Evidence for bidirectional gut-spleen crosstalk in rodent models: scoping review of possible mechanisms and therapeutic implications

INTRODUCTION: The gut-spleen axis has been proposed to link the gut environment with splenic immune regulation and systemic homeostasis. This scoping review examines this interaction in rodent models. METHODS: Following PRISMA-ScR guidelines, we analyzed literature (2015-2025) from PubMed, Scopus, and other major databases, including English-language rodent studies reporting gut and splenic outcomes. RESULTS: Analysis of 48 studies suggests that gut dysbiosis may alter splenic architecture and immune function mainly via microbial metabolites, particularly short-chain fatty acids. Limited evidence indicates that splenic dysfunction could impair gut barrier integrity. Systemic stressors (e.g., infection or allergy) may reinforce this bidirectional inflammatory loop. Microbiota-targeted therapies have been observed primarily through gut-initiated mechanisms. Vagus nerve-mediated signaling points to a gut-brain-spleen network, though its directional hierarchy remains unresolved. CONCLUSION: Evidence supports a gut-spleen axis in rodents, with gut-derived microbial metabolites appearing to influence splenic immunity. Support for a reciprocal spleen-to-gut pathway remains limited and emergent, highlighting a research asymmetry. Together, these interactions suggest a partially bidirectional network linking the gut ecosystem to systemic immunity, with additional neural integration extending this framework toward a gut-brain-spleen axis. This integrative model proposes the gut-spleen axis as a potential therapeutic target warranting further investigation in inflammatory, metabolic, and neurological diseases.