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Neurobiology of Disease Dec 20233,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA...
3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut-brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.
Topics: Humans; Mice; Animals; N-Methyl-3,4-methylenedioxyamphetamine; Brain-Gut Axis; Resilience, Psychological; Prefrontal Cortex; Vagus Nerve
PubMed: 37956855
DOI: 10.1016/j.nbd.2023.106348 -
Obesity Surgery Dec 2023The obesity epidemic is rapidly growing, and visceral adiposity is associated with metabolic consequences secondary to peroxisome proliferator-activated receptor...
INTRODUCTION/PURPOSE
The obesity epidemic is rapidly growing, and visceral adiposity is associated with metabolic consequences secondary to peroxisome proliferator-activated receptor (PPAR)-induced inter-organ signaling pathways. PPARs are ligand-activated transcription factors that modulate vagal pathways which can improve blood pressure, arterial remodeling, cholesterol levels, and insulin sensitivity. However, an obesity-induced inflammatory milieu can interfere with the beneficial effects of PPAR activity, suggesting that a dysregulated PPAR-vagus pathway may play a role in the pathogenesis of obesity-related hypertension. Therefore, we hypothesized that hepatic vagotomy (HV) in patients with obesity would result in a significant reduction in blood pressure and/or the number of hypertension medications compared to control.
METHODS
We conducted a retrospective chart review of 160 patients undergoing laparoscopic sleeve gastrectomy. Patients were divided into HV and control groups, and information was collected at each clinic visit.
RESULTS
At six-months post-operation, the HV group was found to have significantly lower total cholesterol (TC)/high-density lipoprotein (HDL) ratios than the control group. The HV group also had a numerically better blood profile for TC, HDL, low-density lipoprotein (LDL), triglycerides, C-reactive protein, and LDL/HDL ratio. Hypertensive patients in the HV group showed numerically lower hypertension medication counts after six weeks when compared to control.
CONCLUSION
We present the first study to report clinically significant changes related to HV in human subjects. Our results did not support our initial hypothesis but did demonstrate an improvement of the TC/HDL ratio with HV in patients with obesity. Future studies should confirm these findings in a randomized control trial.
Topics: Humans; Lipoproteins, HDL; Peroxisome Proliferator-Activated Receptors; Retrospective Studies; Cholesterol, HDL; Cholesterol, LDL; Obesity, Morbid; Cholesterol; Obesity; Triglycerides; Hypertension; Vagotomy
PubMed: 37924466
DOI: 10.1007/s11695-023-06800-2 -
Molecular Medicine (Cambridge, Mass.) Oct 2023Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a...
BACKGROUND
Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4 T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis.
METHODS
The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed.
RESULTS
Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine.
CONCLUSION
Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.
Topics: Humans; Mice; Animals; Galantamine; alpha7 Nicotinic Acetylcholine Receptor; Acetylcholinesterase; Ceruletide; Acute Disease; Pancreatitis; Cytokines; Anti-Inflammatory Agents; Body Weight
PubMed: 37907853
DOI: 10.1186/s10020-023-00746-y -
The Journal of International Medical... Oct 2023To compare clinical and operative results between laparoscopic primary repair (LPR) alone and LPR with highly selective vagotomy (LPR-HSV) in patients with duodenal...
OBJECTIVE
To compare clinical and operative results between laparoscopic primary repair (LPR) alone and LPR with highly selective vagotomy (LPR-HSV) in patients with duodenal ulcer perforation.
METHODS
Clinical data from patients who underwent either LPR or LPR-HSV by resecting both sides of the neurovascular bundle using an ultrasonic or bipolar electrosurgical device for duodenal ulcer perforations, between 2010 and 2020, were retrospectively collected. Between-group differences in continuous and categorical variables were statistically analysed.
RESULTS
Data from 184 patients (mean age, 49.6 years), who underwent either LPR ( = 132) or LPR-HSV ( = 52) were included. The mean operation time was significantly longer in the LPR-HSV group (116.5 ± 39.8 min) than in the LPR group (91.2 ± 33.3 min). Hospital stay was significantly shorter in the LPR-HSV group (8.6 ± 2.6 days) versus the LPR group (11.3 ± 7.1 days). The mean postoperative day of starting soft fluid diet was also significantly shorter in the LPR-HSV group (4.5 ± 1.4 days) than in the LPR group (5.6 ± 4 days). No between-group difference in morbidity rate was observed. The learning curve of the HSV procedure showed a stable procedure time after 10 operations.
CONCLUSIONS
LPR with HSV may be a safe and feasible procedure for selective cases who are at high risk for ulcer recurrence.
Topics: Humans; Middle Aged; Duodenal Ulcer; Vagotomy, Proximal Gastric; Retrospective Studies; Peptic Ulcer Perforation; Laparoscopy; Recurrence; Postoperative Complications
PubMed: 37890147
DOI: 10.1177/03000605231206319 -
Journal of Affective Disorders Jan 2024Depression is a frequent symptom in patients with chronic liver disease; however, the mechanisms underlying this association remain unclear. Dysbiosis of gut microbiota...
Depression is a frequent symptom in patients with chronic liver disease; however, the mechanisms underlying this association remain unclear. Dysbiosis of gut microbiota plays a critical role in depression through the gut-brain axis via the vagus nerve. In this study, we investigated whether the gut-microbiota-liver-brain axis plays a role in depression-like phenotypes in mice with hepatic ischemia/reperfusion (HI/R) injury via the vagus nerve. Behavioral tests for depression-like behaviors were performed 7 days after sham or HI/R injury surgery. Mice with HI/R injury exhibited splenomegaly, systemic inflammation, depression-like behaviors, reduced expression of synaptic proteins in the prefrontal cortex (PFC), abnormal composition of gut microbiota, and altered blood metabolites and lipids. Furthermore, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Moreover, subdiaphragmatic vagotomy significantly blocked these changes in mice with HI/R injury. Notably, depression-like phenotypes in mice with HI/R injury were ameliorated after subsequent single injection of the new antidepressant arketamine. The current findings suggest that HI/R injury induces depression-like phenotypes in mice through the gut-microbiota-liver-brain axis via the subdiaphragmatic vagus nerve. Furthermore, arketamine may have therapeutic potential in the treatment of depression in patients with chronic liver disease.
Topics: Humans; Mice; Animals; Depression; Brain-Gut Axis; Microbiota; Vagus Nerve; Phenotype; Prefrontal Cortex; Liver Diseases; Reperfusion Injury; Ischemia; Lipids
PubMed: 37879416
DOI: 10.1016/j.jad.2023.10.142 -
BMB Reports Mar 2024The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and...
The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomachspecific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis. [BMB Reports 2024; 57(3): 149-154].
Topics: Mice; Animals; Ghrelin; Eating; Clusterin; Cholecystokinin; Stomach; Feeding Behavior
PubMed: 37817436
DOI: 10.5483/BMBRep.2023-0117 -
Cureus Sep 2023Background The incidence of gastric stump carcinoma (GSC) is not declining because of the long latency period. The survival rate of treated gastric cancer patients has...
Background The incidence of gastric stump carcinoma (GSC) is not declining because of the long latency period. The survival rate of treated gastric cancer patients has increased due to early detection and improvements in surgical techniques and chemotherapy. Increased survival rates and improved surveillance following gastric surgery have increased the incidence of GSC. Aim The study aims to investigate the clinicopathological factors affecting the interval between index gastric surgery and the occurrence of GSC, and our experience in the management of GSC is presented. Methods A retrospective review of patients diagnosed with GSC in our institution was completed. Patient characteristics and clinicopathological outcomes were analyzed. Results A total of 28 patients were included in this cohort with 17 (60.71%) males and 11 (39.28%) females. The mean interval from index surgery to the incidence of GSC was 24.42 years for benign etiology and six years for malignant etiology. Index surgeries were truncal vagotomy with 14 gastrojejunostomies (50%) and 14 subtotal gastrectomies (50%). The interval between index surgery and the incidence of GSC is not statistically significant concerning the type of surgery (p: 0.661), pathological TNM (tumor, nodes, metastases) stage (p: 0.520), pathological differentiation (p: 0.828), lymphovascular invasion (p: 0.252), perineural invasion (p: 0.672), and adjuvant therapy (p: -0.655). Survival was significantly higher in those patients who received curative resection in comparison to a palliative procedure (p: 0.041). Conclusion Strict surveillance for at least 10 years after initial gastric surgery is of utmost importance as half of the patients fated to develop GSC will do so within this time. In those patients with early diagnosis, no evidence of metastasis, and good performance status, curative surgery is feasible with acceptable morbidity.
PubMed: 37809185
DOI: 10.7759/cureus.44798 -
The Journal of Physiology Nov 2023A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates...
A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.
Topics: Humans; Rats; Animals; Stomach; Rats, Sprague-Dawley; Substantia Nigra; Vagus Nerve; Gastrointestinal Motility; Colon; Constipation
PubMed: 37772988
DOI: 10.1113/JP284238 -
BMJ Open Sep 2023Benign gastric outlet obstruction (BGOO) severely impacts the quality of life of patients. The main treatment methods for BGOO include surgery and endoscopy, but both...
Exploring the safety and efficacy of stomach-partitioning gastrojejunostomy with distal selective vagotomy versus conventional gastrojejunostomy with highly selective vagotomy for treating benign gastric outlet obstruction: study protocol for a randomised controlled trial.
INTRODUCTION
Benign gastric outlet obstruction (BGOO) severely impacts the quality of life of patients. The main treatment methods for BGOO include surgery and endoscopy, but both have significant drawbacks. Therefore, this study aims to explore the safety and efficacy of a new technique, to develop a new option for treating BGOO.
METHODS AND ANALYSIS
This is an ongoing prospective, single-centre, single-blind randomised controlled trial. The study will be conducted from January 2022 to December 2025, and 50 patients will be enrolled. The participants will be randomly assigned in a 1:1 ratio to either the experimental (stomach-partitioning gastrojejunostomy with distal selective vagotomy) or control groups (conventional gastrojejunostomy with highly selective vagotomy). We will collect baseline characteristics, laboratory tests, auxiliary examinations, operation, postoperative conditions and follow-up data. Follow-up will last for 3 years. The main outcome is the incidence of delayed gastric emptying within 30 days after surgery. Secondary outcomes include the efficacy indicator (consisting of serum gastrin level, pepsinogen level, 13C breath test, gastrointestinal quality of life index, operation time, blood loss and postoperative recovery), a safety evaluation index (consisting of complications and mortality within 30 days after surgery) and follow-up data (consisting of the incidence of primary ulcer progression in 3 years after surgery, and the gastroscopy results in 1 and 3 years after surgery).
ETHICS AND DISSEMINATION
This study was approved by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (no. 2021-P2-274-02). The study conformed to the provisions of the Declaration of Helsinki (as revised in 2013). Written informed consent will be obtained prior to study enrolment. The results of this study will be published in peer-reviewed publications.
TRIAL REGISTRATION NUMBER
ChiCTR2100052197.
Topics: Humans; Vagotomy, Proximal Gastric; Gastric Bypass; Prospective Studies; Quality of Life; Single-Blind Method; Vagotomy; Gastric Outlet Obstruction; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37770279
DOI: 10.1136/bmjopen-2022-070735 -
Journal of Psychiatric Research Oct 2023Chronic inflammatory pain (CIP) is a common public medical problem, often accompanied by memory impairment. However, the mechanisms underlying CIP and comorbid memory...
The role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in chronic inflammatory pain and comorbid spatial working memory impairment in complete Freund's adjuvant mice.
Chronic inflammatory pain (CIP) is a common public medical problem, often accompanied by memory impairment. However, the mechanisms underlying CIP and comorbid memory impairment remain elusive. This study aimed to examine the role of the gut-microbiota-brain axis in CIP and comorbid memory impairment in mice treated with complete Freund's adjuvant (CFA). 16S rRNA analysis showed the altered diversity of gut microbiota from day 1 to day 14 after CFA injection. Interestingly, fecal microbiota transplantation (FMT) from healthy naive mice ameliorated comorbidities, such as mechanical allodynia, thermal hyperalgesia, spatial working memory impairment, neuroinflammation, and abnormal composition of gut microbiota in the CFA mice. Additionally, subdiaphragmatic vagotomy (SDV) blocked the onset of these comorbidities. Interestingly, the relative abundance of the bacterial genus or species was also correlated with these comorbidities after FMT or SDV. Therefore, our results suggest that the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve is crucial for the development of CIP and comorbid spatial working memory impairment in CFA mice.
Topics: Mice; Animals; Freund's Adjuvant; Memory, Short-Term; RNA, Ribosomal, 16S; Chronic Pain; Hyperalgesia; Microbiota; Memory Disorders; Brain; Vagus Nerve
PubMed: 37741061
DOI: 10.1016/j.jpsychires.2023.09.003