The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review

The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys. This publication reviews gut-liver-derived mediators, which were tested and validated in vivo in humans and rodents , together with the current knowledge of their systemic effects on key vital organs. Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science. During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys. The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression. Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk. • BACKGROUND AND CONTEXT: Soluble mediators trigger distant receptor-mediated and receptor-independent signalling cascades in parenchymal and non-parenchymal cells, including the immune cells. However, a mechanistic overview of the interaction between gut-liver mediators and their impact on other vital organs is currently lacking. • NEW FINDINGS: 28 soluble components mediating gut-liver organ crosstalk, validated by in vivo studies in humans/rodents, were identified and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones (d) lipids and, (e) proteins. Additionally, the action mechanism of the brain, heart, and kidneys for each of the 28 identified mediators was reviewed. • LIMITATIONS: Given the systematic approach of this manuscript, only the gut-liver mediators validated by in vivo experimental studies or clinical trials were included. • CLINICAL RESEARCH RELEVANCE: This study identifies new potential therapeutic targets that affect multiple organs. The findings highlight that certain therapeutic targets can be used to treat several conditions at once. • BASIC RESEARCH RELEVANCE: In addition to highlighting the overlaps and gaps in the mechanistic pathways through which gut-liver mediators affect vital organs like the heart, kidneys, and brain, this systematic review underscores the urgent need to prioritize basic science on inter-organ communication. This approach paves the way for a holistic therapeutic approach of diseases, rather than the current silo-approach focusing on isolated organs.