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Increasing viability of pathological liver grafts from brain dead donors via intestinal parasympathetic nerve stimulation, or exogenous serotonin
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  • Published: 10 April 2026

Increasing viability of pathological liver grafts from brain dead donors via intestinal parasympathetic nerve stimulation, or exogenous serotonin

  • Francisco Sanus1,2 na1,
  • Cristina Maroto-Serrat1,2 na1,
  • Gloria de la Rosa3,
  • Baltasar Pérez-Saborido4,
  • Carolina Almohalla4,
  • Jordi Gracia-Sancho1,5,6,7,
  • Albert Caballeria-Casals1,2,
  • Marc Micó-Carnero1,
  • Fátima del Carmen Navarro-Martínez8,
  • Alan Omar González-Hernández9,
  • Araní Casillas-Ramírez10,11 &
  • …
  • Carmen Peralta1 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Diseases
  • Gastroenterology
  • Medical research
  • Neuroscience

Abstract

Livers from donors after brain death (DBDs) with alcohol-associated liver disease (ALD) or steatosis, which undergo prolonged cold ischemia are often not considered for transplantation. We evaluate whether norepinephrine and acetylcholine (ACh) deficiencies impair intestinal serotonin (5-HT) delivery to the liver in extended-criteria DBDs liver transplantation (LT). A DBD rat model with ALD or severe steatosis was used. Norepinephrine, ACh and 5-HT levels were evaluated in liver and intestine. Pharmacological (ACh or 5-HT administration) and electrical stimulation of intestinal parasympathetic nervous system (IPNS) were applied to evaluate their effects on ACh, 5-HT, liver and intestinal damage. Our results indicate that norepinephrine levels were maintained in DBDs, whereas ACh and 5-HT were depleted in both intestine and liver. IPNS stimulation or ACh infusion via mesenteric artery restored intestinal ACh, generating 5-HT and intestinal protection. Platelets potentially transported this 5-HT, with restoration of hepatic 5-HT and protection. Intravenous 5-HT (not intravenous ACh) produced similar benefits, which persisted after 24 h cold ischemia and reperfusion, improving survival. Thus, IPNS electrical stimulation or ACh administration via mesenteric artery (which reversed 5-HT deficiencies in intestine and liver) or 5-HT administration can make steatotic or ALD grafts from extended-criteria DBDs viable after prolonged ischemia, improving LT outcomes.

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Data availability

The data supporting the findings of this study are available within the article and its supplementary information. Additional datasets are available from the corresponding author upon reasonable request.

Abbreviations

5-HT:

Serotonin

ACh:

Acetylcholine

ALD:

Alcoholic liver disease

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BD:

Brain death

BDNF:

Brain-derived neurotrophic factor

CI:

Cold ischemia

CI/R:

Cold ischemia–reperfusion

CNTF:

Cilliary neurotrophic factor

DBDs:

Donors after brain death

ECs:

Enterochromaffin cells

H&E:

Hematoxylin & eosin

HGF:

Hepatocyte growth factor

IPNS:

Intestinal parasympathetic nervous system

IL-10:

Interleukin 10

iv:

Intravenous

LT:

Liver transplantation

ma:

Mesenteric artery

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

NE:

Norepinephrine

PCNA:

Proliferating cell nuclear antigen

SD:

Sprague–Dawley

SNS:

Sympathetic nervous system

TGF-β:

Transforming growth factor β

TNF-α:

Tumor necrosis factor α

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

UW:

University of Wisconsin

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Acknowledgements

The authors thank Dr. Christopher Evans, a native English speaker and professional copy editor specialized in scientific research documents, for revising the English text.

Funding

Supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (PID2021-123123OB-100 and PID2024-155529OB-I00); the European Union (ERDF “Una manera de hacer Europa”); CERCA Programme/Generalitat de Catalunya; and the Catalan Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2021 SGR 01130).

Author information

Author notes

  1. Francisco Sanus and Cristina Maroto-Serrat contributed equally to this work.

Authors and Affiliations

  1. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Protective Strategies Against Hepatic Ischemia Reperfusion Injury Research Group, Roselló 149-153, 08036, Barcelona, Spain

    Francisco Sanus, Cristina Maroto-Serrat, Jordi Gracia-Sancho, Albert Caballeria-Casals, Marc Micó-Carnero & Carmen Peralta

  2. University of Barcelona, Barcelona, Spain

    Francisco Sanus, Cristina Maroto-Serrat & Albert Caballeria-Casals

  3. Spanish National Transplant Organization, Madrid, Spain

    Gloria de la Rosa

  4. Unidad Hepatología, Hospital Universitario Río Hortega, Valladolid, Spain

    Baltasar Pérez-Saborido & Carolina Almohalla

  5. Liver Vascular Biology Research Group, IDIBAPS, Barcelona, Spain

    Jordi Gracia-Sancho

  6. CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain

    Jordi Gracia-Sancho

  7. Biomedical Research Department, Inselspital and University of Bern, Bern, Switzerland

    Jordi Gracia-Sancho

  8. Universidad del Valle de México Campus Victoria, Ciudad, Mexico

    Fátima del Carmen Navarro-Martínez

  9. Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico

    Alan Omar González-Hernández

  10. Servicios de Salud Instituto Mexicano de Seguro Social para el Bienestar (IMSS-BIENESTAR), Hospital Regional Alta Especialidad de Cd Victoria, Tamaulipas 126, 87084, Cd Victoria, Mexico

    Araní Casillas-Ramírez

  11. Facultad de Medicina Matamoros, Autonoma University, Tamaulipas, Mexico

    Araní Casillas-Ramírez

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Contributions

FS and CM-S: Investigation, Methodology, Writing–original draft, Writing–review and editing, Formal Analysis; GS, BP-S, CA and JG-S: Conceptualization, Validation, Writing–review and editing, Visualization; AC-C and MM-C: Investigation, Methodology, Writing–original draft and editing; FN-M and AG-H: Methodology and Formal Analysis; and AC-R and CP: Conceptualization, Formal Analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Writing–original draft, Writing–review and editing.

Corresponding authors

Correspondence to Jordi Gracia-Sancho, Araní Casillas-Ramírez or Carmen Peralta.

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Sanus, F., Maroto-Serrat, C., de la Rosa, G. et al. Increasing viability of pathological liver grafts from brain dead donors via intestinal parasympathetic nerve stimulation, or exogenous serotonin. Sci Rep (2026). https://doi.org/10.1038/s41598-026-47831-w

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  • Received: 29 December 2025

  • Accepted: 03 April 2026

  • Published: 10 April 2026

  • DOI: https://doi.org/10.1038/s41598-026-47831-w

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