Abstract

Methamphetamine (METH) is a psychotropic drug known to cause cardiotoxicity. The gut-heart axis is emerging as an important pathway linking gut microbiota to cardiovascular disease, but the precise association between METH-induced cardiotoxicity and gut microbiota has yet to be elucidated. In this study, we established an escalating dose-multiple METH administration model in male BALB/c mice, examined cardiac injury and gut microbiota, and investigated the contribution of gut microbiota to cardiotoxicity induced by METH. Additionally, we treated mice with antibiotics and fecal microbiota transplantation (FMT) to assess the impact of gut microbiota on cardiotoxicity. Our results showed that METH exposure altered the p53 and PI3K/Akt signaling pathways and modulated the apoptosis pathway in heart tissue, accompanied by elevated levels of Bax/BCL-2 expression and cleaved caspase-3 proteins. METH exposure increased the diversity and richness of gut microbiota, and significantly changed the microbial community composition, accompanied by elevated abundance of Lactobacillus , Bifidobacterium , and decreased abundance of Bacteroides , norank_f_Muribaculaceae and Alistipes . Eliminating gut microbiota by antibiotics treatment alleviated METH-induced cardiotoxicity, while FMT treatment transferred similar cardiac injury manifestations from METH-exposed mice to healthy recipient mice. Our study unveils the crucial involvement of gut microbiota in the development of cardiotoxicity induced by METH and provides potential strategies for treating cardiac complications caused by METH.