• Alzheimer’s disease
• HPA axis
• brain-gut-microbiota axis
• microbiota
• transcutaneous vagus nerve stimulation

• Alcoholic liver disease
• Inflammation
• Microbiota
• Sea grape
• TLR4

• Depressive disorder
• Intestinal permeability
• Mechanism

• Humans
• Hypothalamo-Hypophyseal System
• Pituitary-Adrenal System
• Intestines/microbiology
• Permeability
• Depressive Disorder/metabolism
• Depressive Disorder/pathology
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Intestinal Mucosa/pathology

• depressive disorder
• gut microbiota
• gut permeability
• microbiota-gut-brain axis
• vagus nerve

• cholinergic anti-inflammatory pathway
• enteric glial cells
• inflammation
• intestinal barrier
• stress
• vagal nerve stimulation
• vagus nerve

• corticotropin releasing hormone (CRH)
• intestinal barrier dysfunction
• intestinal fatty acid binding protein (I-FABP)
• transcutaneous vagal nerve stimulation
• urine dual sugar test

• Emerging treatments
• GI dysfunction
• Improved recovery
• Innovation
• Neurotrauma

• R25 NS108939 NINDS NIH HHS

The vagus nerve is crucial in the bidirectional communication between the gut and the brain. It is involved in the modulation of a variety of gut and brain functions. Human studies indicate that the descending vagal signaling from the brain is impaired in functional dyspepsia. Growing evidence indicate that the vagal signaling from gut to brain may also be altered, due to the alteration of a variety of gut signals identified in this disorder. The pathophysiological roles of vagal signaling in functional dyspepsia is still largely unknown, although some studies suggested it may contribute to reduced food intake and gastric motility, increased psychological disorders and pain sensation, nausea and vomiting. Understanding the alteration in vagal signaling and its pathophysiological roles in functional dyspepsia may provide information for new potential therapeutic treatments of this disorder. In this review, we summarize and speculate possible alterations in vagal gut-to-brain and brain-to-gut signaling and the potential pathophysiological roles in functional dyspepsia.

Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved.

Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied.

Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation.

Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.

• dextran sodium sulfate
• epithelial barrier
• inflammatory bowel diseases
• macrophage - cell
• vagus nerve stimulation

• Autonomic nervous system
• Growth hormone secretagogoue
• Inflammation
• Myocardial ischemia-reperfusion
• Remodelling

Human and mouse studies have shown that rotavirus infection is associated with low inflammation and unaffected intestinal barrier at the time of diarrhea, properties different from most bacterial and inflammatory diseases of the gut. We showed by in vitro, ex vivo, and in vivo experiments that neurotrophic factors and 5-HT have barrier protective properties during rotavirus insult. These observations advance our understanding of how the gut barrier is protected against rotavirus and suggest that rotavirus affects the gut barrier differently from bacteria. This is the first report to show that neurotrophic factors contribute to maintain the gut epithelial barrier during viral insult.

Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system, which is composed of neurons and enteric glial cells (EGCs). We investigated whether the vagus nerve, serotonin (5-HT), EGCs, and neurotropic factors contribute to maintaining gut barrier homeostasis during rotavirus infection. Using subdiaphragmatic vagotomized and 5-HT₃ receptor knockout mice, we found that the unaffected epithelial barrier during rotavirus infection is independent of the vagus nerve but dependent on 5-HT signaling through enteric intrinsic 5-HT₃ receptors. Immunofluorescence analysis showed that rotavirus-infected enterocytes were in close contact with EGCs and enteric neurons and that the glial cell-derived neurotrophic factor (GDNF) was strongly upregulated in enterocytes of infected mice. Moreover, rotavirus and 5-HT activated EGCs (P < 0.001). Using Ussing chambers, we found that GDNF and S-nitrosoglutathione (GSNO) led to denser epithelial barriers in small intestinal resections from noninfected mice (P < 0.01) and humans (P < 0.001) and that permeability was unaffected in rotavirus-infected mice. GSNO made the epithelial barrier denser in Caco-2 cells by increasing the expression of the tight junction protein zona occludens 1 (P < 0.001), resulting in reduced passage of fluorescein isothiocyanate dextran (P < 0.05) in rotavirus-infected monolayers. This is the first report to show that neurotropic factors contribute to maintaining the gut epithelial barrier during viral insult.

• diarrhea
• neurotrophic factors
• permeability
• rotavirus

• colorectal cancer (CRC)
• corticotropin releasing hormone (CRH)
• inflammation
• stress

• R01 DK101671 NIDDK NIH HHS

The vagus nerve has emerged as an important modulator of the intestinal immune system. Its anti‐inflammatory properties have been previously shown in innate and Th1/Th17 predominant inflammatory models. To what extent the vagus nerve is of importance in Th2 inflammatory responses like food allergy is still unclear. In this study, we therefore aimed to investigate the effect of vagotomy (VGX) and vagus nerve stimulation (VNS), on the development and severity of experimental food allergy.

Balb/C mice were first sensitized with ovalbumin (OVA) in the presence of alum. Prior to oral challenges with OVA, mice were subjected to VGX or VNS. Disease severity was determined by assessing severity and onset of diarrhoea, OVA‐specific antibody production, mast cell number and activity, inflammatory gene expression in duodenal tissue and lamina propria immune cells by flow cytometry analysis.

When compared to control mice, VGX did not significantly affect the development and severity of the disease in our model of food allergy. VNS, on the other hand, resulted in a significant amelioration of the different inflammatory parameters assessed. This effect was independent of α7nAChR and is possibly mediated through the dampening of mast cells and increased phagocytosis of OVA by CX3CR1^hi macrophages.

These results underscore the anti‐inflammatory properties of the vagus nerve and the potential of neuro‐immune interactions in the intestine. Further insight into the underlying mechanisms could ultimately lead to novel therapeutic approaches in the treatment of not only food allergy but also other immune‐mediated diseases.

• CX3CR1 macrophages
• cholinergic anti-inflammatory pathway
• food allergy
• mast cells
• vagus nerve stimulation

• autonomic nervous system
• blood pressure
• hypertension
• metabolomics
• microbiota

• Animals
• Autonomic Nervous System/metabolism
• Autonomic Nervous System/microbiology
• Blood Pressure/physiology
• Gastrointestinal Microbiome/physiology
• Gastrointestinal Tract/metabolism
• Gastrointestinal Tract/microbiology
• Humans
• Hypertension/genetics
• Hypertension/metabolism
• Hypertension/microbiology

• R01 HL102033 NHLBI NIH HHS
• R21 AT010192 NCCIH NIH HHS
• R01 HL033610 NHLBI NIH HHS
• R37 HL033610 NHLBI NIH HHS
• R01 HL132448 NHLBI NIH HHS
• R01 HL056921 NHLBI NIH HHS

Gastrointestinal prokinetic agents function as serotonin-4 receptor (5-HT₄R) agonists to activate myenteric plexus neurons to release acetylcholine (ACh), which then induce anti-inflammatory action. Details of this pathway, however, remain unknown. The aim of this study is to clarify the anti-inflammatory mechanism underlying the 5-HT₄R agonist, mosapride citrate (MOS)-induced anti-inflammatory action on postoperative ileus (POI). POI models were generated from wild-type C57BL6/J (WT), 5-HT₄R knock-out (S4R KO), α7 nicotinic AChR KO (α7 R KO), and M2 muscarinic ACh receptor KO (M2R KO) mice. MOS attenuated leukocyte infiltration in WT. MOS-induced anti-inflammatory action was completely abolished in both S4R KO and S4R KO mice upon wild-type bone marrow transplantation. MOS-induced anti-inflammatory action against macrophage infiltration, but not neutrophil infiltration, was attenuated in α7 R KO mice. Selective α7nAChR agonists (PNU-282987 and AR-R17779) also inhibited only macrophage infiltration in POI. MOS-mediated inhibition of neutrophil infiltration was diminished by atropine, M2AChR antagonist, methoctramine, and in M2R KO mice. Stimulation with 5-HT₄R inhibits leukocyte infiltration in POI, possibly through myenteric plexus activation. Released ACh inhibited macrophage and neutrophil infiltration likely by activation of α7nAChR on macrophages and M2AChR. Thus, macrophage and neutrophil recruitment into inflamed sites is regulated by different types of AChR in the small intestine.

The emergence of uniquely human genes during hominid speciation enabled numerous human-specific adaptations that presumably included changes in resilience to disease but potentially increased susceptibility as well. Here we show that the transgenic expression of one such gene, called CHRFAM7A, changes the mouse reservoir of hematopoietic stem cells in bone marrow and amplifies the mouse inflammatory response in a model of human systemic inflammatory response syndrome (SIRS). Because the CHRFAM7A gene is a dominant-negative inhibitor of ligand binding to α7 nicotinic acetylcholine receptor (α7nAChR), a neurotransmitter receptor implicated in immunity, inflammation, neurodegeneration, and cognitive function, the results underscore the importance of understanding the contribution of species-specific genes to human disease and the impact they may have on the fidelity of animal models for translational medicine.

A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease.

• acetylcholine receptor
• hematopoietic stem cells
• inflammation
• injury
• α7 nicotinic acetylcholine receptor

• autonomic nervous system
• enteric mucosal immune system
• inflammatory bowel disorders
• intestinal epithelium
• mucosal permeability

Anti-infection therapy combined with immunotherapy is one of the important research approaches for treating sepsis. However, the combination of anti-infection and immunotherapy therapeutic agents may have an adverse effect on intestinal barrier function. In the present study, it was hypothesized that imipenem combined with low-dose cyclophosphamide (CTX) could improve the sepsis survival rate compared with imipenem treatment alone. In addition, the alterations in the intestinal barrier were investigated and the possible mechanisms of altering intestinal barrier function in septic rats treated with imipenem combined with low-dose CTX or imipenem alone were explored. To investigate the effect of imipenem combined with low-dose CTX on the intestinal barrier, the markers of histopathology, intestinal permeability, intestinal epithelial apoptosis, cytokines interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α, and tight junction proteins zonula occludens (ZO)-1, occludin and claudin-2, were quantitatively and qualitatively evaluated. The results indicated that imipenem combined with low-dose CTX significantly improved the survival rate of rats compared with imipenem alone (P<0.05). However, no significantly difference between the treatment with imipenem combined with low-dose CTX and imipenem treatment alone was indicated with regard to histopathology, intestinal permeability, intestinal epithelial apoptosis and the expression of claudin-2, ZO-1 and TNF-α. However, imipenem combined with low-dose CTX significantly reduced IL-6 and IL-10 expression and significantly increased occludin expression compared with imipenem alone (P<0.05). It was concluded that imipenem combined with low-dose CTX could improve the survival rate of rats with sepsis compared with rats treated with imipenem alone. The present findings suggest that imipenem combined with low-dose CTX may cause damage to the intestinal barrier function and the mechanism may be associated with a reduction in IL-10 expression.

• cyclophosphamide
• imipenem
• intestinal barrier
• rat
• sepsis

The microbiota, the gut, and the brain communicate through the microbiota-gut-brain axis in a bidirectional way that involves the autonomic nervous system. The vagus nerve (VN), the principal component of the parasympathetic nervous system, is a mixed nerve composed of 80% afferent and 20% efferent fibers. The VN, because of its role in interoceptive awareness, is able to sense the microbiota metabolites through its afferents, to transfer this gut information to the central nervous system where it is integrated in the central autonomic network, and then to generate an adapted or inappropriate response. A cholinergic anti-inflammatory pathway has been described through VN's fibers, which is able to dampen peripheral inflammation and to decrease intestinal permeability, thus very probably modulating microbiota composition. Stress inhibits the VN and has deleterious effects on the gastrointestinal tract and on the microbiota, and is involved in the pathophysiology of gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) which are both characterized by a dysbiosis. A low vagal tone has been described in IBD and IBS patients thus favoring peripheral inflammation. Targeting the VN, for example through VN stimulation which has anti-inflammatory properties, would be of interest to restore homeostasis in the microbiota-gut-brain axis.

• cholinergic anti-inflammatory pathway
• microbiota-gut-brain axis
• stress
• vagus nerve
• vagus nerve stimulation

In recent years, the bidirectional relationship between the nervous and immune system has become increasingly clear, and its role in both homeostasis and inflammation has been well documented over the years. Since the introduction of the cholinergic anti-inflammatory pathway, there has been an increased interest in parasympathetic regulation of both innate and adaptive immune responses, including T helper 2 responses. Increasing evidence has been emerging suggesting a role for the parasympathetic nervous system in the pathophysiology of allergic diseases, including allergic rhinitis, asthma, food allergy, and atopic dermatitis. In this review, we will highlight the role of cholinergic modulation by both nicotinic and muscarinic receptors in several key aspects of the allergic inflammatory response, including barrier function, innate and adaptive immune responses, and effector cells responses. A better understanding of these cholinergic processes mediating key aspects of type 2 immune disorders might lead to novel therapeutic approaches to treat allergic diseases.

• allergic inflammation
• cholinergic anti-inflammatory pathway
• neuroimmune interactions
• parasympathetic nervous system
• type 2 immunity
• vagus nerve

• Chronic Traumatic Encephalopathy
• Concussion
• Gut
• Gut-brain axis
• Intestinal dysfunction
• Microbiota
• Microglia
• Neurodegenerative disease
• Neuroinflammation
• Traumatic Brain Injury

• Animals
• Brain/immunology
• Brain/physiopathology
• Brain Diseases/immunology
• Brain Diseases/microbiology
• Brain Diseases/physiopathology
• Brain Injuries, Traumatic/immunology
• Brain Injuries, Traumatic/microbiology
• Brain Injuries, Traumatic/physiopathology
• Encephalitis/immunology
• Encephalitis/microbiology
• Encephalitis/physiopathology
• Gastrointestinal Microbiome
• Humans

• autonomic
• cholinergic
• hypotension
• orthostatic
• tachycardia
• vagal

• enteric glia cells
• entric neurons
• ischemia-reperfusion
• vagal anti-inflammatory

• 123489-1 Canadian Institutes of Health Research

• Biliary tract external drainage
• Heme oxygenase-1
• Hemorrhagic shock
• Occludin

• Acute Kidney Injury/enzymology
• Acute Kidney Injury/etiology
• Acute Kidney Injury/pathology
• Acute Kidney Injury/surgery
• Animals
• Biliary Tract Surgical Procedures
• Heme Oxygenase (Decyclizing)/metabolism
• Kidney/enzymology
• Kidney/pathology
• Liver/enzymology
• Male
• Occludin/metabolism
• Random Allocation
• Rats, Sprague-Dawley
• Shock, Hemorrhagic/complications
• Shock, Hemorrhagic/enzymology
• Shock, Hemorrhagic/pathology

• CHRNA7
• dup-α7nAChR
• human-specific genes
• α7nAChR

• CHRNA7
• SLURP1
• dupα7nAChR
• neuroinflammation
• vagus nerve
• α7nAChR

Inflammation plays a major role in the multifactorial process of trauma associated coagulopathy. The vagus nerve regulates the cholinergic anti-inflammatory pathway. We hypothesized that efferent vagus nerve stimulation (VNS) can improve coagulopathy by modulating the inflammatory response to hemorrhage.

Wistar rats (n = 24) were divided in 3 groups: Group (G1) Sham hemorrhagic shock (HS); (G2) HS w/o VNS; (G3) HS followed by division of the vagus nerves and VNS of the distal stumps. Hemorrhage (45% of baseline MAPx15 minutes) was followed by normotensive resuscitation with LR. Vagus nerves were stimulated (3.5 mA, 5 Hz) for 30 sec 7 times. Samples were obtained at baseline and at 60 minutes for thromboelastometry (Rotem®) and cytokine assays (IL-1 and IL-10). ANOVA was used for statistical analysis; significance was set at p < 0.05.

Maximum clot firmness (MCF) significantly decreased in G2 after HS (71.5 ± 1.5 vs. 64 ± 1.6) (p < 0.05). MCF significantly increased in G3 compared to baseline (67.3 ± 2.7 vs. 71.5 ± 1.2) (p < 0.05). G3 also showed significant improvement in Alfa angle, and Clot Formation Time (CFT) compared to baseline. IL-1 increased significantly in group 2 and decrease in group 3, while IL-10 increased in group 3 (p < 0.05).

Electrical stimulation of efferent vagus nerves, during resuscitation (G3), decreases inflammatory response to hemorrhage and improves coagulation.

• Coagulopathy
• Cytokines
• Hemorrhage
• Resuscitation
• Shock
• Thromboelastometry
• Trauma
• Vagal nerve

• Acute lung injury
• Burn
• Organ/tissue injury
• Sepsis/inflammatory response
• Vagal nerve stimulation

• Apoptosis
• Diarrhea
• E-cadherin
• ER stress
• Erlotinib

AIM: To investigate whether electroacupuncture (EA) at Zusanli (ST36) prevents intestinal barrier and remote organ dysfunction following prolonged hemorrhagic shock through a vagus anti-inflammatory mechanism.

METHODS: Sprague-Dawley rats were subjected to about 45% of total blood volume loss followed by delayed fluid replacement (DFR) with Ringer lactate 3h after hemorrhage. In a first study, rats were randomly divided into six groups: (1) EAN: EA at non-channel acupoints followed by DFR; (2) EA: EA at ST36 after hemorrhage followed by DFR; (3) VGX/EA: vagotomy (VGX) before EA at ST36 and DFR; (4) VGX/EAN: VGX before EAN and DFR; (5) α-bungarotoxin (α-BGT)/EA: intraperitoneal injection of α-BGT before hemorrhage, followed by EA at ST36 and DFR; and (6) α-BGT/EAN group: α-BGT injection before hemorrhage followed by EAN and DFR. Survival and mean arterial pressure (MAP) were monitored over the next 12 h. In a second study, with the same grouping and treatment, cytokine levels in plasma and intestine, organ parameters, gut injury score, gut permeability to 4 kDa FITC-dextran, and expression and distribution of tight junction protein ZO-1 were evaluated.

RESULTS: MAP was significantly lowered after blood loss; EA at ST36 improved the blood pressure at corresponding time points 3 and 12 h after hemorrhage. EA at ST36 reduced tumor necrosis factor-α and interleukin (IL)-6 levels in both plasma and intestine homogenates after blood loss and DFR, while vagotomy or intraperitoneal injection of α-BGT before EA at ST36 reversed its anti-inflammatory effects, and EA at ST36 did not influence IL-10 levels in plasma and intestine. EA at ST36 alleviated the injury of intestinal villus, the gut injury score being significantly lower than that of EAN group (1.85 ± 0.33 vs 3.78 ± 0.59, P < 0.05). EA at ST36 decreased intestinal permeability to FITC-dextran compared with EAN group (856.95 ng/mL ± 90.65 ng/mL vs 2305.62 ng/mL ± 278.32 ng/mL, P < 0.05). EA at ST36 significantly preserved ZO-1 protein expression and localization at 12 h after hemorrhage. However, EA at non-channel acupoints had no such effect, and abdominal vagotomy and α-BGT treatment could weaken or eliminate the effects of EA at ST36. Besides, EA at ST36 decreased blood aminotransferase, MB isoenzyme of creatine kinase and creatinine vs EAN group at corresponding time points. At the end of 12-h experiment, the survival rate of the EA group was significantly higher than that of the other groups.

CONCLUSION: EA at ST36 attenuates the systemic inflammatory response, protects intestinal barrier integrity, improves organ function and survival rate after hemorrhagic shock via activating the cholinergic anti-inflammatory mechanism.

• Hemorrhagic shock
• Zusanli
• Electro-acupuncture
• Intestinal permeability
• Tight junction

• Animals
• Arterial Pressure
• Bungarotoxins/pharmacology
• Cytokines/blood
• Disease Models, Animal
• Electroacupuncture
• Inflammation/blood
• Inflammation/immunology
• Inflammation/pathology
• Inflammation/physiopathology
• Inflammation/therapy
• Inflammation Mediators/blood
• Intestinal Absorption
• Intestinal Mucosa/metabolism
• Intestines/innervation
• Intestines/pathology
• Male
• Permeability
• Rats
• Rats, Sprague-Dawley
• Shock, Hemorrhagic/blood
• Shock, Hemorrhagic/immunology
• Shock, Hemorrhagic/pathology
• Shock, Hemorrhagic/physiopathology
• Shock, Hemorrhagic/therapy
• Time Factors
• Vagotomy
• Vagus Nerve/physiopathology
• Vagus Nerve/surgery
• Zonula Occludens-1 Protein/metabolism

• chorioamnionitis
• inflammation
• intestines
• necrotizing enterocolitis
• neuroimmunology
• preterm birth
• prevention
• vagus nerve

Mitochondria play a central role in the integration and execution of a wide variety of apoptotic signals. In the present study, we examined the deleterious effects of burn injury on heart tissue. We explored the effects of vagal nerve stimulation (VNS) on cardiac injury in a murine burn injury model, with a focus on the protective effect of VNS on mitochondrial dysfunction in heart tissue. Mice were subjected to a 30% total body surface area, full-thickness steam burn followed by right cervical VNS for 10 min. and compared to burn alone. A separate group of mice were treated with the M₃-muscarinic acetylcholine receptor (M₃-AchR) antagonist 4-DAMP or phosphatidylinositol 3 Kinase (PI3K) inhibitor LY294002 prior to burn and VNS. Heart tissue samples were collected at 6 and 24 hrs after injury to measure changes in apoptotic signalling pathways. Burn injury caused significant cardiac pathological changes, cardiomyocyte apoptosis, mitochondrial swelling and decrease in myocardial ATP content at 6 and 24 hrs after injury. These changes were significantly attenuated by VNS. VNS inhibited release of pro-apoptotic protein cytochrome C and apoptosis-inducing factor from mitochondria to cytosol by increasing the expression of Bcl-2, and the phosphorylation level of Bad (pBad¹³⁶) and Akt (pAkt³⁰⁸). These protective changes were blocked by 4-DAMP or LY294002. We demonstrated that VNS protected against burn injury–induced cardiac injury by attenuating mitochondria dysfunction, likely through the M₃-AchR and the PI3K/Akt signalling pathways.

• burn
• intestinal injury
• gut targeting
• epithelial barrier
• drug delivery

• Amino Acid Sequence
• Animals
• Bacteriophage M13/genetics
• Burns/complications
• Cross Reactions
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Epithelial Cells
• Humans
• Intestinal Mucosa/metabolism
• Intestines/injuries
• Male
• Mice
• Mice, Inbred BALB C
• Peptide Library
• Peptides/administration & dosage
• Peptides/genetics
• Peptides/immunology
• Peptides/metabolism

• P20 GM078421 NIGMS NIH HHS
• R21 EY018479 NEI NIH HHS