Simiao Yongan decoction alleviates sepsis-induced liver injury by modulating macrophage polarization via gut-derived ursodeoxycholic acid.

BACKGROUND

Sepsis-induced liver injury (SLI) is a severe complication of sepsis; however, its pathogenesis remains incompletely understood, and effective therapeutic agents are still lacking.

PURPOSE: This study was to analyze alterations in metabolic profiles in patients with sepsis and to elucidate the mechanisms by which the traditional Chinese medicine formula Simiao Yongan (SMYA) Decoction ameliorates SLI through an integrated multi-omics approach.

METHODS

An integrated multi-omics approach, including metabolomics, transcriptomics, 16S rRNA sequencing, and mass spectrometry, was employed to investigate metabolic alterations in sepsis and to elucidate the protective mechanisms of SMYA against sepsis-induced liver injury. Subsequently, immunofluorescence staining, Western blot analysis, and Surface plasmon resonanc (SPR) were performed to evaluate the regulatory effects of SMYA and ursodeoxycholic acid (UDCA) on macrophage polarization. Finally, an ApoB-modified liposome delivery system was constructed to enhance drug delivery efficiency and therapeutic efficacy.

RESULTS

We observed that serum UDCA levels were markedly reduced in patients with sepsis and were inversely correlated with the expression of pro-inflammatory mediators. SMYA ameliorated SLI by enhancing intestinal UDCA biosynthesis. Mechanistically, UDCA inhibited TLR4/NF-κB-mediated macrophage polarization, thereby attenuating hepatic inflammatory responses. In addition, an ApoB-modified liposome delivery system significantly enhanced the therapeutic efficacy of UDCA.

CONCLUSION

we elucidated that the Gut microbiota-UDCA-Macrophage axis underlies the hepatoprotective effects of SMYA, offering a promising integrative therapeutic strategy for SLI.