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

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.