Liver–Microbiome Crosstalk Mediates the Protective Effects of Artemisinin in <i>Clostridium perfringens</i> Models

Clostridium perfringens is a multi-host opportunistic pathogen whose plasmid-encoded toxins cause gas gangrene, necrotic enteritis and enterotoxemia, resulting in substantial economic losses in animal husbandry. In light of antibiotic bans and the need for alternatives, we employed reverse network pharmacology to screen and in vitro validate artemisinin (ART), then assessed its efficacy in murine and rabbit infection models challenged with C. perfringens type F. ART treatment did not significantly affect body weight change or intestinal histopathological damage. However, it significantly modulated inflammatory cytokines and antioxidant parameters in a tissue- and species-dependent manner. Specifically, ART increased serum TNF-α in mice, decreased IL-1β in rabbits and elevated IL-10 in multiple tissues. In addition, ART enhanced hepatic SOD and T-AOC in mice and reduced hepatic MDA in rabbits. Microbiota analysis revealed limited and subtle shifts in community structure following ART intervention. Transcriptomic analysis further indicated that ART treatment induced marked changes in hepatic gene expression, particularly involving detoxification, lipid metabolism and stress response pathways, with notable species-specific differences in enrichment profiles. While correlation analysis suggested associations of Anaerotruncus with hepatic detoxification genes and Bacteroides with inflammation-regulatory genes, these genus-level findings are based on correlation only and should be interpreted with caution given the lack of significant changes in overall microbial community structure. Collectively, these results indicate that ART can modulate host inflammatory and antioxidant responses, but its impact on gut microbiota composition in C. perfringens infection models appears limited, and the biological significance of observed genus-level associations remains to be elucidated.