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Molecular Medicine (Cambridge, Mass.) May 2022Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and...
BACKGROUND
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.
METHODS
The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.
RESULTS
Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.
CONCLUSIONS
These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
Topics: Animals; Anti-Inflammatory Agents; COVID-19; Cytokine Release Syndrome; Famotidine; Histamine; Histamine H2 Antagonists; Lipopolysaccharides; Mice; Reflex; Vagus Nerve; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35578169
DOI: 10.1186/s10020-022-00483-8 -
The American Surgeon Jun 2023A subset of patients with marginal ulcers after Roux-en-Y gastric bypass (RNYGB) is refractory to medical management. Here we report a retrospective review of a single...
A subset of patients with marginal ulcers after Roux-en-Y gastric bypass (RNYGB) is refractory to medical management. Here we report a retrospective review of a single institution cohort (N = 10) of video- or robotic-assisted thoracoscopic (VATS or RATS) truncal vagotomies performed between 2013 and 2018. All patients had recurrent marginal ulcers following RNYGB complicated by bleeding or perforation, refractory to medical management for a median of 3.5 months prior to undergoing truncal vagotomy. With a median of 23 months' follow-up, only three patients had continued symptoms (70% symptom resolution) post-operatively. Only one patient who had repeat endoscopy after the procedure had documented endoscopic evidence of recurrent marginal ulcer (83% endoscopic resolution). VATS or RATS truncal vagotomy is a safe and effective method to treat complicated marginal ulceration after RNYGB. After an average duration of unsuccessful medical treatment lasting three months, vagotomy led to successful resolution in 70-83% of patients.
Topics: Humans; Vagotomy, Truncal; Robotic Surgical Procedures; Endoscopy; Peptic Ulcer; Gastric Bypass
PubMed: 35471188
DOI: 10.1177/00031348221087385 -
Acta Psychiatrica Scandinavica Jan 2022To 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...
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.
Topics: Hospitals; Humans; Mental Disorders; Risk Factors; Vagotomy; Vagus Nerve
PubMed: 34195992
DOI: 10.1111/acps.13343 -
Cancers May 2022Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate... (Review)
Review
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
PubMed: 35565462
DOI: 10.3390/cancers14092333 -
Frontiers in Neuroscience 2022Gastrointestinal (GI) symptoms represented by constipation were significant non-motor symptoms of Parkinson's disease (PD) and were considered early manifestations and... (Review)
Review
Gastrointestinal (GI) symptoms represented by constipation were significant non-motor symptoms of Parkinson's disease (PD) and were considered early manifestations and aggravating factors of the disease. This paper reviewed the research progress of the mechanism of the gut-brain axis (GBA) in PD and discussed the roles of α-synuclein, gut microbiota, immune inflammation, neuroendocrine, mitochondrial autophagy, and environmental toxins in the mechanism of the GBA in PD. Treatment of PD based on the GBA theory has also been discussed, including (1) dietary therapy, such as probiotics, vitamin therapy, Mediterranean diet, and low-calorie diet, (2) exercise therapy, (3) drug therapy, including antibiotics; GI peptides; GI motility agents, and (4) fecal flora transplantation can improve the flora. (5) Vagotomy and appendectomy were associated but not recommended.
PubMed: 35873830
DOI: 10.3389/fnins.2022.878239 -
BioRxiv : the Preprint Server For... Sep 2023The gut-brain axis, a bidirectional signaling network between the intestine and the central nervous system, is crucial to the regulation of host physiology and...
The gut-brain axis, a bidirectional signaling network between the intestine and the central nervous system, is crucial to the regulation of host physiology and inflammation. Recent advances suggest a strong correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that gut commensal bacteria can translocate directly to the brain when mice are fed an altered diet that causes dysbiosis and intestinal permeability, and that this also occurs without diet alteration in distinct murine models of neurological disease. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Unilateral cervical vagotomy significantly reduced the number of bacteria in the brain, implicating the vagus nerve as a conduit for translocation. The presence of bacteria in the brain correlated with microglial activation, a marker of neuroinflammation, and with neural protein aggregation, a hallmark of several neurodegenerative diseases. In at least one model, the presence of bacteria in the brain was reversible as a switch from high-fat to standard diet resulted in amelioration of intestinal permeability, led to a gradual loss of detectable bacteria in the brain, and reduced the number of neural protein aggregates. Further, in murine models of Alzheimer's disease, Parkinson's disease, and autism spectrum disorder, we observed gut dysbiosis, gut leakiness, bacterial translocation to the brain, and microglial activation. These data reveal a commensal bacterial translocation axis to the brain in models of diverse neurological diseases.
PubMed: 37693595
DOI: 10.1101/2023.08.30.555630 -
Surgical Endoscopy Jul 2021You 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...
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.
Topics: Drainage; Duodenal Ulcer; Gastric Bypass; Humans; Stomach; Vagotomy; Vagotomy, Truncal
PubMed: 32671523
DOI: 10.1007/s00464-020-07797-w -
JCI Insight Dec 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. Although 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 intestinal mucosa express α-synuclein. Here, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of α-synuclein. In mice expressing human α-synuclein, but no mouse α-synuclein, α-synuclein fibril-templating activity emerged in α-synuclein-seeded fibril aggregation assays in intestine, 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 transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of α-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of α-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
Topics: Animals; Humans; Mice; alpha-Synuclein; Brain; Neurons; Parkinson Disease; Vagus Nerve; Gastric Mucosa
PubMed: 38063197
DOI: 10.1172/jci.insight.172192 -
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 -
Gastrointestinal Endoscopy Clinics of... Apr 2024The use of surgery in managing upper gastrointestinal (GI) bleeding has rapidly diminished secondary to advances in our understanding of the pathologies that underlie... (Review)
Review
The use of surgery in managing upper gastrointestinal (GI) bleeding has rapidly diminished secondary to advances in our understanding of the pathologies that underlie upper GI bleeding, pharmaceutical treatments for peptic ulcer disease, and endoscopic procedures used to gain hemostasis. A surgeon must work collaboratively with gastroenterologist and interventional radiologist to determine when, and what kind of, surgery is appropriate for the patient with upper GI bleeding.
Topics: Humans; Endoscopy, Gastrointestinal; Gastrointestinal Hemorrhage; Peptic Ulcer; Hemostasis, Endoscopic; Gastroenterologists
PubMed: 38395485
DOI: 10.1016/j.giec.2023.09.005