Abstract
Alveolar echinococcosis (AE), a chronic parasitic disease caused by Echinococcus multilocularis (E. multilocularis), remains poorly characterized with respect to central nervous system (CNS) involvement, and its long-term effects on mental health have not been systematically investigated. In this study, we established a BALB/c mouse model of chronic E. multilocularis infection and applied an integrative framework combining behavioral assessments, histomorphological analyses (hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy), cytometric bead array (CBA), and multi-omics approaches (16S rRNA sequencing, metagenomics, and untargeted metabolomics) to investigate infection-induced neuroimmune-gut microbiota interactions. Chronically infected mice exhibited pronounced depression-like behavioral phenotypes, accompanied by hippocampal neuronal nuclear membrane atrophy and disrupted microglial homeostasis. Both peripheral and central inflammatory profiling revealed elevated levels of pro-inflammatory mediators, particularly IL-6 and MCP-1, suggesting coordinated systemic immune activation and neuroimmune alterations. Notably, fecal microbiota transplantation (FMT) from infected donors was sufficient to induce depression-like behaviors in recipient mice, supporting a contributory role of infection-associated gut microbiota alterations in behavioral abnormalities. Integrated multi-omics analyses further revealed a marked reduction in Lactobacillus abundance in infected mice, which was positively correlated with decreased levels of key metabolites within the tryptophan/5-hydroxytryptamine (5-HT) metabolic pathway. Collectively, these findings suggest that chronic E. multilocularis infection may be associated with depression-like behaviors through gut microbiota dysbiosis and related metabolic perturbations. This study provides initial insights into the potential mechanisms underlying neuropsychiatric complications in AE and proposes a conceptual framework for future investigations into early intervention and microbiota-targeted therapeutic strategies.