Vagal Pathways Research Articles

Gut-Derived Sterile Inflammation and Parkinson's Disease.

The etiology of Parkinson's disease (PD) is unknown, but evidence is increasing that there is a prominent inflammatory component to the illness. Epidemiological, genetic, and preclinical evidence support a role for gut-derived sterile inflammation. Pro-inflammatory bacteria are over-represented in the PD gut microbiota. There is evidence for decreased gut barrier function and leak of bacterial antigen across the gut epithelium with sub-mucosal inflammation and systemic exposure to the bacterial endotoxin lipopolysaccharide. Preclinical evidence supports these clinical findings and suggests that systemic inflammation can affect the CNS through vagal pathways or the systemic circulation. We will review recent preclinical and clinical evidence to support this mechanism and suggest possible treatments directed at the gut-brain axis.

Stress-induced neuroplasticity in the gastric response to brainstem oxytocin in male rats.

Previous studies have shown that pharmacological manipulations with stress-related hormones such as corticotropin-releasing factor and thyrotropin-releasing hormone induce neuroplasticity in brainstem vagal neurocircuits, which modulate gastric tone and motility. The prototypical antistress hormone oxytocin (OXT) has been shown to modulate gastric tone and motility via vagal pathways, and descending hypothalamic oxytocinergic inputs play a major role in the vagally dependent gastric-related adaptations to stress. The aim of this study was to investigate the possible cellular mechanisms through which OXT modulates central vagal brainstem and peripheral enteric neurocircuits of male Sprague-Dawley rats in response to chronic repetitive stress. After chronic (5 consecutive days) of homotypic or heterotypic stress load, the response to exogenous brainstem administration of OXT was examined using whole cell patch-clamp recordings from gastric-projecting vagal motoneurons and in vivo recordings of gastric tone and motility. GABAergic currents onto vagal motoneurons were decreased by OXT in stressed, but not in naïve rats. In naïve rats, microinjections of OXT in vagal brainstem nuclei-induced gastroinhibition via peripheral release of nitric oxide (NO). In stressed rats, however, the OXT-induced gastroinhibition was determined by the release of both NO and vasoactive intestinal peptide (VIP). Taken together, our data indicate that stress induces neuroplasticity in the response to OXT in the neurocircuits, which modulate gastric tone and motility. In particular, stress uncovers the OXT-mediated modulation of brainstem GABAergic currents and alters the peripheral gastric response to vagal stimulation.NEW & NOTEWORTHY The prototypical antistress hormone, oxytocin (OXT), modulates gastric tone and motility via vagal pathways, and descending hypothalamic-brainstem OXT neurocircuits play a major role in the vagally dependent adaptation of gastric motility and tone to stress. The current study suggests that in the neurocircuits, which modulate gastric tone and motility, stress induces neuroplasticity in the response to OXT and may reflect the dysregulation observed in stress-exacerbated functional motility disorders.

The potential of invasive and non-invasive vagus nerve stimulation to improve verbal memory performance in epilepsy patients

It has been demonstrated that acute vagus nerve stimulation (VNS) improves word recognition memory in epilepsy patients. Transcutaneous auricular vagus nerve stimulation (taVNS) has gained interest as a non-invasive alternative to improve cognition. In this prospective randomized cross-over study, we investigated the effect of both invasive VNS and taVNS on verbal memory performance in 15 patients with drug-resistant epilepsy. All patients conducted a word recognition memory paradigm in 3 conditions: VNS ON, VNS OFF and taVNS (3-period 3-treatment cross-over study design). For each condition, patients memorized 21 highlighted words from text paragraphs. Afterwards, the intervention was delivered for 30 s. Immediate recall and delayed recognition scores were obtained for each condition. This memory paradigm was repeated after 6 weeks of VNS therapy in 2 conditions: VNS ON and VNS OFF (2-period 2-treatment cross-over study design). Acute VNS and taVNS did not improve verbal memory performance. Immediate recall and delayed recognition scores were significantly improved after 6 weeks of VNS treatment irrespective of the acute intervention. We can conclude that the previously described positive effects of invasive VNS on verbal memory performance could not be replicated with invasive VNS and taVNS. An improved verbal memory performance was seen after 6 weeks of VNS treatment, suggesting that longer and more repetitive stimulation of the vagal pathway is required to modulate verbal memory performance.Clinical trial registration number: NCT05031208.

A Numerical Model of the Acute Cardiac Effects Provoked by Cervical Vagus Nerve Stimulation.

Today, the diverse acute cardiac effects of vagus nerve stimulation (VNS) are still not fully understood. Therefore, we propose a numerical model that can predict the acute cardiac responses to VNS and explain the underlying mechanisms on different levels. We integrated a model of vagal nerve fiber recruitment and acetylcholine (ACh) kinetics at vagal nerve terminals into a cardiovascular system model. A sensitivity analysis was performed to identify the most important parameters of vagal cardiac pathways. These parameters were tuned, and the model was validated based on published data of experiments in anesthetized sheep. The four most important parameters are related to vagus nerve anatomy (electrode-fiber distances, fiber diameters) and ACh kinetics in the vagal neuroeffector junction (rate of ACh release and -hydrolysis) which together explain >53% of the observed variability in acute cardiac responses to VNS. The mean electrode-fiber distance and nerve fiber diameters obtained from tuning are 1.3 ± 0.09 mm, and 4.9 ± 0.25 μm; the ACh release and -hydrolysis rate constants are 0.023 s-1 and 0.77 s-1, respectively. With this parameterization, the model could accurately predict published data on the acute cardiac effects of VNS. The model can explain the cardiac responses to VNS on multiple levels. The results highlight the importance of four parameters tied to ACh dynamics and vagus nerve anatomy for predicting the cardiac effects of VNS. The model represents a substantial improvement in terms of comprehensibility of the underlying mechanisms of the acute cardiac responses to VNS.

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity.

Although transcutaneous auricular vagus nerve stimulation (taVNS) is thought to increase central noradrenergic activity, findings supporting such mechanism are scarce and inconsistent. This study aimed to investigate whether taVNS modulates indirect markers of phasic and tonic noradrenergic activity. Sixty-six healthy participants performed a novelty auditory oddball task twice on separate days: once while receiving taVNS (left cymba concha), once during sham (left earlobe) stimulation. To maximize potential effects, the stimulation was delivered continuously (frequency: 25Hz; width: 250μs) at an intensity individually calibrated to the maximal level below pain threshold. The stimulation was administered 10min before the oddball task and maintained throughout the session. Event-related pupil dilation (ERPD) to target stimuli and pre-stimulus baseline pupil size were assessed during the oddball task as markers of phasic and tonic noradrenergic activity, respectively. Prior to and at the end of stimulation, tonic pupil size at rest, cortisol, and salivary alpha-amylase were assessed as markers of tonic noradrenergic activity. Finally, we explored the effect of taVNS on cardiac vagal activity, respiratory rate, and salivary flow rate. Results showed a greater ERPD to both target and novelty compared to standard stimuli in the oddball task. In contrast to our hypotheses, taVNS did not impact any of the tested markers. Our findings strongly suggest that continuous stimulation of the cymba concha with the tested stimulation parameters is ineffective to increase noradrenergic activity via a vagal pathway.

New Insights on Extrinsic Innervation of the Enteric Nervous System and Non-neuronal Cell Types That Influence Colon Function.

The enteric nervous system not only innervates the colon to execute various functions in a semi-autonomous manner but also receives neural input from three extrinsic sources, (1) vagal, (2) thoracolumbar (splanchnic), and (3) lumbosacral (pelvic) pathways, that permit bidirectional communication between the colon and central nervous system. Extrinsic pathways signal sensory input via afferent fibers, as well as motor autonomic output via parasympathetic or sympathetic efferent fibers, but the shared and unique roles for each pathway in executing sensory-motor control of colon function have not been well understood. Here, we describe the recently developed approaches that have provided new insights into the diverse mechanisms utilized by extrinsic pathways to influence colon functions related to visceral sensation, motility, and inflammation. Based on the cumulative results from anatomical, molecular, and functional studies, we propose pathway-specific functions for vagal, thoracolumbar, and lumbosacral innervation of the colon.

Cervical Spinal Cord Transection (SCT) Increases Gastric Compliance in Anesthetized Rats

Abstract Spinal cord injury (SCI) can markedly alter the autonomic nervous system’s functions. It immediately causes autonomic and somatic hypo- or arreflexia, a state known as spinal shock. SCI determines the enhancement of two gastric reflexes that appear in normal conditions: the receptive and adaptative reflexes. Furthermore, this study also tried to evaluate the causes that led to such modifications: either vagal control, nitric oxide (NO)-pathways or intestine-intestinal reflexes. Male Wistar rats (N=25) were subjected to laminectomy (Sham group) or laminectomy + complete Spinal Cord Transection (SCT), between C7 and T1 vertebrae under anesthesia (SCT group). Before the surgery, the rats had water and food ad libitum; after the surgery, rats were fasted for 24 hours, still having access to water. The next day, all animals were subjected to a catheterism of their right carotid artery, a tracheostomy and a flexible balloon introduction down to the stomach’s fundix region, also under anesthesia. Rats were connected to a Power-Lab® system, via a pressure transducer (in order to measure the arterial pressure – MAP - and the heart rate - HR), and to a modified Plethysmometer (in order to measure the fundical gastric volume - GV variation). Vagal control was studied via cervical vagotomy; NO-mediation - via NO synthesis inhibitors (L-NAME); intestinointestinal reflexes - by using laxatives (Lactulone). Statistical analysis revealed, in some cases, that GV is significantly (p<0.05) augmented in SCT rats (2,4±0,09; 3,1±0,05; 3,7±0,06 ml) than in Sham (2,2±0,12; 2,9±0,12; 3,3±0,15 ml). Nevertheless, MAP and HR, were subsequently lower (p<0.05) in SCT (63,5±21,1mm Hg; 227,1±25,2 BPM) than in the control group (88,2±14,4mm Hg; 427,0±19,2 BPM). In summary, the increase of GV in SCT, seems to involve vagal pathways and/or NO-mediation, but still not neglecting the colic-gastric reflexes.

Supraglottic Botulinum Toxin Improves Symptoms in Patients with Laryngeal Sensory Dysfunction Manifesting as Abnormal Throat Sensation and/or Chronic Refractory Cough.

Laryngeal sensory dysfunction (LSD) encompasses disorders of the vagal sensory pathways. Common manifestations include chronic refractory cough (CRC) and abnormal throat sensation (ATS). This study examined clinical characteristics and treatment outcomes of LSD using a novel approach of laryngeal supraglottic Onabotulinum toxin Type A injection (BTX). This was a retrospective review of clinical data and treatment outcomes of supraglottic BTX in patients with LSD. Between November 2019 and May 2021, 14 patients underwent 25 injection cycles of supraglottic BTX for treatment of symptoms related to LSD, including ATS and CRC. Primary outcome measures included the Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ), Cough Severity Index (CSI), Reflux Symptom Index (RSI), and Voice Handicap Index-10 (VHI-10) at baseline and within three months of treatment. Pre- and post-treatment data were compared using a linear mixed model. After supraglottic BTX, LHQ scores improved by 2.6. RSI and CSI improved by 8.0 and 5.0, respectively. VHI-10 did not change as a result of treatment. Short-term response to SLN block was significantly associated with longer term response to BTX treatment. These findings suggest that LSD presents clinically as ATS and CRC along with other upper airway symptoms. Supraglottic BTX injection is a safe and effective technique in the treatment of symptoms of LSD.

Activation of α7nAChR Protects Against Gastric Inflammation and Dysmotility in Parkinson's Disease Rats.

The cholinergic anti-inflammatory pathway (CAIP) has been proposed to regulate gastrointestinal inflammation via acetylcholine released from the vagus nerve activating α7 nicotinic receptor (α7nAChR) on macrophages. Parkinson’s disease (PD) patients and PD rats with substantia nigra (SN) lesions exhibit gastroparesis and a decayed vagal pathway. To investigate whether activating α7nAChR could ameliorate inflammation and gastric dysmotility in PD rats, ELISA, western blot analysis, and real-time PCR were used to detect gastric inflammation. In vitro and in vivo gastric motility was investigated. Proinflammatory mediator levels and macrophage numbers were increased in the gastric muscularis of PD rats. α7nAChR was located on the gastric muscular macrophages of PD rats. The α7nAChR agonists PNU-282987 and GTS-21 decreased nuclear factor κB (NF-κB) activation and monocyte chemotactic protein-1 mRNA expression in the ex vivo gastric muscularis of PD rats, and these effects were abolished by an α7nAChR antagonist. After treatment with PNU-282987 in vivo, the PD rats showed decreased NF-κB activation, inflammatory mediator production, and contractile protein expression and improved gastric motility. The present study reveals that α7nAChR is involved in the development of gastroparesis in PD rats and provides novel insight for the treatment of gastric dysmotility in PD patients.

The effects of frequency-specific, non-invasive, median nerve stimulation on food-related attention and appetite

Median nerve stimulation (MNS) in the existing literature has been used for treating gastrointestinal disorders and amelioration of nausea and vomiting. Recently, studies have shown that MNS can also exert effects on olfactory performances and corresponding anatomical regions through the activation of vagal pathways. This study aimed to test effects of specific frequencies of MNS on food-related attention and appetite. The experiment used an odourised, dot probe task for testing food-related attention and a combination of behavioural (i.e., visual analogue scales; VAS) and physiological approaches (i.e., electrocardiograph; ECG - root mean square of successive differences between normal heartbeats-RMSSD: parasympathetic nervous system activation (RMSSD), stress index-SI: sympathetic nervous system activation) for measuring hunger, appetite, and satiation. Twenty-four healthy, male adults completed a VAS and dot probe task before and after receiving either 40 Hz-, 80 Hz-, 120 Hz MNS or sham (control) across four different sessions with continuous ECG recording throughout each session. Data from the dot probe task were analysed using repeated-measures ANOVA, while pair-wise tests were used for ECG recordings and VAS. Improvements on the dot probe task, not specific to odour-food congruence were found after 40 Hz MNS (p-value = 0.048; strong effect size (0.308 partial eta squared)) while increased ratings of hunger (VAS) (p-value = 0.03, small effect size (0.47 Cohen-D)) and RMSSD scores (p-value < 0.001; medium effect size (0.76 Cohen-D)) were found after 120 Hz MNS. These findings implore further testing of MNS frequency parameters on improving RMSSD, a characteristic marker of measuring parasympathetic/autonomic nervous system activation pertaining to the vagal network. Furthermore, improving sympathovagal balance is associated with cardiovascular benefits in numerous health-related conditions such as obesity, hypertension and diabetes.

Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury.

The systemic inflammatory response (SIRS) drives late morbidity and mortality after injury. The α7 nicotinic acetylcholine receptor (α7nAchR) expressed on immune cells regulates the vagal anti-inflammatory pathway that prevents an overwhelming SIRS response to injury. Nonspecific pharmacologic stimulation of the vagus nerve has been evaluated as a potential therapeutic to limit SIRS. Unfortunately, the results of clinical trials have been underwhelming. We hypothesized that directly targeting the α7nAchR would more precisely stimulate the vagal anti-inflammatory pathway on immune cells and decrease gut and lung injury after severe burn. C57BL/6 mice underwent 30% total body surface area steam burn. Mice were treated with an intraperitoneal injection of a selective agonist of the α7nAchR (AR-R17779) at 30 minutes postburn. Intestinal permeability to 4 kDa FITC-dextran was measured at multiple time points postinjury. Lung vascular permeability was measured 6 hours after burn injury. Serial behavioral assessments were performed to quantify activity levels. Intestinal permeability peaked at 6 hours postburn. AR-R17779 decreased burn-induced intestinal permeability in a dose-dependent fashion (p < 0.001). There was no difference in gut permeability to 4 kDa FITC-dextran between sham and burn-injured animals treated with 5 mg/kg of AR-R17779. While burn injury increased lung permeability 10-fold, AR-R17779 prevented burn-induced lung permeability with no difference compared with sham (p < 0.01). Postinjury activity levels were significantly improved in burned animals treated with AR-R17779. Directly stimulating the α7nAchR prevents burn-induced gut and lung injury. Directly targeting the α7nAChR that mediates the cholinergic anti-inflammatory response may be an improved strategy compared with nonspecific vagal agonists.

Vagal Tone and Proinflammatory Cytokines Predict Feeding Intolerance and Necrotizing Enterocolitis Risk.

Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal disease in preterm neonates; yet, clinicians lack reliable and noninvasive predictive tools. We aimed to test that diminished high-frequency heart rate variability (HF-HRV) and elevated levels of proinflammatory cytokines would have utility in NEC prediction. In this multisite prospective study, we enrolled 250 preterm (26-34 weeks' postmenstrual age [PMA]) neonates with physiological stability at 72 hours of life. HRV was measured noninvasively using electrocardiograhic data from standardized cardiorespiratory monitors at postnatal week 1 of life and weekly thereafter until 35 weeks' PMA or discharge; blood was collected for cytokines at postnatal weeks 1 and 3. NEC was diagnosed via Modified Bell's Staging Criteria. HF-HRV was decreased at weeks 1 and 2 in neonates (47% females) who developed feeding intolerance or stage 2+ NEC. In addition, these neonates displayed elevated levels of IL-8 at week 1 and increased levels of IL-1β, IL-6, TNF-α, and IL-8 at week 3 of life. Low HF-HRV was associated with elevated IL-6 or IL-8 levels at weeks 1 and 3 of life. Logistic regression indicated that only HF-HRV was a significant predictor of feeding intolerance or NEC development. HRV is a promising noninvasive modality for NEC risk detection. The association of low HF-HRV with elevated proinflammatory cytokines provides evidence for a putative role of the vagal cholinergic pathway in NEC pathogenesis. Future studies should focus on application of these techniques to test clinical therapeutics.Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?autoPlay=false&videoId=54.

Auricular Vagal Nerve Stimulation Improves Constipation by Enhancing Colon Motility via the Central-Vagal Efferent Pathway in Opioid-Induced Constipated Rats

Constipation and opioid-induced constipation (OIC) are common with limited treatment options. We investigated whether a noninvasive method of auricular vagal nerve stimulation (aVNS) could be used for treating OIC and explored its potential mechanisms and neural pathways in a rodent model of OIC. Sprague-Dawley were chronically implanted with one pair of auricular electrodes for aVNS. Sixteen rats were treated with loperamide for a week while another 16 rats received bilateral vagotomy, then randomly treated with aVNS or sham-aVNS for a week. In addition, eight normal rats were implanted with a polyethylene catheter in the proximal colon for assessing whole colon transit. 1) The number of fecal pellets and water content in feces increased after aVNS, compared with sham-aVNS. 2) aVNS accelerated colon transit and whole gut transit, compared with sham-aVNS. 3) In colon tissues, aVNS increased the protein expression of choline acetyltransferase, glial cell line-derived neurotrophic factor and the c-kit expression in myenteric interstitial cells of Cajal but decreased the protein expression of neural nitric oxide synthase (p < 0.05 for all, vs. sham-VNS). 4) The prokinetic effects of aVNS were abolished by both subdiaphragmatic vagotomy and atropine. 5) aVNS increased the c-fos expression in both nucleus tractus solitarius and dorsal motor nucleus of vagus, and increased vagal efferent activity (p < 0.05, vs. sham-VNS). aVNS improves OIC by enhancing colon motility and restoring enteric neural functions mediated via the central and vagal efferent pathway.

Biomarkers of neuroinflammation: Focus on monocyte chemotaxis

According to the amyloid cascade hypothesis, beta-amyloid (Abeta) aggregation represents the core pathogenic mechanism in Alzheimer's disease (AD). Neuroinflammation, as an inflammatory process confined to the CNS, plays a key role as well, fueling a response against Abeta, and eventually further damaging the surrounding neurons. Research currently points out at microglia cells as the central players of this game. However, an important role for periphery should be advocated, since peripheral blood monocytes cross the blood-brain barrier (BBB) attracted by Abeta and chemokines, and contribute to neuroinflammation by transforming into blood-born macrophages. Interestingly, this process of “neuroinvasion” from periphery represents the afferent arc of the inflammatory reflex, regulating a response against protein aggregates. The efferent arc is represented by a vagal cholinergic pathway projecting onto alpha7nAChR expressed by spleen mononuclear cells for shutting off the inflammasome and so modulating the process. In this talk we will focus on the role of peripheral monocytes, and in particular on the process of chemotaxis and neuroinvasion. Attention will be also given to the expression of the monocyte chemotactic systems, and among them, in particular, to the TSPO receptor (marker of activated microglia) and of the cognate biological ligand, the Diazepam Binding Inhibitor (DBI).

The gut, its microbiome, and the brain: connections and communications.

Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.

Topical Neck Cooling Prolongs Survival of Rats with Intra-Abdominal Feculent Sepsis by Activation of the Vagus Nerve.

Global hypothermia prolongs survival in rats with intraabdominal feculent sepsis by inhibiting inflammatory responses. We hypothesized that topical neck cooling (TNC) has similar benefits. Septic shock was induced by cecal ligation and incision (CLI) in Sprague Dawley rats. Rats were randomized to sham laparotomy, control with CLI, CLI with TNC, or vagotomy at the gastroesophageal junction before CLI and TNC. Two more groups underwent peritoneal washout with and without TNC two hours after CLI. TNC significantly lowered neck skin temperature (16.7 ± 1.4 vs. 30.5 ± 0.6 °C, p < 0.05) while maintaining core body normothermia. TNC rats recovered from anesthesia 70 min earlier than the control (p < 0.05). Three hours following CLI, the control and vagotomy with TNC groups had significantly more splenic contraction, fewer circulating leukocytes and higher plasma IL-1β, IL-10 and TNF-α levels than TNC rats (p < 0.05). TNC prolonged survival duration after CLI by a median of four hours vs. control (p < 0.05), but no benefit was seen if vagotomy preceded TNC. Peritoneal washout alone increased survival by 3 h (9.2 (7.8–10.5) h). Survival duration increased dramatically with TNC preceding washout, to a 56% survival rate (>10 days). TNC significantly prolonged the survival of rats with severe intraabdominal sepsis by inhibiting systemic proinflammatory responses by activating vagal anti-inflammatory pathways.

Peripheral nerve stimulation and immunity: the expanding opportunities for providing mechanistic insight and therapeutic intervention.

Pre-clinical research advances our understanding of the vagus nerve-mediated regulation of immunity and clinical trials successfully utilize electrical vagus nerve stimulation in the treatment of patients with inflammatory disorders. This symbiotic relationship between pre-clinical and clinical research exploring the vagus nerve-based 'inflammatory reflex' has substantially contributed to establishing the field of bioelectronic medicine. Recent studies identify a crosstalk between the vagus nerve and other neural circuitries in controlling inflammation and delineate new neural immunoregulatory pathways. Here we outline current mechanistic insights into the role of vagal and non-vagal neural pathways in neuro-immune communication and inflammatory regulation. We also provide a timely overview of expanding opportunities for bioelectronic neuromodulation in the treatment of various inflammatory disorders.

Neuronal regulation of the gut immune system and neuromodulation for treating inflammatory bowel disease.

The gut immune system in the healthy intestine is anti‐inflammatory, but can move to a pro‐inflammatory state when the gut is challenged by pathogens or in disease. The nervous system influences the level of inflammation through enteric neurons and extrinsic neural connections, particularly vagal and sympathetic innervation of the gastrointestinal tract, each of which exerts anti‐inflammatory effects. Within the enteric nervous system (ENS), three neuron types that influence gut immune cells have been identified, intrinsic primary afferent neurons (IPANs), vasoactive intestinal peptide (VIP) neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers. The enteric neuropeptides, calcitonin gene‐related peptide (CGRP), tachykinins, and neuromedin U (NMU), which are contained in IPANs, and VIP produced by the mucosa innervating neurons, all influence immune cells, notably innate lymphoid cells (ILCs). ILC2 are stimulated by VIP to release IL‐22, which promotes microbial defense and tissue repair. Enteric neurons are innervated by the vagus, and, in the large intestine, by the pelvic nerves. Vagal nerve stimulation reduces gut inflammation, which may be both by stimulation of efferent (motor) pathways to the ENS, and stimulation of afferent pathways that connect to integrating centers in the CNS. Efferent pathways from the CNS have their anti‐inflammatory effects through either or both vagal efferent neurons and sympathetic pathways. The final neurons in sympathetic pathways reduce gut inflammation by the action of noradrenaline on β2 adrenergic receptors expressed by immune cells. Activation of neural anti‐inflammatory pathways is an attractive option to treat inflammatory bowel disease that is refractory to other treatments. Further investigation of the ways in which enteric reflexes, vagal pathways and sympathetic pathways integrate their effects to modulate the gut immune system and gut inflammation is needed to optimize neuromodulation therapy.

Dedicated C-fiber vagal sensory afferent pathways to the paraventricular nucleus of the hypothalamus

The nucleus of the solitary tract (NTS) receives viscerosensory information from the vagus nerve to regulate diverse homeostatic reflex functions. The NTS projects to a wide network of other brain regions, including the paraventricular nucleus of the hypothalamus (PVN). Here we examined the synaptic characteristics of primary afferent pathways to PVN-projecting NTS neurons in rat brainstem slices.Expression of the Transient Receptor Potential Vanilloid receptor (TRPV1+ ) distinguishes C-fiber afferents within the solitary tract (ST) from A-fibers (TRPV1-). We used resiniferatoxin (RTX), a TRPV1 agonist, to differentiate the two. The variability in the latency (jitter) of evoked excitatory postsynaptic currents (ST-EPSCs) distinguished monosynaptic from polysynaptic ST-EPSCs. Rhodamine injected into PVN was retrogradely transported to identify PVN-projecting NTS neurons within brainstem slices. Graded shocks to the ST elicited all-or-none EPSCs in rhodamine-positive NTS neurons with latencies that had either low jitter (<200 µs – monosynaptic), high jitter (>200 µs - polysynaptic inputs) or both. RTX blocked ST-evoked TRPV1 + EPSCs whether mono- or polysynaptic. Most PVN-projecting NTS neurons (17/21 neurons) had at least one input polysynaptically connected to the ST. Compared to unlabeled NTS neurons, PVN-projecting NTS neurons were more likely to receive indirect inputs and be higher order. Surprisingly, sEPSC rates for PVN-projecting neurons were double that of unlabeled NTS neurons. The ST synaptic responses for PVN-projecting NTS neurons were either all TRPV1+ or all TRPV1-, including neurons that received both direct and indirect inputs. Overall, PVN-projecting NTS neurons received direct and indirect vagal afferent information with strict segregation regarding TRPV1 expression.

Microbial metabolites and the vagal afferent pathway in the control of food intake

The gut microbiota is able to influence overall energy balance via effects on both energy intake and expenditure, and is a peripheral target for potential obesity therapies. However, the precise mechanism by which the gut microbiota influences energy intake and body weight regulation is not clear. Microbes use small molecules to communicate with each other; some of these molecules are ligands at mammalian receptors and this may be a mechanism by which microbes communicate with the host. Here we briefly review the literature showing beneficial effects of microbial metabolites on food intake regulation and examine the potential role for vagal afferent neurons, the gut-brain axis.