evidence from Mendelian randomization and animal models

TL;DR

This study shows that host stress proteins influence hemorrhagic shock through changes in gut microbiota, suggesting new therapeutic strategies targeting the microbiome.

Contribution

The paper introduces a novel integrative framework linking host stress proteins, gut microbiota, and hemorrhagic shock using MR and animal models.

Findings

HSPB1 and HIF1A are protective proteins, while APAF1, F7, and F10 increase susceptibility to HS.

Gut microbiota diversity decreases after HS but partially recovers, with shifts in dominant genera like Lactobacillus, Blautia, and Romboutsia.

Microbial metabolism, especially amino acid and protein synthesis, is enriched during recovery, suggesting a role in stress adaptation.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12967-025-07364-8.

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