orexigenic hormone, is reduced in sepsis. Ghrelin treatment,

mediated through ghrelin receptors in the brain, attenuates sepsis-

induced inflammation and mortality. Gut barrier dysfunction is

common in sepsis. High-mobility group B1 (HMGB1) increases gut

whether ghrelin has any effects on HMGB1 and gut barrier

function in sepsis. We hypothesized that ghrelin decreases

HMGB1 release and attenuates sepsis-induced gut barrier dysfunction

through central ghrelin receptors.

injection/infusion of ghrelin.

intravenous injection of 2 nmol of ghrelin was followed by a

continuous infusion of 12 nmol of ghrelin via an osmotic minipump

for 15 hrs. Twenty hours after CLP, brain ghrelin levels,

serum HMGB1 levels, ileal mucosal permeability to fluorescein

isothiocyanate dextran, bacterial counts in the mesenteric lymph

nodes complex, and gut water content were determined. In additional

groups of animals, bilateral trunk vagotomy was performed

at 5 hrs after CLP before ghrelin injection. Furthermore, to

confirm the role of central ghrelin receptors in ghrelin’s effect,

ghrelin (1 nmol) was administered through intracerebroventricular

injection at 5 hrs after CLP. Our results showed that brain

levels of ghrelin decreased by 34% at 20 hrs after CLP. Intravenous

administration of ghrelin completely restored brain levels of

ghrelin, significantly reduced the elevated HMGB1 levels, and

attenuated gut barrier dysfunction. Vagotomy eliminated ghrelin’s

inhibition of HMGB1 and attenuation of gut barrier dysfunction.

Intracerebroventricular injection of ghrelin decreased serum

HMGB1 levels and ameliorated gut barrier dysfunction.

gut barrier dysfunction in sepsis by vagus nerve activation

via central ghrelin receptors. Ghrelin can be further developed

as a novel agent to protect gut barrier function in sepsis.

(Crit Care Med 2009; 37:000–000)