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BioRxiv : the Preprint Server For... Sep 2023Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the...
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
PubMed: 37645945
DOI: 10.1101/2023.08.14.553305 -
Bioengineering (Basel, Switzerland) Jul 2023A code is generally defined as a system of signals or symbols for communication. Experimental evidence is synthesized for the presence and utility of such communication... (Review)
Review
A code is generally defined as a system of signals or symbols for communication. Experimental evidence is synthesized for the presence and utility of such communication in heart rate variability (HRV) with particular attention to fetal HRV: HRV contains signatures of information flow between the organs and of response to physiological or pathophysiological stimuli as signatures of states (or syndromes). HRV exhibits features of time structure, phase space structure, specificity with respect to (organ) target and pathophysiological syndromes, and universality with respect to species independence. Together, these features form a spatiotemporal structure, a phase space, that can be conceived of as a manifold of a yet-to-be-fully understood dynamic complexity. The objective of this article is to synthesize physiological evidence supporting the existence of HRV code: hereby, the process-specific subsets of HRV measures indirectly map the phase space traversal reflecting the specific information contained in the code required for the body to regulate the physiological responses to those processes. The following physiological examples of HRV code are reviewed, which are reflected in specific changes to HRV properties across the signal-analytical domains and across physiological states and conditions: the fetal systemic inflammatory response, organ-specific inflammatory responses (brain and gut), chronic hypoxia and intrinsic (heart) HRV (iHRV), allostatic load (physiological stress due to surgery), and vagotomy (bilateral cervical denervation). Future studies are proposed to test these observations in more depth, and the author refers the interested reader to the referenced publications for a detailed study of the HRV measures involved. While being exemplified mostly in the studies of fetal HRV, the presented framework promises more specific fetal, postnatal, and adult HRV biomarkers of health and disease, which can be obtained non-invasively and continuously.
PubMed: 37508849
DOI: 10.3390/bioengineering10070822 -
World Journal of Surgical Oncology Jul 2023The 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...
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.
Topics: Humans; Retrospective Studies; Stomach Neoplasms; Case-Control Studies; Palliative Care; Prospective Studies; Vagotomy; Gastric Outlet Obstruction
PubMed: 37480111
DOI: 10.1186/s12957-023-03111-9 -
Journal of Clinical Medicine Jun 2023Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention... (Review)
Review
Marginal ulcer (MU) is a potential complication following Roux-en-Y gastric bypass (RYGB), with a mean prevalence of 4.6%. Early identification and prompt intervention are crucial to mitigating further complications. The pathophysiology of MU is complex and involves multiple factors, including smoking, infection, non-steroidal anti-inflammatory drug (NSAID) use, and larger pouch size. Patients with MU may experience acute or chronic abdominal pain. Rarely, they may present with a complication from the ulceration, such as bleeding, perforation, or strictures. Following diagnosis by endoscopy, management of MU typically involves modification of risk factors and medical therapy focused on proton pump inhibitors. In case of complicated ulcers, surgical intervention is often required for the repair of the perforation or resection of the stricture. For recurrent or recalcitrant ulcers, endoscopic coverage of the ulcer bed, resection of the anastomosis, and abdominal or thoracoscopic truncal vagotomy may be considered. This review aims at providing an overview of the etiology, diagnosis, and management of MU after RYGB.
PubMed: 37445371
DOI: 10.3390/jcm12134336 -
Nature Aug 2023The 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...
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 avoidance. Here, we show that antigen-specific avoidance behaviour in inbred mice 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.
Topics: Animals; Mice; Allergens; Avoidance Learning; Hypersensitivity; Immunoglobulin E; Mast Cells; Stomach; Vagotomy; Immunity, Innate; Immunity, Mucosal; Th2 Cells; Cytokines; Leukotrienes; Intestine, Small
PubMed: 37438525
DOI: 10.1038/s41586-023-06188-0 -
Science Advances Jul 2023The blood circulation is considered the only way for the orally administered nanoparticles to enter the central nervous systems (CNS), whereas non-blood route-mediated...
The blood circulation is considered the only way for the orally administered nanoparticles to enter the central nervous systems (CNS), whereas non-blood route-mediated nanoparticle translocation between organs is poorly understood. Here, we show that peripheral nerve fibers act as direct conduits for silver nanomaterials (Ag NMs) translocation from the gut to the CNS in both mice and rhesus monkeys. After oral gavage, Ag NMs are significantly enriched in the brain and spinal cord of mice with particle state however do not efficiently enter the blood. Using truncal vagotomy and selective posterior rhizotomy, we unravel that the vagus and spinal nerves mediate the transneuronal translocation of Ag NMs from the gut to the brain and spinal cord, respectively. Single-cell mass cytometry analysis revealed that enterocytes and enteric nerve cells take up significant levels of Ag NMs for subsequent transfer to the connected peripheral nerves. Our findings demonstrate nanoparticle transfer along a previously undocumented gut-CNS axis mediated by peripheral nerves.
Topics: Animals; Mice; Silver; Central Nervous System; Spinal Cord; Peripheral Nerves; Nanostructures
PubMed: 37418525
DOI: 10.1126/sciadv.adg2252 -
Journal of Neuroinflammation Jul 2023Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve,...
BACKGROUND
Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established. As an alternative to direct innervation, an anti-inflammatory reflex pathway has been proposed which involves the vagus nerve, the sympathetic celiac ganglion, and the neurotransmitter norepinephrine. Although sympathetic regulation of inflammation has been shown, the interaction of the vagus nerve and the celiac ganglia requires a unique interaction of parasympathetic and sympathetic inputs, making this putative mechanism of brain-spleen interaction controversial. BODY: As neuropeptides can be expressed at relatively high levels in neurons, we reasoned that DMN neuropeptide immunoreactivity could be used to determine their target innervation. Employing immunohistochemistry, subdiaphragmatic vagotomy, viral tract tracing, CRISPR-mediated knock-down, and functional assays, we show that cocaine and amphetamine-regulated transcript (CART) peptide-expressing projection neurons in the caudal DMN directly innervate the spleen. In response to lipopolysaccharide (LPS) stimulation, CART acts to reduce inflammation, an effect that can be augmented by intrasplenic administration of a synthetic CART peptide. These in vivo effects could be recapitulated in cultured splenocytes, suggesting that these cells express the as yet unidentified CART receptor(s).
CONCLUSION
Our results provide evidence for direct connections between the caudal DMN and spleen. In addition to acetylcholine, these neurons express the neuropeptide CART that, once released, acts to suppress inflammation by acting directly upon splenocytes.
Topics: Humans; Spleen; Neurons; Neuropeptides; Vagus Nerve; Inflammation
PubMed: 37403174
DOI: 10.1186/s12974-023-02838-2 -
BioRxiv : the Preprint Server For... May 2023The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute...
BACKGROUND
The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications, but the anti-inflammatory efficacy of electrical DMN stimulation (eDMNS) was not previously investigated. Here, we examined the effects of eDMNS on heart rate (HR) and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis.
METHODS
Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (50, 250 or 500 μA and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days.
RESULTS
Either left or right eDMNS at 250 μA and 500 μA decreased HR, compared with pre- and post-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and were not associated with serum corticosterone alterations. Right side eDMNS suppressed serum TNF levels but had no effects on serum IL-10 and on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum TNF and IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice.
CONCLUSIONS
For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation and these effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.
PubMed: 37292846
DOI: 10.1101/2023.05.17.541191 -
Nutrients May 2023During esophagectomy, the vagus nerve is transected, which may add to the development of postoperative complications. The vagus nerve has been shown to attenuate...
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 ( > 0.999). There was a trend in aggravation of LIS after cervical vagotomy ( = 0.051), even after an α7nAChR-agonist ( = 0.090). Cervical vagotomy with an α7nAChR-antagonist aggravated lung injury ( = 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 ( = 0.012) and selective vagotomy ( = 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.
Topics: Rats; Animals; Lipopolysaccharides; alpha7 Nicotinic Acetylcholine Receptor; Vagus Nerve; Vagotomy; Acute Lung Injury
PubMed: 37242210
DOI: 10.3390/nu15102327 -
Biomedicines Apr 2023GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body...
GLP-1 is a gastro-intestinal hormone acting within the gut/brain axis for energy balance regulation. We aimed to evaluate the role of the vagus nerve in whole-body energy homeostasis and in mediating GLP-1 effects. For this, rats submitted to truncal vagotomy and sham-operated controls underwent a comprehensive evaluation, including eating behavior, body weight, percentage of white (WAT) and brown adipose tissue (BAT), resting energy expenditure (REE) and acute response to GLP-1. Truncal vagotomized rats had significantly lower food intake, body weight, body weight gain, WAT and BAT, with a higher BAT/WAT ratio, but no significant difference in REE when compared to controls. Vagotomized rats also had significantly higher fasting ghrelin and lower glucose and insulin levels. After GLP-1 administration, vagotomized rats depicted a blunted anorexigenic response and higher plasma leptin levels, as compared to controls. However, in vitro stimulation of VAT explants with GLP-1 resulted in no significant changes in leptin secretion. In conclusion, the vagus nerve influences whole-body energy homeostasis by modifying food intake, body weight and body composition and by mediating the GLP-1 anorectic response. The higher leptin levels in response to acute GLP-1 administration observed after truncal vagotomy suggest the existence of a putative GLP-1-leptin axis that relies on the integrity of gut-brain vagal pathway.
PubMed: 37238993
DOI: 10.3390/biomedicines11051322