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.

Vagal Regulation of Group 3 Innate Lymphoid Cells and the Immunoresolvent PCTR1 Controls Infection Resolution.

Uncovering mechanisms that control immune responses in the resolution of bacterial infections is critical for the development of new therapeutic strategies that resolve infectious inflammation without unwanted side effects. We found that disruption of the vagal system in mice delayed resolution of Escherichia coli infection. Dissection of the right vagus decreased peritoneal group 3 innate lymphoid cell (ILC3) numbers and altered peritoneal macrophage responses. Vagotomy resulted in an inflammatory peritoneal lipid mediator profile characterized by reduced concentrations of pro-resolving mediators, including the protective immunoresolvent PCTR1, along with elevated inflammation-initiating eicosanoids. We found that acetylcholine upregulated the PCTR biosynthetic pathway in ILC3s. Administration of PCTR1 or ILC3s to vagotomized mice restored tissue resolution tone and host responses to E. coli infections. Together these findings elucidate a host protective mechanism mediated by ILC3-derived pro-resolving circuit, including PCTR1, that is controlled by local neuronal output to regulate tissue resolution tone and myeloid cell responses.

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.

Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway.

Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.

Alleviating effect of vagus nerve cutting in Salmonella-induced gut infections and anxiety-like behavior via enhancing microbiota-derived GABA.

The vagus nerve, a pivotal link within the gut-brain axis, plays a critical role in maintaining homeostasis and mediating communication between the gastrointestinal tract and the brain. It has been reported that gastrointestinal infection by Salmonella typhimurium (S. typhimurium) triggers gut inflammation and manifests as anxiety-like behaviors, yet the mechanistic involvement of the vagus nerve remains to be elucidated. In this study, we demonstrated that unilateral cervical vagotomy markedly attenuated anxiety-like behaviors induced by S. typhimurium SL1344 infection in C57BL/6 mice, as evidenced by the open field test and marble burying experiment. Furthermore, vagotomy significantly diminished neuronal activation within the nucleus of the solitary tract and amygdala, alongside mitigating aberrant glial cell activation in the hippocampus and amygdala. Additionally, vagotomy notably decreases serum endotoxin levels, counters the increase in splenic Salmonella concentration, and modulates the expression of inflammatory cytokines-including IL-6, IL-1ß, and TNF-α-in both the gastrointestinal tract and brain, with a concurrent reduction in IL-22 and CXCL1 expression. This intervention also fostered the enrichment of beneficial gut microbiota, including Alistipes and Lactobacillus species, and augmented the production of gamma-aminobutyric acid (GABA) in the gut. Administration of GABA replicated the vagotomy's beneficial effects on reducing gut inflammation and anxiety-like behavior in infected mice. However, blockade of GABA receptors with picrotoxin abrogated the vagotomy's protective effects against gut inflammation, without influencing its impact on anxiety-like behaviors. Collectively, these findings suggest that vagotomy exerts a protective effect against infection by promoting GABA synthesis in the colon and alleviating anxiety-like behavior. This study underscores the critical role of the vagus nerve in relaying signals of gut infection to the brain and posits that targeting the gut-brain axis may offer a novel and efficacious approach to preventing gastrointestinal infections and associated behavioral abnormalities.

Vagus Nerve Suppression in Ischemic Stroke by Carotid Artery Occlusion: Implications for Metabolic Regulation, Cognitive Function, and Gut Microbiome in a Gerbil Model.

The vagus nerve regulates metabolic homeostasis and mediates gut-brain communication. We hypothesized that vagus nerve dysfunction, induced by truncated vagotomy (VGX) or carotid artery occlusion (AO), would disrupt gut-brain communication and exacerbate metabolic dysregulation, neuroinflammation, and cognitive impairment. This study aimed to test the hypothesis in gerbils fed a high-fat diet. The gerbils were divided into four groups: AO with VGX (AO_VGX), AO without VGX (AO_NVGX), no AO with VGX (NAO_VGX), and no AO without VGX (NAO_NVGX). After 5 weeks on a high-fat diet, the neuronal cell death, neurological severity, hippocampal lipids and inflammation, energy/glucose metabolism, intestinal morphology, and fecal microbiome composition were assessed. AO and VGX increased the neuronal cell death and neurological severity scores associated with increased hippocampal lipid profiles and lipid peroxidation, as well as changes in the inflammatory cytokine expression and brain-derived neurotrophic factor (BDNF) levels. AO and VGX also increased the body weight, visceral fat mass, and insulin resistance and decreased the skeletal muscle mass. The intestinal morphology and microbiome composition were altered, with an increase in the abundance of Bifidobacterium and a decrease in Akkermansia and Ruminococcus. Microbial metagenome functions were also impacted, including glutamatergic synaptic activity, glycogen synthesis, and amino acid biosynthesis. Interestingly, the effects of VGX were not significantly additive with AO, suggesting that AO inhibited the vagus nerve activity, partly offsetting the effects of VGX. In conclusion, AO and VGX exacerbated the dysregulation of energy, glucose, and lipid metabolism, neuroinflammation, and memory deficits, potentially through the modulation of the gut-brain axis. Targeting the gut-brain axis by inhibiting vagus nerve suppression represents a potential therapeutic strategy for ischemic stroke.

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.

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.

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.

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.

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.

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.

Unilateral vagotomy alters astrocyte and microglial morphology in the nucleus tractus solitarii of the rat.

The nucleus tractus solitarii (nTS) is the initial site of integration of sensory information from the cardiorespiratory system and contributes to reflex responses to hypoxia. Afferent fibers of the bilateral vagus nerves carry input from the heart, lungs, and other organs to the nTS where it is processed and modulated. Vagal afferents and nTS neurons are integrally associated with astrocytes and microglia that contribute to neuronal activity and influence cardiorespiratory control. We hypothesized that vagotomy would alter glial morphology and cardiorespiratory responses to hypoxia. Unilateral vagotomy (or sham surgery) was performed in rats. Prior to and seven days after surgery, baseline and hypoxic cardiorespiratory responses were monitored in conscious and anesthetized animals. The brainstem was sectioned and caudal, mid-area postrema (mid-AP), and rostral sections of the nTS were prepared for immunohistochemistry. Vagotomy increased immunoreactivity (-IR) of astrocytic glial fibrillary acidic protein (GFAP), specifically at mid-AP in the nTS. Similar results were found in the dorsal motor nucleus of the vagus (DMX). Vagotomy did not alter nTS astrocyte number, yet increased astrocyte branching and altered morphology. In addition, vagotomy both increased nTS microglia number and produced morphologic changes indicative of activation. Cardiorespiratory baseline parameters and hypoxic responses remained largely unchanged, but vagotomized animals displayed fewer augmented breaths (sighs) in response to hypoxia. Altogether, vagotomy alters nTS glial morphology, indicative of functional changes in astrocytes and microglia that may affect cardiorespiratory function in health and disease.

Lack of evidence for impaired preload or Bezold-Jarisch activation during brief umbilical cord occlusions in fetal sheep.

Impaired cardiac preload secondary to umbilical cord occlusion (UCO) has been hypothesized to contribute to intrapartum decelerations, brief falls in fetal heart rate (FHR), through activation of the Bezold-Jarisch reflex. This cardioprotective reflex increases parasympathetic and inhibits sympathetic outflows triggering hypotension, bradycardia, and peripheral vasodilation, but its potential to contribute to intrapartum decelerations has never been systematically examined. In this study, we performed bilateral cervical vagotomy to remove the afferent arm and the efferent parasympathetic arm of the Bezold-Jarisch reflex. Twenty-two chronically instrumented fetal sheep at 0.85 of gestation received vagotomy (n = 7) or sham vagotomy (control, n = 15), followed by three 1-min complete UCOs separated by 4-min reperfusion periods. UCOs in control fetuses were associated with a rapid fall in FHR and reduced femoral blood flow mediated by intense femoral vasoconstriction, leading to hypertension. Vagotomy abolished the rapid fall in FHR (P < 0.001) and, despite reduced diastolic filling time, increased both carotid (P < 0.001) and femoral (P < 0.05) blood flow during UCOs, secondary to carotid vasodilation (P < 0.01) and delayed femoral vasoconstriction (P < 0.05). Finally, vagotomy was associated with an attenuated rise in cortical impedance during UCOs (P < 0.05), consistent with improved cerebral substrate supply. In conclusion, increased carotid and femoral blood flows after vagotomy are consistent with increased left and right ventricular output, which is incompatible with the hypothesis that labor-like UCOs impair ventricular filling. Overall, the cardiovascular responses to vagotomy do not support the hypothesis that the Bezold-Jarisch reflex is activated by UCO. The Bezold-Jarisch reflex is therefore mechanistically unable to contribute to intrapartum decelerations.

Age-related decrease of cholinergic parasympathetic reflex vasodilation in the rat masseter muscle.

Skeletal muscle hemodynamics, including that in jaw muscles, is an important in their functions and is modulated by aging. Marked blood flow increases mediated by parasympathetic vasodilation may be important for blood flow in the masseter muscle (MBF); however, the relationship between parasympathetic vasodilation and aging is unclear. We examined the effect of aging on parasympathetic vasodilation evoked by trigeminal afferent inputs and their mechanisms by investigating the MBF during stimulation of the lingual nerve (LN) in young and old urethane-anesthetized and vago-sympathectomized rats. Electrical stimulation of the central cut end of the LN elicited intensity- and frequency-dependent increases in MBF in young rats, while these increases were significantly reduced in old rats. Increases in the MBF evoked by LN stimulation in the young rats were greatly reduced by hexamethonium and atropine administration. Increases in MBF in young rats were produced by exogenous acetylcholine in a dose-dependent manner, whereas acetylcholine did not influence the MBF in old rats. Significant levels of muscarinic acetylcholine receptor type 1 (MR1) and type 3 (MR3) mRNA were observed in the masseter muscle in young rats, but not in old rats. Our results indicate that cholinergic parasympathetic reflex vasodilation evoked by trigeminal afferent inputs to the masseter muscle is reduced by aging and that this reduction may be mediated by suppression of the expression of MR1 and MR3 in the masseter muscle with age.

Vagotomy Affects Lipopolysaccharide-Induced Changes of Urocortin 2 Gene Expression in the Brain and on the Periphery.

The corticotropin-releasing hormone family of peptides is involved in regulating the neuroendocrine stress response. Also, the vagus nerve plays an important role in the transmission of immune system-related signals to brain structures, thereby orchestrating the neuroendocrine stress response. Therefore, we investigated gene expression of urocortin 2 (Ucn2) and c-fos, a markers of neuronal activity, within the hypothalamic paraventricular nucleus (PVN), a brain structure involved in neuroendocrine and neuroimmune responses, as well as in the adrenal medulla and spleen in vagotomized rats exposed to immune challenge. In addition, markers of neuroendocrine stress response activity were investigated in the adrenal medulla, spleen, and plasma. Intraperitoneal administration of lipopolysaccharide (LPS) induced a significant increase of c-fos and Ucn2 gene expression in the PVN, and adrenal medulla as well as increases of plasma corticosterone levels. In addition, LPS administration induced a significant increase in the gene expression of tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) in the adrenal medulla. In the spleen, LPS administration increased gene expression of c-fos, while gene expression of TH and PNMT was significantly reduced, and gene expression of Ucn2 was not affected. Subdiaphragmatic vagotomy significantly attenuated the LPS-induced increases of gene expression of c-fos and Ucn2 in the PVN and Ucn2 in the adrenal medulla. Our data has shown that Ucn2 may be involved in regulation of the HPA axis in response to immune challenge. In addition, our findings indicate that the effect of immune challenge on gene expression of Ucn2 is mediated by vagal pathways.

Vagal-α7nAChR signaling is required for lung anti-inflammatory responses and arginase 1 expression during an influenza infection.

Vagal circuit-α7 nicotinic acetylcholine receptor (α7nAChR, coded by Chrna7) signaling can modulate lung proinflammatory responses. Arginase 1 (ARG1) plays a crucial role in the resolution of lung inflammation. However, whether vagal-α7nAChR signaling can regulate lung inflammation and ARG1 expression during an influenza infection is elusive. Here, we found that lung and spleen IL-4+ cells and lung ARG1 expression were reduced; however, bronchoalveolar lavage (BAL) protein and leukocytes and lung inflammatory cytokines were increased in PR8 (A/Puerto Rico/8/1934, H1N1)-infected vagotomized mice when compared to the control. In PR8-infected α7nAChR-deficient mice, lung Arg1, Il10, and Socs3 expression and BAL Ly6C+CD206+ cells were reduced. PR8-infected Chrna7+/+ recipient mice reconstituted with Chrna7-/- bone marrow had a lower survival as compared to PR8-infected Chrna7+/+ recipient mice reconstituted with Chrna7+/+ bone marrow. Mechanistically, the activation of α7nAChR by its agonist GTS-21 could enhance IL-4-induced Arg1 expression, reduced Nos2, and TNF-α expression in PR8-infected bone marrow-derived macrophages (BMDM). Stimulation with IL-4 increased phosphorylation of STAT6 and activation of α7nAChR increased STAT6 binding with the ARG1 promoter and relieved IL-4-induced H3K27me3 methylation by increasing JMJD3 expression in PR8-infected BMDM. Inhibition of JMJD3 increased H3K27me3 methylation and abolished α7nAChR activation and IL-4 induced ARG1 expression. Activation of α7nAChR also reduced phosphorylation of AKT1 and contained FOXO1 in the nucleus. Knockdown of Foxo1a reduced α7nAChR activation and IL-4 induced Arg1 expression in PR8-infected BMDM. Therefore, vagal-α7nAChR signaling is a novel therapeutic target for treating lung inflammatory responses during an influenza infection.

S043 mythbuster: truncal vagotomy and gastric drainage procedures.

INTRODUCTION: You are sitting for your oral surgery board exam and the examiner asks what you do when you realize that you have accidentally cut the posterior vagus nerve during a hiatal hernia repair. Is the answer to proceed with a gastric drainage procedure correct? The prevailing dogma seems to be that inadvertent vagotomy will produce gastric stasis/paresis and the stomach will not empty and hence should be accompanied by a gastric drainage procedure. This report presents clinical outcomes of 49 patients who underwent truncal vagotomy without a drainage procedure (pyloroplasty or gastrojejunostomy). METHODS: 49 patients underwent truncal vagotomy with laparoscopic adjustable gastric banding in an IRB (Investigational Review Board)-approved clinical trial to determine if the addition of a vagotomy would increase achieved weight loss when compared to gastric banding alone. The details of this trial were presented at SAGES (Martin and Earle in Surg Endosc 25:2522-2525, 2011) in 2010. The patients in this study have been followed for over ten years and their histories were examined to look for evidence of gastric stasis or intractable diarrhea or if they required further surgery for these complaints. RESULTS: 49 patients have been followed for a mean of 10.9 years. All except one have experienced a loss of hunger and cessation of gastric borborygmus. One patient showed mild delayed gastric emptying after developing diabetes. Two other patients with DM carry a diagnosis of gastroparesis. No patient has experienced intractable diarrhea. Five patients have had revisions to sleeve gastrectomy or gastric bypass for weight loss failure or esophageal dilatation and GERD. CONCLUSIONS: Review of these truncal vagotomy patients without drainage procedures at 10 years does not support the myth that the stomach will not empty after vagotomy and a gastric drainage procedure should always accompany truncal vagotomy.

Acute Visceral Pain in Rats: Vagal Nerve Block Compared to Bupivacaine Administered Intramuscularly.

BACKGROUND: Visceral and parietal peritoneum layers have different sensory innervations. Most visceral peritoneum sensory information is conveyed via the vagus nerve to the nucleus of the solitary tract (NTS). We already showed in animal models that intramuscular (i.m.) injection of local anesthetics decreases acute somatic and visceral pain and general inflammation induced by aseptic peritonitis. The goal of the study was to compare the effects of parietal block, i.m. bupivacaine, and vagotomy on spinal cord and NTS stimulation induced by a chemical peritonitis. METHODS: We induced peritonitis in rats using carrageenan and measured cellular activation in spinal cord and NTS under the following conditions, that is, a parietal nerve block with bupivacaine, a chemical right vagotomy, and i.m. microspheres loaded with bupivacaine. Proto-oncogene c-Fos (c-Fos), cluster of differentiation protein 11b (CD11b), and tumor necrosis factor alpha (TNF-α) expression in cord and NTS were studied. RESULTS: c-Fos activation in the cord was inhibited by nerve block 2 hours after peritoneal insult. Vagotomy and i.m. bupivacaine similarly inhibited c-Fos activation in NTS. Forty-eight hours after peritoneal insult, the number of cells expressing CD11b significantly increased in the cord (P = .010). The median difference in the effect of peritonitis compared to control was 30 cells (CI95, 13.5-55). TNF-α colocalized with CD11b. Vagotomy inhibited this microglial activation in the NTS, but not in the cord. This activation was inhibited by i.m. bupivacaine both in cord and in NTS. The median difference in the effect of i.m. bupivacaine added to peritonitis was 29 cells (80% increase) in the cord and 18 cells (75% increase) in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli by inhibiting c-Fos and microglia activation. CONCLUSIONS: In rats receiving intraperitoneal carrageenan, i.m. bupivacaine similarly inhibited c-Fos and microglial activation both in cord and in the NTS. Vagal block inhibited activation only in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli. This emphasizes the effects of systemic local anesthetics on inflammation and visceral pain.