Vagotomy blunts cardiorespiratory responses to vagal afferent stimulation via pre- and postsynaptic effects in the nucleus tractus solitarii.

Viscerosensory information travels to the brain via vagal afferents, where it is first integrated within the brainstem nucleus tractus solitarii (nTS), a critical contributor to cardiorespiratory function and site of neuroplasticity. We have shown that decreasing input to the nTS via unilateral vagus nerve transection (vagotomy) induces morphological changes in nTS glia and reduces sighs during hypoxia. The mechanisms behind post-vagotomy changes are not well understood. We hypothesized that chronic vagotomy alters cardiorespiratory responses to vagal afferent stimulation via blunted nTS neuronal activity. Male Sprague-Dawley rats (6 weeks old) underwent right cervical vagotomy caudal to the nodose ganglion, or sham surgery. After 1 week, rats were anaesthetized, ventilated and instrumented to measure mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively). Vagal afferent stimulation (2-50 Hz) decreased cardiorespiratory parameters and increased neuronal Ca2+ measured by in vivo photometry and in vitro slice imaging of nTS GCaMP8m. Vagotomy attenuated both these reflex and neuronal Ca2+ responses compared to shams. Vagotomy also reduced presynaptic Ca2+ responses to stimulation (Cal-520 imaging) in the nTS slice. The decrease in HR, SSNA and PhrNA due to nTS nanoinjection of exogenous glutamate also was tempered following vagotomy. This effect was not restored by blocking excitatory amino acid transporters. However, the blunted responses were mimicked by NMDA, not AMPA, nanoinjection and were associated with reduced NR1 subunits in the nTS. Altogether, these results demonstrate that vagotomy induces multiple changes within the nTS tripartite synapse that influence cardiorespiratory reflex responses to afferent stimulation. KEY POINTS: Multiple mechanisms within the nucleus tractus solitarii (nTS) contribute to functional changes following vagal nerve transection. Vagotomy results in reduced cardiorespiratory reflex responses to vagal afferent stimulation and nTS glutamate nanoinjection. Blunted responses occur via reduced presynaptic Ca2+ activation and attenuated NMDA receptor expression and function, leading to a reduction in nTS neuronal activation. These results provide insight into the control of autonomic and respiratory function, as well as the plasticity that can occur in response to nerve damage and cardiorespiratory disease.

A ganglionic intestinointestinal reflex activated by acute noxious challenge.

To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected from mesenteric nerves close to the small intestine in anesthetized rats. These exhibited baseline multiunit activity that was almost unaffected by vagotomy (VagX) and reduced only slightly by cutting the splanchnic nerves. The activity was halved by hexamethonium (Hex) treatment. When an adjacent gut segment received an intraluminal stimulus 2,4,6-trinitrobenzenesulfonate (TNBS) in 30% ethanol, mesenteric efferent nerve activity increased for more than 1 h. The increased activity was almost unaffected by bilateral vagotomy or splanchnic nerve section, indicating a lack of central nervous involvement, but it was 60% reduced by hexamethonium. Spike sorting discriminated efferent single and predominantly single-unit spike trains that responded to TNBS, were unaffected by splachnectomy but were silenced by hexamethonium. After noxious stimulation of one segment, the adjacent segment showed no evidence of suppression of gut motility or vasoconstriction. We conclude that luminal application of a noxious stimulus to the small intestine activates an entirely peripheral, intestinointestinal reflex pathway. This pathway involves enteric intestinofugal neurons that excite postganglionic sympathetic neurons via a nicotinic synapse. We suggest that the final sympathetic efferent neurons that respond to a tissue damaging stimulus are distinct from vasoconstrictor, secretomotor, and motility inhibiting neurons.NEW & NOTEWORTHY An intraluminal noxious chemical stimulus applied to one segment of small intestine increased mesenteric efferent nerve activity to an adjacent segment. This was identified as a peripheral ganglionic reflex that did not require vagal or spinal connections. Hexamethonium blocked most, but not all, ongoing and reflex mesenteric efferent activity. The prevertebral sympathetic efferent neurons that are activated likely affect inflammatory and immune functions of other gut segments.

Hepatic Vagotomy in Patients With Obesity Leads to Improvement of the Cholesterol to High-Density Lipoprotein Ratio.

INTRODUCTION/PURPOSE: The obesity epidemic is rapidly growing, and visceral adiposity is associated with metabolic consequences secondary to peroxisome proliferator-activated receptor (PPAR)-induced inter-organ signaling pathways. PPARs are ligand-activated transcription factors that modulate vagal pathways which can improve blood pressure, arterial remodeling, cholesterol levels, and insulin sensitivity. However, an obesity-induced inflammatory milieu can interfere with the beneficial effects of PPAR activity, suggesting that a dysregulated PPAR-vagus pathway may play a role in the pathogenesis of obesity-related hypertension. Therefore, we hypothesized that hepatic vagotomy (HV) in patients with obesity would result in a significant reduction in blood pressure and/or the number of hypertension medications compared to control. METHODS: We conducted a retrospective chart review of 160 patients undergoing laparoscopic sleeve gastrectomy. Patients were divided into HV and control groups, and information was collected at each clinic visit. RESULTS: At six-months post-operation, the HV group was found to have significantly lower total cholesterol (TC)/high-density lipoprotein (HDL) ratios than the control group. The HV group also had a numerically better blood profile for TC, HDL, low-density lipoprotein (LDL), triglycerides, C-reactive protein, and LDL/HDL ratio. Hypertensive patients in the HV group showed numerically lower hypertension medication counts after six weeks when compared to control. CONCLUSION: We present the first study to report clinically significant changes related to HV in human subjects. Our results did not support our initial hypothesis but did demonstrate an improvement of the TC/HDL ratio with HV in patients with obesity. Future studies should confirm these findings in a randomized control trial.

Exploring the safety and efficacy of stomach-partitioning gastrojejunostomy with distal selective vagotomy versus conventional gastrojejunostomy with highly selective vagotomy for treating benign gastric outlet obstruction: study protocol for a randomised controlled trial.

INTRODUCTION: Benign gastric outlet obstruction (BGOO) severely impacts the quality of life of patients. The main treatment methods for BGOO include surgery and endoscopy, but both have significant drawbacks. Therefore, this study aims to explore the safety and efficacy of a new technique, to develop a new option for treating BGOO. METHODS AND ANALYSIS: This is an ongoing prospective, single-centre, single-blind randomised controlled trial. The study will be conducted from January 2022 to December 2025, and 50 patients will be enrolled. The participants will be randomly assigned in a 1:1 ratio to either the experimental (stomach-partitioning gastrojejunostomy with distal selective vagotomy) or control groups (conventional gastrojejunostomy with highly selective vagotomy). We will collect baseline characteristics, laboratory tests, auxiliary examinations, operation, postoperative conditions and follow-up data. Follow-up will last for 3 years. The main outcome is the incidence of delayed gastric emptying within 30 days after surgery. Secondary outcomes include the efficacy indicator (consisting of serum gastrin level, pepsinogen level, 13C breath test, gastrointestinal quality of life index, operation time, blood loss and postoperative recovery), a safety evaluation index (consisting of complications and mortality within 30 days after surgery) and follow-up data (consisting of the incidence of primary ulcer progression in 3 years after surgery, and the gastroscopy results in 1 and 3 years after surgery). ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (no. 2021-P2-274-02). The study conformed to the provisions of the Declaration of Helsinki (as revised in 2013). Written informed consent will be obtained prior to study enrolment. The results of this study will be published in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2100052197.

Is vagotomy necessary in palliative surgery for incurable advanced gastric cancer?: a retrospective case-control study.

BACKGROUND: The interplay between the nervous system and cancer plays an important role in the initiation and progression of gastric cancer. Few studies have presented evidence that the sympathetic nervous system inhibits the occurrence and development of gastric cancer while the parasympathetic nervous system promotes the growth of gastric cancer. To investigate the effect of vagotomy, which is the resection of a parasympathetic nerve innervating the stomach, on the progression of gastric cancer, a retrospective study was conducted comparing the prognosis of simple palliative gastrojejunostomy (PGJ) and palliative gastrojejunostomy with vagotomy (PGJV). METHODS: From January 01, 2000, to December 31, 2021, the medical records of patients who underwent PGJ or PGJV because of gastric outlet obstruction due to incurable advanced gastric cancer at the Yeungnam University Medical Center were retrospectively reviewed. Patients were divided into two groups: locally unresectable gastric cancer (LUGC) or gastric cancer with distant metastasis (GCDM), according to the reason for gastrojejunostomy, and factors affecting overall survival (OS) were analyzed. RESULTS: There was no significant difference in surgical outcomes and postoperative complications between the patients with PGJV and patients with PGJ. In univariate analysis, vagotomy was not a significant factor for OS in the GCDM group (HR 1.14, CI 0.67-1.94, p value 0.642), while vagotomy was a significant factor for OS in the LUGC group (HR 0.38, CI 0.15-0.98, p value 0.045). In multivariate analysis, when vagotomy is performed together with PGJ for LUGC, the OS can be significantly extended (HR 0.25, CI 0.09-0.068, p value 0.007). CONCLUSIONS: When PGJ for LUGC was performed with vagotomy, additional survival benefits could be achieved with low complication risk. However, to confirm the effect of vagotomy on the growth of gastric cancer, further prospective studies using large sample sizes are essential.

Mast cells link immune sensing to antigen-avoidance behaviour.

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1-3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

Exploring the Modulatory Effect of High-Fat Nutrition on Lipopolysaccharide-Induced Acute Lung Injury in Vagotomized Rats and the Role of the Vagus Nerve.

During esophagectomy, the vagus nerve is transected, which may add to the development of postoperative complications. The vagus nerve has been shown to attenuate inflammation and can be activated by a high-fat nutrition via the release of acetylcholine. This binds to α7 nicotinic acetylcholine receptors (α7nAChR) and inhibits α7nAChR-expressing inflammatory cells. This study investigates the role of the vagus nerve and the effect of high-fat nutrition on lipopolysaccharide (LPS)-induced lung injury in rats. Firstly, 48 rats were randomized in 4 groups as follows: sham (sparing vagus nerve), abdominal (selective) vagotomy, cervical vagotomy and cervical vagotomy with an α7nAChR-agonist. Secondly, 24 rats were randomized in 3 groups as follows: sham, sham with an α7nAChR-antagonist and cervical vagotomy with an α7nAChR-antagonist. Finally, 24 rats were randomized in 3 groups as follows: fasting, high-fat nutrition before sham and high-fat nutrition before selective vagotomy. Abdominal (selective) vagotomy did not impact histopathological lung injury (LIS) compared with the control (sham) group (p > 0.999). There was a trend in aggravation of LIS after cervical vagotomy (p = 0.051), even after an α7nAChR-agonist (p = 0.090). Cervical vagotomy with an α7nAChR-antagonist aggravated lung injury (p = 0.004). Furthermore, cervical vagotomy increased macrophages in bronchoalveolar lavage (BAL) fluid and negatively impacted pulmonary function. Other inflammatory cells, TNF-α and IL-6, in the BALF and serum were unaffected. High-fat nutrition reduced LIS after sham (p = 0.012) and selective vagotomy (p = 0.002) compared to fasting. vagotomy. This study underlines the role of the vagus nerve in lung injury and shows that vagus nerve stimulation using high-fat nutrition is effective in reducing lung injury, even after selective vagotomy.

Bilateral subdiaphragmatic vagotomy modulates the peripheral met­enkephalin and striatal monoamine responses to peripheral inflammation in rat.

In the central nervous system, long­term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well­being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met­enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune­derived plasma met­enkephalin to establish a long­term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation­induced increases of plasma met­enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.

The effects of gallic acid and vagotomy on motor function, intestinal transit, brain electrophysiology and oxidative stress alterations in a rat model of Parkinson's disease induced by rotenone.

INTRODUCTION: The neuropathology of Parkinson's disease (PD) is complex and affects multiple systems of the body beyond the central nervous system. This study examined the effects of gallic acid (GA) and gastrointestinal vagotomy (VG) on motor, cognitive, intestinal transit time, and thalamic nuclei electrical power in an animal model of PD induced by rotenone. MATERIALS AND METHODS: Male Wistar rats were divided into 4 groups: Sham, ROT, ROT+GA, VG + ROT. Sham rats received vehicle, those in ROT received rotenone (5 mg/kg/2 ml, ig), PD rats in ROT+GA were treated with GA (100 mg/kg, gavage/once daily, for 28 days), and in VG + ROT, the vagal nerve was dissected. Stride length, motor coordination and locomotion, intestinal transit time, cognitive and pain threshold, and thalamic local EEG were evaluated. Oxidative stress indexes in striatal tissue were also measured. RESULTS: Rotenone diminished significantly the stride length (p < 0.001), motor coordination (p < 0.001), power of thalamic EEG (p < 0.01) and pain (p < 0.001). MDA increased significantly (p < 0.001) while GPx activity decreased (p < 0.001). Intestinal transit time rose significantly (p < 0.01). PD rats treated with GA improved all above disorders (p < 0.001, p < 0.01). Vagotomy prevented significant alterations of motor and non-motor parameters by rotenone. CONCLUSION: According to current findings, rotenone acts as a toxin in GI and plays a role in the pathogenesis of PD through gastric vagal nerve. Thus, vagotomy could prevent the severity of toxicity by rotenone. In addition, GA improved symptoms of PD induced by rotenone. Therefore, GA can be regarded as a promising therapeutic candidate for PD patients.

Unilateral Cervical Vagotomy Modulates Immune Cell Profiles and the Response to a Traumatic Brain Injury.

TBI induces splenic B and T cell expansion that contributes to neuroinflammation and neurodegeneration. The vagus nerve, the longest of the cranial nerves, is the predominant parasympathetic pathway allowing the central nervous system (CNS) control over peripheral organs, including regulation of inflammatory responses. One way this is accomplished is by vagus innervation of the celiac ganglion, from which the splenic nerve innervates the spleen. This splenic innervation enables modulation of the splenic immune response, including splenocyte selection, activation, and downstream signaling. Considering that the left and right vagus nerves have distinct courses, it is possible that they differentially influence the splenic immune response following a CNS injury. To test this possibility, immune cell subsets were profiled and quantified following either a left or a right unilateral vagotomy. Both unilateral vagotomies caused similar effects with respect to the percentage of B cells and in the decreased percentage of macrophages and T cells following vagotomy. We next tested the hypothesis that a left unilateral vagotomy would modulate the splenic immune response to a traumatic brain injury (TBI). Mice received a left cervical vagotomy or a sham vagotomy 3 days prior to a fluid percussion injury (FPI), a well-characterized mouse model of TBI that consistently elicits an immune and neuroimmune response. Flow cytometric analysis showed that vagotomy prior to FPI resulted in fewer CLIP+ B cells, and CD4+, CD25+, and CD8+ T cells. Vagotomy followed by FPI also resulted in an altered distribution of CD11bhigh and CD11blow macrophages. Thus, transduction of immune signals from the CNS to the periphery via the vagus nerve can be targeted to modulate the immune response following TBI.

The vagus nerve mediates the stomach-brain coherence in rats.

Interactions between the brain and the stomach shape both cognitive and digestive functions. Recent human studies report spontaneous synchronization between brain activity and gastric slow waves in the resting state. However, this finding has not been replicated in any animal models. The neural pathways underlying this apparent stomach-brain synchrony is also unclear. Here, we performed functional magnetic resonance imaging while simultaneously recording body-surface gastric slow waves from anesthetized rats in the fasted vs. postprandial conditions and performed a bilateral cervical vagotomy to assess the role of the vagus nerve. The coherence between brain fMRI signals and gastric slow waves was found in a distributed "gastric network", including subcortical and cortical regions in the sensory, motor, and limbic systems. The stomach-brain coherence was largely reduced by the bilateral vagotomy and was different between the fasted and fed states. These findings suggest that the vagus nerve mediates the spontaneous coherence between brain activity and gastric slow waves, which is likely a signature of real-time stomach-brain interactions. However, its functional significance remains to be established.

The effect of subdiaphragmatic vagotomy on heart rate variability and lung inflammation in rats with severe hemorrhagic shock.

BACKGROUND: The influence of cutting the sub-diaphragmatic branch of the vagus nerve on heart rate variability (HRV) and inflammatory reaction to severe hemorrhagic shock has not been determined prior to this study. METHODS: Male Sprague-Dawley rats were divided into four groups of Sham, sub-diaphragmatic vagotomized (Vag), subacute (135 ± 2 min) hemorrhagic shock (SHS), and sub-diaphragmatic vagotomized with SHS (Vag + SHS). Hemodynamic parameters were recorded and HRV calculated during multiple phases in a conscious model of hemorrhagic shock. The expressions of TNF-α and iNOS were measured in the spleen and lung tissues at the conclusion of the protocol. RESULTS: Decreases in blood pressure during blood withdrawal were identical in the SHS and Vag + SHS groups. However, heart rate only decreased in the Nadir-1 phase of the SHS group. HRV indicated increased power in the very-low, low, and high (VLF, LF, and HF) frequency bands during the Nadir-1 phase of the SHS and Vag + SHS groups, albeit the values were higher in the SHS group. In the recovery phase, the HF bands were only lower in the SHS group. After hemorrhagic shock followed by resuscitation, the expression of TNF-α and iNOS increased in the spleen and lung of the SHS group, and the expression of these genes was significantly lower in the Vag + SHS group than in the SHS group. CONCLUSION: Parasympathetic activity increases during the hypotensive phase of hemorrhagic shock, whereas the cardiac vagal tone decreases in the recovery phase. Sub-diapragmatic vagotomy blunts the cardiac vagal tone during hemorrhagic shock, but its effect is reversed in the recovery phase. The vagus nerve plays a role in proinflammatory responses in the lungs and spleen in subacute hemorrhagic shock followed by resuscitation.

The surgical management of complicated peptic ulcer disease: An EAST video presentation.

BACKGROUND: Peptic ulcer disease (PUD), once primary a surgical problem, is now medically managed in the majority of patients. The surgical treatment of PUD is now strictly reserved for life-threatening complications. Free perforation, refractory bleeding and gastric outlet obstruction, although rare in the age of medical management of PUD, are several of the indications for surgical intervention. The acute care surgeon caring for patients with PUD should be facile in techniques required for bleeding control, bypass of peptic strictures, and vagotomy with resection and reconstruction. This video procedures and techniques article demonstrates these infrequently encountered, but critical operations. CONTENT VIDEO DESCRIPTION: A combination of anatomic representations and videos of step-by-step instructions on perfused cadavers will demonstrate the key steps in the following critical operations. Graham patch repair of perforated peptic ulcer is demonstrated in both open and laparoscopic fashion. The choice to perform open versus laparoscopic repair is based on individual surgeon comfort. Oversewing of a bleeding duodenal ulcer via duodenotomy and ligation of the gastroduodenal artery is infrequent in the age of advanced endoscopy and interventional radiology techniques, yet this once familiar procedure can be lifesaving. Repair of giant duodenal or gastric ulcers can present a challenging operative dilemma on how to best repair or exclude the defect. Vagotomy and antrectomy, perhaps the least common of all the aforementioned surgical interventions, may require more complex reconstruction than other techniques making it challenging for inexperienced surgeons. A brief demonstration on reconstruction options will be shown, and it includes Roux-en-Y gastrojejunostomy. CONCLUSION: Surgical management of PUD is reserved today for life-threatening complications for which the acute care surgeon must be prepared. This presentation provides demonstration of key surgical principles in management of bleeding and free perforation, as well as gastric resection, vagotomy and reconstruction. LEVEL OF EVIDENCE: Video procedure and technique, not applicable.

Impact of Vagotomy on Postoperative Weight Loss, Alimentary Intake, and Enterohormone Secretion After Bariatric Surgery in Experimental Translational Models.

Obesity may be treated by bariatric procedures and is related to enterohormone release modulation. Nevertheless, a majority of commonly used surgical procedures have a significant impact on vagus nerve function by breaking the connections with its gastric branches. In the case of an intragastric balloon (BAL), this interaction is unclear. However, BAL-induced weight reduction is not long-lasting. Interestingly, this method has not been used in combination with vagotomy (VAG). Thus, we evaluated, for the first time, the short- and long-term effects of combined BAL and VAG using the animal-based translational model and compared these effects with sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Wistar rats were fed a high-calorie diet for 8 weeks to induce obesity before SG, RYGB, BAL + / - VAG. Animals' weight and eating behaviors were monitored weekly. After 90 days, serum samples were collected to evaluate postprandial and fasting GLP-1, GIP, PYY, ghrelin, glucagon, insulin, leptin, and pancreatic polypeptide concentrations by fluorescent assay. VAG, SG, RYGB, and BAL + VAG significantly reduced body weight 30 and 90 days after surgery. BAL alone induced temporal weight reduction observed after 30 days, reversed after 90 days. Calories intake was reduced at the first half of the observation period in all groups. Fluid intake was reduced in all groups except SG and BAL. Enterohormone profile for BAL + VAG was comparable to SG and RYGB but not BAL. VAG and BAL + VAG but not BAL alone maintain weight reduction, alimentary intake changes, and enterohormone release after long-term observation. VAG may improve the effectiveness of bariatric procedures for obesity treatment in clinical practice.

Influence of intrathoracic vagotomy on the cough reflex in the anesthetized cat.

Recurrent laryngeal afferent fibers are primarily responsible for cough in response to mechanical or chemical stimulation of the upper trachea and larynx in the guinea pig. Lower airway slowly adapting receptors have been proposed to have a permissive effect on the cough reflex. We hypothesized that vagotomy below the recurrent laryngeal nerve branch would depress mechanically or chemically induced cough. In anesthetized, bilaterally thoracotomized, artificially ventilated cats, thoracic vagotomy nearly eliminated cough induced by mechanical stimulation of the intrathoracic airway, significantly depressed mechanically stimulated laryngeal cough, and eliminated capsaicin-induced cough. These results support an important role of lower airway sensory feedback in the production of tracheobronchial and laryngeal cough in the cat. Further, at least some of this feedback is due to excitation from pulmonary volume-sensitive sensory receptors.

The role of the vagus nerve on dexmedetomidine promoting survival and lung protection in a sepsis model in rats.

BACKGROUND: Sepsis often results in acute lung injury (ALI). Dexmedetomidine (Dex) was reported to protect cells and organs due to its direct cellular effects. This study aims to investigate the role of vagus nerves on Dex induced lung protection in lipopolysaccharide (LPS)-induced ALI rats. METHODS: The bilateral cervical vagus nerve of male Sprague-Dawley rats was sectioned or just exposed as sham surgery. After LPS administration, Dex antagonist yohimbine (YOH) and/or Dex was injected intraperitoneally to rats with or without vagotomy. The severity of ALI was determined with survival curve analysis and lung pathological scores. The plasma concentrations of interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), catecholamine and acetylcholine were measured with enzyme-linked immunosorbent assay. RESULTS: The median survival time of LPS-induced ALI rats was prolonged by Dex (22 h, 95% CI, [24.46, 92.20]) vs. 14 h, 95% CI, [14.60, 89.57] of the LPS control group, P < 0.05), and the ALI score was reduced by Dex (6.5, 95% CI, [5.23, 8.10] vs. 11.5, 95% CI, [10.23, 13.10] in the LPS group, P < 0.01). However, these protective effects were significantly decreased by either YOH administration or vagotomy. Dex decreased LPS-induced IL-1ß, TNF-α, and catecholamine but increased acetylcholine in blood serum; these effects of Dex was partially abolished by vagotomy. CONCLUSIONS: Our data suggested that Dex increased vagal nerve tone that partially contributed to its anti-inflammatory and lung-protective effects. The indirect anti-inflammation and direct cytoprotection of Dex are likely through high vagal nerve tone and α2-adrenoceptor activation, respectively.

The role of vagal innervation on the early development of postoperative ileus in mice.

BACKGROUND: Postoperative ileus (POI) involves an intestinal inflammatory response that is modulated by afferent and efferent vagal activation. We aimed to identify the potential influence of the vagus nerve on POI by tracking central vagal activation and its role for peripheral inflammatory changes during the early hours after surgery. METHODS: C57BL6 mice were vagotomized (V) 3-4 days prior to experiments, while control animals received sham vagotomy (SV). Subgroups underwent either laparotomy (sham operation; S-POI) or laparotomy followed by standardized small bowel manipulation to induce postoperative ileus (POI). Three hours and 9 h later, respectively, a jejunal segment was harvested and infiltration of inflammatory cells in intestinal muscularis was evaluated by fluorescein isothiocyanate (FITC) avidin and myeloperoxidase (MPO) staining. Moreover, the brain stem was harvested, and central nervous activation was investigated by Fos immunochemistry in both the nucleus of the solitary tract (NTS) and the area postrema (AP). Data are presented as mean ± SEM, and a p < 0.05 was considered statistically significant. KEY RESULTS: Three hour experiments revealed no significant differences between all experimental groups, except MPO staining: 3 h after abdominal surgery, there were significantly more MPO-positive cells in vagotomized S-POI animals compared to sham-vagotomized S-POI animals (26.7 ± 7.1 vs. 5.1 ± 2.4, p < 0.01). Nine hour postoperatively intramuscular mast cells (IMMC) were significantly decreased in the intestinal muscularis of V/POI animals compared to SV/POI animals (1.5 ± 0.3 vs. 5.9 ± 0.2, p < 0.05), while MPO-positive cells were increased in V/POI animals compared to SV/POI animals (713.2 ± 99.4 vs. 46.9 ± 5.8, p < 0.05). There were less Fos-positive cells in the NTS of V/POI animals compared to SV/POI animals (64.7 ± 7.8 vs. 132.8 ± 23.9, p < 0.05) and more Fos-positive cells in the AP of V/POI animals compared to SV/POI animals 9 h postoperatively (38.0 ± 2.0 vs. 13.7 ± 0.9, p < 0.001). CONCLUSIONS AND INTERFERENCES: Afferent nerve signaling to the central nervous system during the development of early POI seems to be mediated mainly via the vagus nerve and to a lesser degree via systemic circulation. During the early hours of POI, the intestinal immune response may be attenuated by vagal modulation, suggesting interactions between the central nervous system and the intestine.

Vagotomy and the risk of mental disorders: A nationwide population-based study.

OBJECTIVE: To investigate vagotomy, the severance of the vagus nerve, and its association with mental disorders, as gut-brain communication partly mediated by the vagus nerve have been suggested as a risk factor. METHODS: Nationwide population-based Danish register study of all individuals alive and living in Denmark during the study period 1977-2016 and who had a hospital contact for ulcer with or without vagotomy. Follow-up was until any diagnosis of mental disorders requiring hospital contact, emigration, death, or end of follow-up on December 31, 2016, whichever came first. Data were analyzed using survival analysis and adjusted for sex, age, calendar year, ulcer type, and Charlson comorbidity index score. RESULTS: During the study period, 113,086 individuals had a hospital contact for ulcer. Of these, 5,408 were exposed to vagotomy where 375 (6.9%) subsequently developed a mental disorder. Vagotomy overall was not associated with mental disorders (HR: 1.10; 95%CI: 0.99-1.23), compared to individuals with ulcer not exposed to vagotomy. However, truncal vagotomy was associated with an increased HR of 1.22 (95%CI: 1.06-1.41) for mental disorders, whereas highly selective vagotomy was not associated with mental disorders (HR: 0.98; 95%CI: 0.84-1.15). Truncal vagotomy was also associated with higher risk of mental disorders when compared to highly selective vagotomy (p = 0.034). CONCLUSIONS: Overall, vagotomy did not increase the risk of mental disorders; however, truncal vagotomy specifically was associated with a small risk increase in mental disorders, whereas no association was found for highly selective vagotomy. Thus, the vagus nerve does not seem to have a major impact on the development of mental disorders.

RhANP attenuates endotoxin-derived cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis.

BACKGROUND: Atrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment. METHODS: LPS (5 mg/kg) was given intraperitoneally to mice. Recombinant human ANP (rhANP) (1.0 mg/kg) was injected intravenously 24 h before and/or 10 min after LPS injection. Subdiaphragmatic vagotomy (SDV) was performed 14 days before LPS injection or 28 days before fecal microbiota transplantation (FMT). ANA-12 (0.5 mg/kg) was administrated intraperitoneally 30 min prior to rhANP treatment. RESULTS: LPS (5.0 mg/kg) induced remarkable splenomegaly and an increase in the plasma cytokines at 24 h after LPS injection. There were positive correlations between spleen weight and plasma cytokines levels. LPS also led to increased protein levels of ionized calcium-binding adaptor molecule (iba)-1, cytokines and inducible nitric oxide synthase (iNOS) in the hippocampus. LPS impaired the natural and learned behavior, as demonstrated by an increase in the latency to eat the food in the buried food test and a decrease in the number of entries and duration in the novel arm in the Y maze test. Combined prophylactic and therapeutic treatment with rhANP reversed LPS-induced splenomegaly, hippocampal and peripheral inflammation as well as cognitive impairment. However, rhANP could not further enhance the protective effects of SDV on hippocampal and peripheral inflammation. We further found that PGF mice transplanted with fecal bacteria from rhANP-treated endotoxemia mice alleviated the decreased protein levels of hippocampal polyclonal phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotrophic factor (BDNF) and cognitive impairment, which was abolished by SDV. Moreover, TrkB/BDNF signaling inhibitor ANA-12 abolished the improving effects of rhANP on LPS-induced cognitive impairment. CONCLUSIONS: Our results suggest that rhANP could mitigate LPS-induced hippocampal inflammation and cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota-brain axis.

Parasympathetic, but not sympathetic denervation, suppressed colorectal cancer progression.

Disruption in the nerve-tumor interaction is now considered as a possible anticancer strategy for treating various cancer types, particularly colorectal cancer. However, the underlying mechanisms are not still fully understood. Therefore, the present study aimed to evaluate the effects of sympathetic and parasympathetic denervation on the inhibition of colorectal cancer progression in early and late phases and assess the involvement of nerve growth factor in denervation mediated anticancer effects. One-hundred and fifty male Wistar rats were assigned into 15 groups. Seven groups comprising the control group, 1,2-dimethylhydrazine (DMH) group, sympathetic denervation group (celiac-mesenteric ganglionectomy and guanethidine sulphate administration), parasympathetic denervation group (vagotomy and atropine administration), and combination group were used in the early-stage protocol. For the late-stage protocol, eight groups comprising the control, DMH, surgical and pharmacological sympathetic and parasympathetic denervation groups, combination group, and 5-flourouracil group were considered. After 8 weeks, sympathetic and parasympathetic denervation significantly reduced ACF numbers in rats receiving DMH. On the other hand, in the late stages, parasympathetic but not sympathetic denervation resulted in significant reductions in tumor incidence, tumor volume and weight, cell proliferation (indicated by reduced immunostaining of PCNA and ki-67), and angiogenesis (indicated by reduced immunostaining of CD31 and VEGF expression levels), and downregulated NGF, ß2 adrenergic, and M3 receptors. It can be concluded that parasympathetic denervation may be of high importance in colon carcinogenesis and suggested as a possible therapeutic modality in late stages of colorectal cancer.