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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 -
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 -
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 -
The Journal of Trauma and Acute Care... Jul 2022Peptic ulcer disease (PUD), once primary a surgical problem, is now medically managed in the majority of patients. The surgical treatment of PUD is now strictly reserved...
BACKGROUND
Peptic ulcer disease (PUD), once primary a surgical problem, is now medically managed in the majority of patients. The surgical treatment of PUD is now strictly reserved for life-threatening complications. Free perforation, refractory bleeding and gastric outlet obstruction, although rare in the age of medical management of PUD, are several of the indications for surgical intervention. The acute care surgeon caring for patients with PUD should be facile in techniques required for bleeding control, bypass of peptic strictures, and vagotomy with resection and reconstruction. This video procedures and techniques article demonstrates these infrequently encountered, but critical operations.
CONTENT VIDEO DESCRIPTION
A combination of anatomic representations and videos of step-by-step instructions on perfused cadavers will demonstrate the key steps in the following critical operations. Graham patch repair of perforated peptic ulcer is demonstrated in both open and laparoscopic fashion. The choice to perform open versus laparoscopic repair is based on individual surgeon comfort. Oversewing of a bleeding duodenal ulcer via duodenotomy and ligation of the gastroduodenal artery is infrequent in the age of advanced endoscopy and interventional radiology techniques, yet this once familiar procedure can be lifesaving. Repair of giant duodenal or gastric ulcers can present a challenging operative dilemma on how to best repair or exclude the defect. Vagotomy and antrectomy, perhaps the least common of all the aforementioned surgical interventions, may require more complex reconstruction than other techniques making it challenging for inexperienced surgeons. A brief demonstration on reconstruction options will be shown, and it includes Roux-en-Y gastrojejunostomy.
CONCLUSION
Surgical management of PUD is reserved today for life-threatening complications for which the acute care surgeon must be prepared. This presentation provides demonstration of key surgical principles in management of bleeding and free perforation, as well as gastric resection, vagotomy and reconstruction.
LEVEL OF EVIDENCE
Video procedure and technique, not applicable.
Topics: Duodenal Ulcer; Gastrectomy; Humans; Peptic Ulcer; Peptic Ulcer Perforation; Vagotomy
PubMed: 35358158
DOI: 10.1097/TA.0000000000003636 -
BioRxiv : the Preprint Server For... Jan 2024Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences...
Liver cancer ranks amongst the deadliest cancers. Nerves have emerged as an understudied regulator of tumor progression. The parasympathetic vagus nerve influences systemic immunity via acetylcholine (ACh). Whether cholinergic neuroimmune interactions influence hepatocellular carcinoma (HCC) remains uncertain. Liver denervation via hepatic vagotomy (HV) significantly reduced liver tumor burden, while pharmacological enhancement of parasympathetic tone promoted tumor growth. Cholinergic disruption in Rag1KO mice revealed that cholinergic regulation requires adaptive immunity. Further scRNA-seq and in vitro studies indicated that vagal ACh dampens CD8+ T cell activity via muscarinic ACh receptor (AChR) CHRM3. Depletion of CD8+ T cells abrogated HV outcomes and selective deletion of on CD8 T cells inhibited liver tumor growth. Beyond tumor-specific outcomes, vagotomy improved cancer-associated fatigue and anxiety-like behavior. As microbiota transplantation from HCC donors was sufficient to impair behavior, we investigated putative microbiota-neuroimmune crosstalk. Tumor, rather than vagotomy, robustly altered fecal bacterial composition, increasing Desulfovibrionales and Clostridial taxa. Strikingly, in tumor-free mice, vagotomy permitted HCC-associated microbiota to activate hepatic CD8+ T cells. These findings reveal that gut bacteria influence behavior and liver anti-tumor immunity via a dynamic and pharmaceutically targetable, vagus-liver axis.
PubMed: 38328040
DOI: 10.1101/2024.01.23.576951 -
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 -
IScience Feb 2021Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of...
Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/α-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.
PubMed: 33598644
DOI: 10.1016/j.isci.2021.102091 -
NeuroImage Nov 2022Interactions between the brain and the stomach shape both cognitive and digestive functions. Recent human studies report spontaneous synchronization between brain...
Interactions between the brain and the stomach shape both cognitive and digestive functions. Recent human studies report spontaneous synchronization between brain activity and gastric slow waves in the resting state. However, this finding has not been replicated in any animal models. The neural pathways underlying this apparent stomach-brain synchrony is also unclear. Here, we performed functional magnetic resonance imaging while simultaneously recording body-surface gastric slow waves from anesthetized rats in the fasted vs. postprandial conditions and performed a bilateral cervical vagotomy to assess the role of the vagus nerve. The coherence between brain fMRI signals and gastric slow waves was found in a distributed "gastric network", including subcortical and cortical regions in the sensory, motor, and limbic systems. The stomach-brain coherence was largely reduced by the bilateral vagotomy and was different between the fasted and fed states. These findings suggest that the vagus nerve mediates the spontaneous coherence between brain activity and gastric slow waves, which is likely a signature of real-time stomach-brain interactions. However, its functional significance remains to be established.
Topics: Humans; Rats; Animals; Stomach; Vagus Nerve; Brain; Vagotomy; Neural Pathways
PubMed: 36113737
DOI: 10.1016/j.neuroimage.2022.119628 -
Life Sciences May 2021The aim of this study was to explore the potential effect of electroacupuncture (EA) at ST36 on mice bearing breast tumors by regulating inflammatory cytokines to...
AIMS
The aim of this study was to explore the potential effect of electroacupuncture (EA) at ST36 on mice bearing breast tumors by regulating inflammatory cytokines to enhance antitumor immunity via vagus nerve.
MATERIALS AND METHODS
Female BALB/c mice were implanted with 4T1-luc2 breast tumor cells to establish a murine mammary cancer model. Tumor growth was evaluated by tumor volume, weight and bioluminescence imaging. Inflammatory conditions in serum and tumor tissue were assessed by cytokines (IL-1β, TNF-α and IL-10) and HE staining. Proportions and functions of CD8 T cells, NK cells and MDSCs were identified by flow cytometry and western blot. Involvement of vagal efferent components was confirmed by ChAT and c-Fos double labeling immunohistochemistry in dorsal motor nucleus of vagus (DMV). Subdiaphragmatic vagotomy was employed to determine if the effect of EA was mediated by vagus nerve.
KEY FINDINGS
EA at ST36 reduced the volume and weight of tumors within 22 days after implantation. Proinflammatory cytokines IL-1β and TNF-α in serum, tumor and local inflammatory infiltration were obviously attenuated after EA. Meanwhile, EA intervention significantly augmented the proportion and cytolytic function of CD8 T cells and NK cells, along with a decline in the accumulation and immunosuppressive activities of MDSCs. Finally, c-Fos expression in ChAT neurons in DMV increased following EA, and the ameliorating effect of EA was obviously blocked by subdiaphragmatic vagotomy.
SIGNIFICANCE
EA intervention relieved tumor progression in breast tumor-bearing mice by alleviating inflammation and enhancing antitumor immunity, which was mediated by eliciting efferent vagus nerve activity.
Topics: Animals; Breast Neoplasms; CD8-Positive T-Lymphocytes; China; Cytokines; Electroacupuncture; Female; Inflammation; Interleukin-1beta; Mice; Mice, Inbred BALB C; Tumor Necrosis Factor-alpha; Vagus Nerve
PubMed: 33636172
DOI: 10.1016/j.lfs.2021.119259