Infection| Volume 167, ISSUE 3, P638-645, March 2020

Download started.


Electrical stimulation of the vagus nerve improves intestinal blood flow after trauma and hemorrhagic shock

Published:November 20, 2019DOI:



      Gut damage after trauma/hemorrhagic shock contributes to multiple organ dysfunction syndrome. Electrical vagal nerve stimulation is known to prevent gut damage in animal models of trauma/hemorrhagic shock by altering the gut inflammatory response; however, the effect of vagal nerve stimulation on intestinal blood flow, which is an essential function of the vagus nerve, is unknown. This study aimed to determine whether vagal nerve stimulation influences the abdominal vagus nerve activity, intestinal blood flow, gut injury, and the levels of autonomic neuropeptides.


      Male Sprague Dawley rats were anesthetized, and the cervical and abdominal vagus nerves were exposed. One pair of bipolar electrodes was attached to the cervical vagus nerve to stimulate it; another pair of bipolar electrodes were attached to the abdominal vagus nerve to measure action potentials. The rats underwent trauma/hemorrhagic shock (with maintenance of mean arterial pressure of 25 mmHg for 30 min) without fluid resuscitation and received cervical vagal nerve stimulation post-injury. A separate cohort of animals were subjected to transection of the abdominal vagus nerve (vagotomy) just before the start of cervical vagal nerve stimulation. Intestinal blood flow was measured by laser Doppler flowmetry. Gut injury and noradrenaline level in the portal venous plasma were also assessed.


      Vagal nerve stimulation evoked action potentials in the abdominal vagus nerve and caused a 2-fold increase in intestinal blood flow compared to the shock phase (P < .05). Abdominal vagotomy eliminated the effect of vagal nerve stimulation on intestinal blood flow (P < .05). Vagal nerve stimulation protected against trauma/hemorrhagic shock -induced gut injury (P < .05), and circulating noradrenaline levels were decreased after vagal nerve stimulation (P < .05).


      Cervical vagal nerve stimulation evoked abdominal vagal nerve activity and relieved the trauma/hemorrhagic shock–induced impairment in intestinal blood flow by modulating the vasoconstriction effect of noradrenaline, which provides new insight into the protective effect of vagal nerve stimulation.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Baker C.C.
        • Oppenheimer L.
        • Stephens B.
        • Lewis F.R.
        • Trunkey D.D.
        Epidemiology of trauma deaths.
        Am J Surg. 1980; 140: 144-150
        • Sauaia A.
        • Moore E.E.
        • Johnson J.L.
        • et al.
        Temporal trends of postinjury multiple-organ failure: still resource intensive, morbid, and lethal.
        J Trauma Acute Care Surg. 2014; 76 (discussion 592–593): 582-592
        • Swank G.M.
        • Deitch E.A.
        Role of the gut in multiple organ failure: bacterial translocation and permeability changes.
        World J Surg. 1996; 20: 411-417
        • Meng J.
        • Huang Y.C.
        • Huang J.
        • Yang K.
        The role of the sensor kinase, QseC, an adrenergic receptor of Escherichia coli, in bacterial translocation during hemorrhagic shock.
        J Trauma Acute Care Surg. 2016; 80: 972-976
        • Magnotti L.J.
        • Upperman J.S.
        • Xu D.Z.
        • Lu Q.
        • Deitch E.A.
        Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock.
        Ann Surg. 1998; 228: 518-527
        • Morishita K.
        • Aiboshi J.
        • Kobayashi T.
        • et al.
        Lipidomics analysis of mesenteric lymph after trauma and hemorrhagic shock.
        J Trauma Acute Care Surg. 2012; 72: 1541-1547
        • Bonaz B.
        • Sinniger V.
        • Pellissier S.
        Vagal tone: effects on sensitivity, motility, and inflammation.
        Neurogastroenterol Motil. 2016; 28: 455-462
        • Uesaka T.
        • Young H.M.
        • Pachnis V.
        • Enomoto H.
        Development of the intrinsic and extrinsic innervation of the gut.
        Dev Biol. 2016; 417: 158-167
        • Costantini T.W.
        • Bansal V.
        • Peterson C.Y.
        • et al.
        Efferent vagal nerve stimulation attenuates gut barrier injury after burn: modulation of intestinal occludin expression.
        J Trauma. 2010; 68 (discussion 1354–1356): 1349-1354
        • Borovikova L.V.
        • Ivanova S.
        • Zhang M.
        • et al.
        Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.
        Nature. 2000; 405: 458-462
        • Bernik T.R.
        • Friedman S.G.
        • Ochani M.
        • et al.
        Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion.
        J Vasc Surg. 2002; 36: 1231-1236
        • Morishita K.
        • Costantini T.W.
        • Eliceiri B.
        • Bansal V.
        • Coimbra R.
        J Trauma Acute Care Surg. 2014; 76 (discussion 617–618): 610-617
        • Levy G.
        • Fishman J.E.
        • Xu D.Z.
        • et al.
        Vagal nerve stimulation modulates gut injury and lung permeability in trauma-hemorrhagic shock.
        J Trauma Acute Care Surg. 2012; 73 (discussion 342): 338-342
        • Levy G.
        • Fishman J.E.
        • Xu D.
        • et al.
        Parasympathetic stimulation via the vagus nerve prevents systemic organ dysfunction by abrogating gut injury and lymph toxicity in trauma and hemorrhagic shock.
        Shock. 2013; 39: 39-44
        • Wang H.
        • Yu M.
        • Ochani M.
        • et al.
        Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
        Nature. 2003; 421: 384-388
        • Huston J.M.
        • Ochani M.
        • Rosas-Ballina M.
        • et al.
        Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.
        J Exp Med. 2006; 203: 1623-1628
        • Rosas-Ballina M.
        • Ochani M.
        • Parrish W.R.
        • et al.
        Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.
        Proc Natl Acad Sci U S A. 2008; 105: 11008-11013
        • Rosas-Ballina M.
        • Olofsson P.S.
        • Ochani M.
        • et al.
        Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.
        Science. 2011; 334: 98-101
        • Matteoli G.
        • Gomez-Pinilla P.J.
        • Nemethova A.
        • et al.
        A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen.
        Gut. 2014; 63: 938-948
        • Costantini T.W.
        • Bansal V.
        • Krzyzaniak M.
        • et al.
        Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells.
        Am J Physiol Gastrointest Liver Physiol. 2010; 299: G1308-G1318
        • Langness S.
        • Kojima M.
        • Coimbra R.
        • Eliceiri B.P.
        • Costantini T.W.
        Enteric glia cells are critical to limiting the intestinal inflammatory response after injury.
        Am J Physiol Gastrointest Liver Physiol. 2017; 312: G274-G282
        • Patel Y.A.
        • Saxena T.
        • Bellamkonda R.V.
        • Butera R.J.
        Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.
        Sci Rep. 2017; 7: 39810
        • Hoff D.A.
        • Gregersen H.
        • Hatlebakk J.G.
        Mucosal blood flow measurements using laser Doppler perfusion monitoring.
        World J Gastroenterol. 2009; 15: 198-203
        • Akiba Y.
        • Watanabe C.
        • Mizumori M.
        • Kaunitz J.D.
        Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats.
        Am J Physiol Gastrointest Liver Physiol. 2009; 297: G781-G791
        • Andersson A.
        • Rundgren M.
        • Kalman S.
        • et al.
        Gut microcirculatory and mitochondrial effects of hyperdynamic endotoxaemic shock and norepinephrine treatment.
        Br J Anaesth. 2012; 108: 254-261
        • Chiu C.J.
        • McArdle A.H.
        • Brown R.
        • Scott H.J.
        • Gurd F.N.
        Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal.
        Arch Surg. 1970; 101: 478-483
        • Feinman R.
        • Deitch E.A.
        • Watkins A.C.
        • et al.
        HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.
        Am J Physiol Gastrointest Liver Physiol. 2010; 299: G833-G843
        • Rupani B.
        • Caputo F.J.
        • Watkins A.C.
        • et al.
        Relationship between disruption of the unstirred mucus layer and intestinal restitution in loss of gut barrier function after trauma hemorrhagic shock.
        Surgery. 2007; 141: 481-489
        • Esler M.
        • Jennings G.
        • Korner P.
        • Blombery P.
        • Sacharias N.
        • Leonard P.
        Measurement of total and organ-specific norepinephrine kinetics in humans.
        Am J Physiol. 1984; 247: E21-E28
        • Yang S.
        • Koo D.J.
        • Zhou M.
        • Chaudry I.H.
        • Wang P.
        Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis.
        Am J Physiol Gastrointest Liver Physiol. 2000; 279: G1274-G1281
        • Ohta T.
        • Ito S.
        • Ohga A.
        Co-release of PHI and VIP in dog stomach by peripheral and central vagal stimulation.
        Br J Pharmacol. 1990; 100: 231-236
        • Yang Y.
        • Wu X.
        • Wei Z.
        • et al.
        Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca(2+)/CaMKII signaling pathways in the small intestine.
        Pharmacol Res. 2015; 95-96: 71-81
        • Carpenter R.
        • Reddi B.
        Neurophysiology: A Conceptual Approach.
        Fifth Edition. CRC Press, Boca Raton (FL)2012
      1. Mai J.K. Paxinos G. The Human Nervous System. Third Edition. Academic Press, London (UK)2011
        • Yuan H.
        • Silberstein S.D.
        Vagus nerve and vagus nerve stimulation, a comprehensive review: Part I.
        Headache. 2016; 56: 71-78
        • Breit S.
        • Kupferberg A.
        • Rogler G.
        • Hasler G.
        Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders.
        Front Psychiatry. 2018; 9: 44
        • Morishita T.
        • Guth P.H.
        Vagal nerve stimulation causes noncholinergic dilatation of gastric arterioles.
        Am J Physiol. 1986; 250: G660-G664
        • Ito S.
        • Ohga A.
        • Ohta T.
        Gastric vasodilatation and vasoactive intestinal peptide output in response to vagal stimulation in the dog.
        J Physiol. 1988; 404: 669-682
        • Druce H.M.
        • Bonner R.F.
        • Patow C.
        • Choo P.
        • Summers R.J.
        • Kaliner M.A.
        Response of nasal blood flow to neurohormones as measured by laser-Doppler velocimetry.
        J Appl Physiol Respir Environ Exerc Physiol. 1984; 57: 1276-1283
        • Cooke H.J.
        Neurobiology of the intestinal mucosa.
        Gastroenterology. 1986; 90: 1057-1081
        • Goyal R.K.
        • Hirano I.
        The enteric nervous system.
        N Engl J Med. 1996; 334: 1106-1115
        • Cheadle G.A.
        • Costantini T.W.
        • Bansal V.
        • Eliceiri B.P.
        • Coimbra R.
        Cholinergic signaling in the gut: a novel mechanism of barrier protection through activation of enteric glia cells.
        Surg Infect (Larchmt). 2014; 15: 387-393
        • Matteoli G.
        • Boeckxstaens G.E.
        The vagal innervation of the gut and immune homeostasis.
        Gut. 2013; 62: 1214-1222