Cascading effects of malaria on hepatic function and gut microbiota: Investigating the prospective therapeutic utility of Phyllanthus amarus alkaloid extract

Abstract

Malaria remains a critical global health challenge, not only due to its parasitic burden but also because of its capacity to induce severe hepatic dysfunction and disrupt gut microbiota, which together aggravate disease outcomes. In this study, we employed a murine model of Plasmodium berghei infection to evaluate the therapeutic potential of Phyllanthus amarus alkaloid extract. Unlike previous investigations that focused on isolated endpoints, our research integrated detailed histopathological grading, serum liver function assays, immunohistochemical analyses of apoptotic and inflammatory markers, and gut microbiota profiling in a single experimental framework. This comprehensive approach enabled us to gain a complete understanding of the gut–liver axis during malaria infection. We observed that malaria infection significantly elevated serum enzyme levels, bilirubin concentrations, and inflammatory cell infiltration while disturbing gut microbial balance and impairing intestinal barrier integrity, characterizing malaria-induced hepatic dysfunction. Perturbed gut microbiota composition and subsequent immune alterations are also evident. Administration of P. amarus alkaloid extract in a dose-dependent manner effectively restored liver function markers, reduced Kupffer cell hyperplasia, normalized bile acid levels, and modulated gut microbiota composition, thereby mitigating both hepatic inflammation and apoptosis. These findings reveal that the extract not only alleviates malaria-induced liver damage but also preserves intestinal homeostasis, suggesting a novel dual therapeutic role. Conclusively, our study provides new insights into the interplay between liver and gut responses during malaria infection and underscores the potential of P. amarus alkaloid extract as an adjunct or alternative therapeutic strategy to improve clinical outcomes in malaria.