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

Introduction: 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. Aim: 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. Method: Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science. Results: 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. Discussion: The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression. Conclusion: 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. (c) 2025 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).