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Molecular Psychiatry Jul 2023Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown...
Chronic stress constitutes a major risk factor for depression that can disrupt various aspects of homeostasis, including the gut microbiome (GM). We have recently shown that GM imbalance affects adult hippocampal (HPC) neurogenesis and induces depression-like behaviors, with the exact mechanisms being under active investigation. Here we hypothesized that the vagus nerve (VN), a key bidirectional route of communication between the gut and the brain, could relay the effects of stress-induced GM changes on HPC plasticity and behavior. We used fecal samples derived from mice that sustained unpredictable chronic mild stress (UCMS) to inoculate healthy mice and assess standard behavioral readouts for anxiety- and depressive-like behavior, conduct histological and molecular analyses for adult HPC neurogenesis and evaluate neurotransmission pathways and neuroinflammation. To study the potential role of the VN in mediating the effects of GM changes on brain functions and behavior, we used mice that sustained subdiaphragmatic vagotomy (Vx) prior the GM transfer. We found that inoculation of healthy mice with GM from UCMS mice activates the VN and induces early and sustained changes in both serotonin and dopamine neurotransmission pathways in the brainstem and HPC. These changes are associated with prompt and persistent deficits in adult HPC neurogenesis and induce early and sustained neuroinflammatory responses in the HPC. Remarkably, Vx abrogates adult HPC neurogenesis deficits, neuroinflammation and depressive-like behavior, suggesting that vagal afferent pathways are necessary to drive GM-mediated effects on the brain.
Topics: Mice; Animals; Gastrointestinal Microbiome; Neuroinflammatory Diseases; Brain; Vagus Nerve; Depression; Stress, Psychological
PubMed: 37131071
DOI: 10.1038/s41380-023-02071-6 -
Cancer Research May 2020Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and...
Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8 T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8 T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8 T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8 T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8 T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.
Topics: Acetylcholine; Animals; Carcinoma, Pancreatic Ductal; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Neoplasm Invasiveness; Pancreatic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 32098780
DOI: 10.1158/0008-5472.CAN-19-2689 -
Microbiome Jun 2021Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also...
BACKGROUND
Modification of the gut microbiota has been reported to reduce the incidence of type 1 diabetes mellitus (T1D). We hypothesized that the gut microbiota shifts might also have an effect on cognitive functions in T1D. Herein we used a non-absorbable antibiotic vancomycin to modify the gut microbiota in streptozotocin (STZ)-induced T1D mice and studied the impact of microbial changes on cognitive performances in T1D mice and its potential gut-brain neural mechanism.
RESULTS
We found that vancomycin exposure disrupted the gut microbiome, altered host metabolic phenotypes, and facilitated cognitive impairment in T1D mice. Long-term acetate deficiency due to depletion of acetate-producing bacteria resulted in the reduction of synaptophysin (SYP) in the hippocampus as well as learning and memory impairments. Exogenous acetate supplement or fecal microbiota transplant recovered hippocampal SYP level in vancomycin-treated T1D mice, and this effect was attenuated by vagal inhibition or vagotomy.
CONCLUSIONS
Our results demonstrate the protective role of microbiota metabolite acetate in cognitive functions and suggest long-term acetate deficiency as a risk factor of cognitive decline. Video Abstract.
Topics: Acetates; Animals; Bacteria; Brain; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Mice
PubMed: 34172092
DOI: 10.1186/s40168-021-01088-9 -
The EMBO Journal Sep 2021Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may...
Inflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Some evidence suggests that misfolded protein aggregates found in AD brains may have originated from the gut, but the mechanism underlying this phenomenon is not fully understood. C/EBPβ/δ-secretase signaling in the colon was investigated in a 3xTg AD mouse model in an age-dependent manner. We applied chronic administration of 1% dextran sodium sulfate (DSS) to trigger gut leakage or colonic injection of Aβ or Tau fibrils or AD patient brain lysates in 3xTg mice and combined it with excision/cutting of the gut-brain connecting vagus nerve (vagotomy), in order to explore the role of the gut-brain axis in the development of AD-like pathologies and to monitor C/EBPβ/δ-secretase signaling under those conditions. We found that C/EBPβ/δ-secretase signaling is temporally activated in the gut of AD patients and 3xTg mice, initiating formation of Aβ and Tau fibrils that spread to the brain. DSS treatment promotes gut leakage and facilitates AD-like pathologies in both the gut and the brain of 3xTg mice in a C/EBPβ/δ-secretase-dependent manner. Vagotomy selectively blunts this signaling, attenuates Aβ and Tau pathologies, and restores learning and memory. Aβ or Tau fibrils or AD patient brain lysates injected into the colon propagate from the gut into the brain via the vagus nerve, triggering AD pathology and cognitive dysfunction. The results indicate that inflammation activates C/EBPβ/δ-secretase and initiates AD-associated pathologies in the gut, which are subsequently transmitted to the brain via the vagus nerve.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Brain; CCAAT-Enhancer-Binding Proteins; Colitis; Colon; Cysteine Endopeptidases; Mice; Mice, Inbred C57BL; tau Proteins
PubMed: 34260075
DOI: 10.15252/embj.2020106320 -
Neuroscience Research Jul 2021The Microbiota-gut-brain axis describes the bidirectional communication between central nervous system and microorganisms in the gastrointestinal tract. Increasing... (Review)
Review
The Microbiota-gut-brain axis describes the bidirectional communication between central nervous system and microorganisms in the gastrointestinal tract. Increasing evidence has suggests that the vagus nerve, a major neural connection between the gut and brain, plays a key role in facilitating signaling along the microbiota-gut-brain axis. Much of this evidence has come from studies employing surgical subdiaphragmatic vagotomy. Here we provide a review of the use of vagotomy as a tool to explore the role of the vagus nerve in gut to brain signaling and the knowledge this approach has provided. We also examine how, more recently, vagotomy has contributed to the understanding of the vagus nerve as a bridge for multi-systemic communication; linking microbiota, immune and central nervous systems. Finally, we address limitations to surgical vagotomy and identify such limitations may be mitigated in future studies.
Topics: Brain; Gastrointestinal Microbiome; Microbiota; Vagotomy; Vagus Nerve
PubMed: 33887355
DOI: 10.1016/j.neures.2021.04.001 -
Gut Nov 2023Braak's hypothesis states that Parkinson's disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer's...
Gastrointestinal syndromes preceding a diagnosis of Parkinson's disease: testing Braak's hypothesis using a nationwide database for comparison with Alzheimer's disease and cerebrovascular diseases.
OBJECTIVE
Braak's hypothesis states that Parkinson's disease (PD) originates in the gastrointestinal (GI) tract, and similar associations have been established for Alzheimer's disease (AD) and cerebrovascular diseases (CVD). We aimed to determine the incidence of GI syndromes and interventions preceding PD compared with negative controls (NCs), AD and CVD.
DESIGN
We performed a combined case-control and cohort study using TriNetX, a US based nationwide medical record network. Firstly, we compared subjects with new onset idiopathic PD with matched NCs and patients with contemporary diagnoses of AD and CVD, to investigate preceding GI syndromes, appendectomy and vagotomy. Secondly, we compared cohorts with these exposures to matched NCs for the development of PD, AD and CVD within 5 years.
RESULTS
We identified 24 624 PD patients in the case-control analysis and matched 18 cohorts with each exposure to their NCs. Gastroparesis, dysphagia, irritable bowel syndrome (IBS) without diarrhoea and constipation showed specific associations with PD (vs NCs, AD and CVD) in both the case-control (odds ratios (ORs) vs NCs 4.64, 3.58, 3.53 and 3.32, respectively, all p<0.0001) and cohort analyses (relative risks (RRs) vs NCs 2.43, 2.27, 1.17 and 2.38, respectively, all p<0.05). While functional dyspepsia, IBS with diarrhoea, diarrhoea and faecal incontinence were not PD specific, IBS with constipation and intestinal pseudo-obstruction showed PD specificity in the case-control (OR 4.11) and cohort analysis (RR 1.84), respectively. Appendectomy decreased the risk of PD in the cohort analysis (RR 0.48). Neither inflammatory bowel disease nor vagotomy were associated with PD.
CONCLUSION
Dysphagia, gastroparesis, IBS without diarrhoea and constipation might specifically predict Parkinson's disease.
PubMed: 37620120
DOI: 10.1136/gutjnl-2023-329685 -
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 -
Journal of Clinical Medicine Jan 2021Parkinson's disease (PD) is the second most common neurodegenerative disease. Patients show deposits of pathological, aggregated α-synuclein not only in the brain but... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease. Patients show deposits of pathological, aggregated α-synuclein not only in the brain but throughout almost the entire length of the digestive tract. This gives rise to non-motor symptoms particularly within the gastrointestinal tract and patients experience a wide range of frequent and burdensome symptoms such as dysphagia, bloating, and constipation. Recent evidence suggests that progressive accumulation of gastrointestinal pathology is underway several years before a clinical diagnosis of PD. Notably, constipation has been shown to increase the risk of developing PD and in contrast, truncal vagotomy seems to decrease the risk of PD. Animal models have demonstrated gut-to-brain spreading of pathological α-synuclein and it is currently being intensely studied whether PD begins in the gut of some patients. Gastrointestinal symptoms in PD have been investigated by the use of several different questionnaires. However, there is limited correspondence between subjective gastrointestinal symptoms and objective dysfunction along the gastrointestinal tract, and often the magnitude of dysfunction is underestimated by the use of questionnaires. Therefore, objective measures are important tools to clarify the degree of dysfunction in future studies of PD. Here, we summarize the types and prevalence of subjective gastrointestinal symptoms and objective dysfunction in PD. The potential importance of the gastrointestinal tract in the etiopathogenesis of PD is briefly discussed.
PubMed: 33572547
DOI: 10.3390/jcm10030493 -
Pancreas Apr 2021This study aimed to evaluate the effect of vagotomy, when associated with splenectomy, on adiposity and glucose homeostasis in Wistar rats.
OBJECTIVES
This study aimed to evaluate the effect of vagotomy, when associated with splenectomy, on adiposity and glucose homeostasis in Wistar rats.
METHODS
Rats were divided into 4 groups: vagotomized (VAG), splenectomized (SPL), VAG + SPL, and SHAM. Glucose tolerance tests were performed, and physical and biochemical parameters evaluated. Glucose-induced insulin secretion and protein expression (Glut2/glucokinase) were measured in isolated pancreatic islets. Pancreases were submitted to histological and immunohistochemical analyses, and vagus nerve neural activity was recorded.
RESULTS
The vagotomized group presented with reduced body weight, growth, and adiposity; high food intake; reduced plasma glucose and triglyceride levels; and insulin resistance. The association of SPL with the VAG surgery attenuated, or abolished, the effects of VAG and reduced glucose-induced insulin secretion and interleukin-1β area in β cells, in addition to lowering vagal activity.
CONCLUSIONS
The absence of the spleen attenuated or blocked the effects of VAG on adiposity, triglycerides and glucose homeostasis, suggesting a synergistic effect of both on metabolism. The vagus nerve and spleen modulate the presence of interleukin-1β in β cells, possibly because of the reduction of glucose-induced insulin secretion, indicating a bidirectional flow between autonomous neural firing and the spleen, with repercussions for the endocrine pancreas.
Topics: Adiposity; Animals; Blood Glucose; Body Weight; Eating; Insulin; Insulin Resistance; Insulin Secretion; Interleukin-1beta; Islets of Langerhans; Male; Pancreas; Rats, Wistar; Splenectomy; Vagotomy; Rats
PubMed: 33939676
DOI: 10.1097/MPA.0000000000001809 -
Scientific Reports Sep 2023Antibiotics are increasingly recognized as causing neuropsychiatric side effects including depression and anxiety. Alterations in central serotonin and 5-HT receptor...
Antibiotics are increasingly recognized as causing neuropsychiatric side effects including depression and anxiety. Alterations in central serotonin and 5-HT receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with gastrointestinal disorders. Nevertheless, it is still unclear how antibiotics can cause anxiety and depression. In this study, oral administration of cefaclor, a second-generation cephalosporin antibiotic, induced anxiety- and depression-like behaviors and colitis with gut microbiota alteration in mice. Cefaclor reduced serotonin levels and fluctuated 5-HT receptor mRNA expressions such as Htr1a, Htr1b, and Htr6 in the hippocampus. Vagotomy attenuated the cefaclor-induced anxiety- and depression-like symptoms, while the cefaclor-induced changes in gut bacteria alteration and colitis were not affected. Fluoxetine attenuated cefaclor-induced anxiety- and depression-like behaviors. Furthermore, fluoxetine decreased cefaclor-resistant Enterobacteriaceae and Enterococcaceae. Taken together, our findings suggest that the use of antibiotics, particularly, cefaclor may cause gut dysbiosis-dependent anxiety and depression through the microbiota-gut-blood-brain and microbiota-gut-vagus nerve-brain pathway. Targeting antibiotics-resistant pathogenic bacteria may be a promising therapeutic strategy for the treatment of anxiety and depression.
Topics: Animals; Mice; Cefaclor; Depression; Dysbiosis; Fluoxetine; Serotonin; Anti-Bacterial Agents; Vagus Nerve; Colitis
PubMed: 37726354
DOI: 10.1038/s41598-023-42690-1