Angelica sinensis polysaccharides enhance the production and bactericidal ability of macrophages for resisting leptospiral infection through the gut microbiota

Leptospirosis, a globally re-emerging zoonotic disease, poses a significant threat to public and veterinary health, with current prevention strategies being limited. <em>Angelica sinensis</em> polysaccharide (ASP), a natural bioactive compound, is known for its immunomodulatory and microbiota-regulating properties, yet its efficacy against leptospirosis remains unexplored. This study aimed to investigate the preventive effect of ASP and its underlying mechanism in a murine model. We demonstrated that oral pre-treatment with ASP significantly attenuated the leptospiral burden in the kidneys, liver, and lungs, alleviated tissue damage, and reduced systemic inflammation following <em>Leptospira</em> infection. Mechanistically, ASP promoted hematopoiesis in the bone marrow, leading to an increased production of mononuclear-macrophages. These macrophages exhibited enhanced phagocytic and bactericidal capacities against <em>Leptospira</em>, and their depletion abrogated ASP's protective effect. Furthermore, ASP administration markedly altered the gut microbiota composition. Crucially, the protective efficacy of ASP was eliminated upon antibiotic depletion of the gut microbiota, while fecal microbiota transplantation (FMT) from ASP-treated mice conferred significant resistance to leptospiral infection in recipient mice. Our findings reveal that ASP enhances host defense against leptospirosis by modulating the gut microbiota and subsequently boosting the production and antimicrobial functions of macrophages. This study identifies ASP as a promising preventive agent against leptospirosis and provides novel insights into the gut microbiota-macrophage axis as a potential target for intervention.