Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with elusive pathogenesis and lack of targeted therapies. While exercise can ameliorate ASD-like behaviors, its underlying mechanisms remain unclear. Recent studies have identified dysbiosis of gut microbiota and altered levels of short-chain fatty acids (SCFAs), as critical contributors to ASD-associated behavioral abnormalities. This study investigated the potential role of the gut-brain axis, specifically the vagal pathway, in mediating the therapeutic effects of voluntary wheel running exercise in a valproic acid (VPA)-induced ASD-like rat models. We demonstrated that six weeks of voluntary wheel running exercise attenuated ASD-like behavioral deficits. Exercise restructured gut microbial communities and elevated SCFA levels, notably butyrate, in feces and plasma. Concurrently, exercise normalized imbalances of neuroactive substances in the hippocampus and prefrontal cortex and suppressed neuroinflammation, evidenced by reduced microglial/astrocytic reactivity and a shift in microglial polarization toward an anti-inflammatory phenotype. Critically, subdiaphragmatic vagotomy attenuated these exercise-induced improvements, including the restoration of neuroactive substance homeostasis, resolution of neuroinflammation, and the amelioration of behavioral deficits. Our findings suggest that intact vagal signaling plays a critical role in coordinating gut-derived microbial and metabolic signals with central neuroadaptations to mediate the benefits of voluntary exercise on ASD-like behaviors.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration and increasingly associated with gut microbiota alterations. Roseburia intestinalis (R. intestinalis) is consistently reduced in PD; however, its functional contribution remains unknown. We performed two complementary mouse experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model. In the primary intervention experiment, mice received live or heat-killed R. intestinalis, followed by behavioral assessments and multi-layer analyses, including immunofluorescence, western blotting, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, 16S rRNA sequencing, metabolomics, and transcriptomics. In a separate mechanistic experiment, subdiaphragmatic vagotomy was introduced to interrogate vagus-dependent gut-brain communication, with key behavioral and inflammatory endpoints assessed. Live R. intestinalis improved rotarod, pole, and grip strength performance and preserved tyrosine hydroxylase-positive neurons in the substantia nigra; however, these effects were not observed in the heat-killed group. Live R. intestinalis treatment also reduced glial reactivity, restored brain-derived neurotrophic factor expression, and maintained blood-brain barrier integrity. Systemically, R. intestinalis lowered serum lipopolysaccharide, tumor necrosis factor-α, and interleukin-6 levels; preserved colonic structure; and restored mucin-secreting goblet cell function. MPTP-induced dysbiosis was partially corrected. Metabolomic profiling revealed restoration of several acyl-carnitines and higher acetic acid levels. Transcriptomic analysis showed increased immediate early genes after MPTP, and the elevated c-Fos in the substantia nigra was partially normalized by R. intestinalis. Importantly, vagotomy abolished the central neuroprotective and anti-inflammatory effects but did not affect peripheral cytokine suppression, indicating both vagus-dependent and vagus-independent pathways. R. intestinalis supplementation alleviated motor impairments, reduced neuroinflammation, preserved dopaminergic neurons, and improved intestinal and metabolic alterations in mice with an MPTP-induced PD model. Its protective actions may involve both central and peripheral mechanisms, potentially including gut-brain communication pathways. R. intestinalis may be a promising candidate for microbiota-based strategies against PD.

Disruptions in iron homeostasis are common during obese states and are related to chronic inflammation and insulin resistance. Exercise exerts well-recognized anti-adiposity and anti-inflammatory effects, besides modulating iron control. The vagus nerve (VN) influences immune and metabolic responses, in a spleen-dependent manner with an unknown impact on iron. Here, we evaluated the effects of the absence of the VN and of the spleen on adiposity, metabolism, and iron homeostasis in non-obese and hypothalamic-obese rats submitted to swimming training. Hypothalamic obesity was induced by the administration of monosodium glutamate (MSG; 4 g/Kg) during the initial postnatal days (PNDs). Non-obese control (CTL) rats received equimolar saline. At PND 60, MSG and CTL were submitted to surgery consisting of bilateral subdiaphragmatic vagotomy (Sv), splenectomy (Spl), Sv + Spl, or sham surgery. At PND 80, the rats were subdivided into exercised (Ex) or sedentary (Sd). Exercised rats swam for 30 min/day for 40 days. At PND 120, the growth, adiposity, metabolism, and iron homeostasis of rats were evaluated. Major results indicate that the absence of the VN and spleen favors the anti-adiposity effects of exercise, particularly in MSG-obese rats. In CTL rats, exercise increased plasma iron, in association with changes in iron transport capacity and a reduction in circulating hepcidin levels, a response that is influenced by the VN and spleen. In contrast, in the MSG-obese animals, vagal and splenic absence resulted in increased hepcidin, including following exercise, via a response that is independent of systemic iron fluctuations, suggesting disturbed hepcidin-iron homeostasis during hypothalamic obesity.

AimThis study investigates the therapeutic mechanisms of electroacupuncture (EA) in regulating the vagal nerve for functional dyspepsia (FD) using an integrated multi-omics approach.Methods and resultsA rat model of FD was established via iodoacetamide gavage combined with tail-clamp stress. Rats were randomly assigned to five groups (n=6 per group): control (CON), model (MOD), electroacupuncture (EA), subdiaphragmatic vagotomy and electroacupuncture (SDV+EA), and subdiaphragmatic vagotomy (SDV). EA was administered at ST36 (Zusanli) and ST37 (Shangjuxu) for 20 minutes per session, once daily for 14 days. EA treatment restored vagal tone, improved sympathovagal balance, and enhanced gastrointestinal motility in FD model rats. 16S rDNA sequencing revealed that EA modulated vagus nerve-dependent changes in the relative abundance of 12 microbial taxa, including f_Lactobacillaceae and f_Peptostreptococcaceae. Crucially, the vagotomy procedure significantly attenuated EA’s restorative effects on these microbial populations. Metabolomics identified 24 differential metabolites regulated by EA through the vagus nerve, including Cholesta-3,5-dien-7-one, Licofelone, Digoxigenin, 7-Hydroxymethotrexate, Hydroxymethylbilane, among others. Similarly, subdiaphragmatic vagotomy largely reversed the normalizing effects of EA on these metabolite levels. Transcriptomics, on the other hand, identified 23 differential genes, including Prss22, Lypd3, and Tnfrsf12a. KEGG analysis of differential metabolites and differential genes suggested that arachidonic acid metabolism may represent a potential therapeutic target for EA in the treatment of FD through vagus nerve modulation. Mechanistic analyses of the key differentially expressed gene Tnfrsf12a and the arachidonic acid metabolic pathway demonstrated that EA attenuated inflammatory responses by suppressing TWEAK/Fn14/NF-κB pathway activation and arachidonic acid metabolism, leading to decreased levels of TNF-α, IL-1β, IL-6, and PGE2. Importantly, the anti-inflammatory effects of EA were significantly attenuated in the SDV+EA group, confirming that vagal integrity is essential for EA to fully exert its suppressive action on these key inflammatory pathways and mediators.ConclusionEA ameliorates FD by modulating vagal nerve activity, concurrently suppressing TWEAK/Fn14/NF-κB pathway activation and arachidonic acid metabolism, thus attenuating duodenal low-grade inflammation in FD model rats. These findings demonstrate the potential of EA as an effective therapeutic intervention for FD.

A vagus-dependent gut microbiota-metabolite axis drives chronic inflammatory pain and working-memory deficits in mice.

Emerging evidence implicates gut microbiota dysbiosis in exacerbating stroke pathogenesis via the gut-brain axis, suggesting novel therapeutic targets. While electroacupuncture (EA) demonstrates anti-inflammatory effects through vagus nerve activation, its neuroprotective mechanisms via vagus nerve-microbiota crosstalk remain unexplored. Rats with middle cerebral artery occlusion received daily ST36 (Acupoint Zusanli) EA for 1 to 7 days postischemia. Subdiaphragmatic vagotomy and fecal microbiota transplant were implemented to validate pathway specificity. Multimodal assessments included longitudinal neurological scoring, infarct volume, systemic/neuroinflammatory profiling (enzyme-linked immunosorbent assay, immunohistochemistry), intestinal fucosylation dynamics (quantitative polymerase chain reaction, lectin staining), and 16S ribosomal RNA sequencing of gut microbiota. EA significantly improved neurological outcomes and reduced infarct volumes at 3 to 7 days after middle cerebral artery occlusion (versus controls), which was abolished by vagotomy. Mechanistically, EA restored gut barrier integrity through vagus-dependent upregulation of fucosyltransferase 2 (Fut2)-driven epithelial α1,2-fucosylation, enhancing mucin 2+ goblet cell density and tight junction protein expression (ZO-1/occludin/claudin-1). Concurrent microbiota shifts included Lactobacillales/Bacteroidales enrichment (linear discriminant analysis >4.0) and pathobiont suppression, which was reversed by vagotomy. Crucially, fecal microbiota transplant from EA-treated donors replicated neuroprotection in germ-free recipients, achieving 33% infarct reduction and 30% survival improvement (P=0.012), whereas fecal microbiota transplant from vagotomized donors showed no therapeutic benefits. EA at ST36 produced neuroprotection through activating vagal efferent pathways to orchestrate intestinal mucosal repair via Fut2-mediated fucosylation, which reshape microbial ecosystems and attenuate neuroinflammation. These findings establish a previously unrecognized vagus nerve-gut-brain axis mechanism for stroke recovery, positioning microbiota-directed neuromodulation by EA as a translatable therapeutic strategy.

Stress-induced physiological changes are crucial for adaptive responses to threats. Catecholamines, specifically epinephrine, activate peripheral β-adrenergic receptors, facilitating contextual fear memory consolidation. The vagus nerve is thought to be essential in transmitting physiological signals to the brain, influencing emotional memory consolidation. We aimed to evaluate the vagus nerve's role in contextual fear memory strengthening induced by epinephrine. Male 129×1/SvJ mice underwent bilateral subdiaphragmatic vagotomy, right or left cervical vagotomy, or sham surgeries. After a seven-day recovery, mice were subjected to the fear conditioning paradigm, receiving three foot shocks on conditioning day, followed by contextual reminder exposure. Epinephrine (0.1mg/kg, intraperitoneal, i.p.) was administered to a subset of left cervically vagotomized mice 3min before each session. Freezing behavior was evaluated. Catecholamines were quantified by reverse-phase high-performance liquid chromatography (HPLC) with electrochemical detection. Subdiaphragmatic vagotomy did not alter freezing behavior on both days. In cervical vagotomies, while no differences were observed on the conditioning day, a significant decrease in freezing behavior was observed on the context day. In left cervically vagotomized mice, epinephrine administration significantly increased freezing behavior. In conclusion, unilateral left or right cervical vagotomy impaired contextual fear memory, contrary to subdiaphragmatic vagotomy. Impaired contextual fear memory in left cervical vagotomy was reversed by exogenous epinephrine, possibly due to the intact right cervical vagus. We suggest that stress-induced catecholamine release may activate thoracic peripheral β-adrenergic receptors and elevate systolic blood pressure, signals that are transmitted through the vagus nerve, influencing the hippocampus and facilitating contextual fear memory consolidation.

Splenic γδ T cells are required for vagotomy-mediated protection against LPS-induced depression- and anxiety-like behaviors through the spleen-brain axis.

Triclosan (TCS) can influence energy metabolism and is a potential obesogen. However, its underlying mechanisms remain largely unknown. This study investigated how low-dose TCS exposure (0.5 mg/kg/day) disrupts energy metabolism in Sprague-Dawley rats. TCS increased body weight, visceral fat, liver lipid accumulation, and serum triglyceride levels. It also promoted hyperphagia by altering hypothalamic appetite regulation, activating orexigenic neuropeptide Y neurons and suppressing anorexigenic pro-opiomelanocortin neurons. Furthermore, TCS may reduce brown adipose tissue thermogenesis, as indicated by decreased mitochondrial uncoupling protein 1 and tyrosine hydroxylase. These metabolic effects were blocked by subdiaphragmatic vagotomy, confirming gut-brain neural circuit involvement. Mechanistically, TCS reduced gut microbial diversity and butyrate levels. Crucially, both fecal microbiota transplantation from control rats and butyrate supplementation reversed TCS-induced metabolic dysregulation. These findings reveal that TCS-induced gut dysbiosis and butyrate reduction as key drivers of metabolic disturbances and offer insights into the role of environmental chemicals in obesity and potential therapeutic strategies targeting the gut microbiota and butyrate.

Corticotropin‐releasing factor (CRF) plays roles in stress‐related responses through its type 1 (CRF1) and type 2 receptors. Both CRF and CRF1 are expressed in the rat colon. Peripheral CRF administration and various stressors increase colonic motility and defecation. Stress induces CRF release in the colon, suggesting CRF may mediate stress‐related responses of the colon. The vagal nodose ganglion (NG) transduces visceral information, including colonic sensation, to the brain. However, it remains unclear whether the CRF/CRF1 system is involved in vagal afferent functions. This study, therefore, aimed to clarify the involvement of the CRF/CRF1 system in relaying visceral sensory information to the brain and the effect of stress exposure on vagal nerve function. The experiments were conducted in male rats. First, CRF1‐like immunoreactivity (CRF1‐LI) was characterized in the NG. Second, the effects of vagotomy on CRF1‐LI in the NG, intraperitoneally administered CRF‐induced fecal output, and c‐Fos expression in the nucleus tractus solitarius (NTS) were evaluated. Subsequently, a fast blue retrograde tracer was microinjected into the proximal colon. Finally, we analyzed CRF‐ or stress‐induced phosphorylation of cyclic AMP‐response element‐binding protein (pCREB) in the NG. CRF1 mRNA and CRF1‐LI were detected, and CRF1‐LI accumulated on the proximal side of the ligated region of the nerve trunk, and CRF1‐LI was detected in most cholinergic neurons. CRF1 siRNA suppressed the expression of CRF1‐LI in the NG. Subdiaphragmatic vagotomy decreased the number of CRF1‐positive cells in the NG while it did not affect CRF‐induced fecal output. CRF‐induced c‐Fos expression in the NTS was suppressed by vagotomy. A neuronal tracing study showed that approximately half of CRF1‐positive cells expressed fast blue in the NG. Intraperitoneal CRF, a selective CRF1 agonist, or immobilization stress induced pCREB expression and increases in CRF1‐positive cells in the NG. In contrast, a CRF1 antagonist reduced the immobilization‐induced increase in the expression of pCREB in the NG. These results suggest that the CRF/CRF1 system is involved in the signal transduction of colonic sensory information to the central nervous system via the NG.

ABSTRACT Background Cancer cachexia is a multifactorial metabolic syndrome characterized by anorexia and the progressive loss of skeletal muscle and adipose tissue, severely impairing quality of life, shortening survival and reducing treatment efficacy in cancer patients. The development of effective therapies has been hampered by the lack of preclinical models that faithfully replicate the clinical features and underlying mechanisms of cachexia. This study aimed to establish a novel murine model of cancer cachexia using subcutaneous implantation of renal carcinoma (RenCa) cells that align with clinical diagnostic criteria. Methods On Day 0, 8‐week‐old male BALB/c mice were anaesthetised and subcutaneously injected with murine RenCa cells or vehicle (control). A subset of mice was subjected to pair‐feeding with RenCa‐bearing mice, while another subset underwent subdiaphragmatic vagotomy (SDV) 2 weeks before cell implantation. Plasma levels of acyl‐ghrelin and insulin‐like growth factor‐1 (IGF‐1) were measured by ELISA. The gastrocnemius muscle was analysed for gene and protein expression related to atrophy and energy metabolism using quantitative RT‐PCR and Western blotting, respectively, and for metabolic alterations using capillary electrophoresis time‐of‐flight mass spectrometry (CE‐TOF‐MS). Results Mice bearing RenCa tumours exhibited progressive cachexia. By Day 30, compared to controls, RenCa‐bearing mice had significantly reduced tumour‐free body weight (20.3 vs. 26.1 g), daily food intake (1.8 vs. 3.0 g/day), gastrocnemius muscle mass (112.1 vs. 140.7 mg) and epididymal fat mass (18.6 vs. 307.3 mg; all p < 0.01). Grip strength normalized to body mass remained unchanged even on Day 30. The pair‐feeding experiment revealed that anorexia largely contributed to the onset of cachexic‐like symptoms. SDV further exacerbated gastrocnemius atrophy ( p < 0.05), implicating vagal signalling in the pathogenesis of cachexia, other than anorexia. Muscle expression of Trim63 and Fbxo32 peaked on Day 20, showing 5.5‐ and 4.4‐fold increases compared with controls, respectively. The expression of Ctsl and 4ebp1 increased on Day 7 and remained elevated until Day 20. Metabolomic analyses revealed impaired glutathione and Akt‐mediated glucose metabolism. Plasma acyl‐ghrelin levels were elevated in RenCa‐bearing mice (38.5–49.1 pg/mL) compared to controls (33.3–37.9 pg/mL) from Day 14 to Day 30, while IGF‐1 levels were significantly reduced on Day 14 (94.6 vs. 220.2 ng/mL; p < 0.05). Conclusions We developed a RenCa‐induced mouse model of cancer cachexia that recapitulates key clinical features—including progressive anorexia, body weight loss, muscle atrophy and altered ghrelin–IGF‐1 signalling—providing a valuable tool for mechanistic studies and therapeutic development.

Natural compounds identified via the SELFormer pipeline for cognitive enhancement may exert neuroprotective effects in ischemic stroke (IS) through both direct actions on the central nervous system and potential modulation of the gut microbiota. However, it remains unclear whether such benefits persist under conditions in which gut-brain neural communication is compromised. We aimed to evaluate the neuroprotective potential of β-citronellol (BCT), β-caryophyllene (BCP), and citronellyl acetate (CTA) in an IS model with compromised vagal signaling. Mongolian gerbils received daily oral treatment with dextrin (Control), BCT (100 mg/kg), BCP (20 mg/kg), or CTA (100 mg/kg) for 2 weeks before undergoing subdiaphragmatic vagotomy followed by bilateral common carotid artery occlusion; sham-operated animals treated with dextrin served as Normal-C. During an additional 4 weeks of treatment, we assessed neuronal survival, cognitive function, metabolism, neuroinflammation, and gut microbiota composition and metabolism. BCT demonstrated superior neuroprotection, followed by BCP, with CTA showing modest efficacy compared to the control. BCT and BCP increased hippocampal CA1 neurons and improved memory function. Treatments reduced hippocampal acetylcholinesterase activity, lipid peroxidation, and inflammatory markers (TNF-α and IL-1β) while enhancing cerebral blood flow, glucose metabolism, and lipid profiles. Gut microbiota analysis revealed increased α-diversity and restoration of beneficial bacteria, including Akkermansia and Faecalibacterium, particularly with BCT treatment. BCT and BCP increased butyrate-producing bacteria. These improvements occurred despite vagal nerve disruption, indicating alternative neuroprotective mechanisms through enhanced intestinal barrier integrity and microbiota-derived metabolites. In conclusion, these compounds, especially BCT, protect against neuronal death and cognitive impairment in IS conditions through integrated effects on neuroinflammation, oxidative stress, and non-vagal gut-brain communication pathways. Therefore, BCT and BCP were potential for IS prevention and treatment strategies.

Diabetic gastroparesis (DGP), characterized by delayed gastric emptying and impaired motility, poses significant therapeutic challenges due to its complex neural and molecular pathophysiology. Emerging evidence suggests that electroacupuncture (EA) at ST36 modulates gastrointestinal function; however, the precise neuromolecular pathways underlying its efficacy in DGP remain incompletely defined. To elucidate the neural mechanisms underlying EA at ST36 improving DGP gastric motility through the nucleus tractus solitarius (NTS)-vagal axis. The DGP model was established via a single high-dose intraperitoneal injection of 2% streptozotocin combined with an 8-week high-sugar/high-fat diet. Interventions included EA at ST36, pharmacological modulation [choline acetyltransferase (ChAT) agonist polygalacic acid (PA) and inhibitor antagonist alpha-NETA], and subdiaphragmatic vagotomy. Post-intervention observations included body weight and blood glucose levels. Gastric emptying was evaluated using phenol red assays, gastric slow-wave recordings, and dynamic positron emission tomography-computed tomography imaging. Histopathological analysis (hematoxylin-eosin staining) and molecular assessments (Western blot, immunofluorescence) were performed to quantify gastric smooth muscle-associated factors [neuronal nitric oxide synthase (nNOS), cluster of differentiation 117 (C-kit), stem cell factor (SCF)] and vagal targets [ChAT, α7 nicotinic acetylcholine receptor (α7nAChR)] in the ST36 acupoint region, L4-L6 spinal segments, and NTS. Gastrointestinal peptides [gastrin (Gas), motilin (MLT) and vasoactive intestinal peptide (VIP)] were measured via enzyme-linked immunosorbent assay. The study found that EA significantly increased the rate of gastric emptying, restored the slow-wave rhythms of the stomach, and improved the architecture of the smooth muscles in the stomach. This was evidenced by a reduction in inflammatory infiltration and an increase in the expression of nNOS, C-kit, and SCF. Mechanistically, EA activated vagal targets (ChAT and α7nAChR) at ST36, transmitting signals via spinal segments L4-L6 to the NTS, subsequently regulating gastrointestinal peptides (Gas, MLT, VIP) and restoring interstitial cells of Cajal (ICCs) function via subdiaphragmatic vagal efferent pathways. It is crucial to note that subdiaphragmatic vagotomy led to the abrogation of EA-induced enhancements in gastric motility and ICC recovery, thereby confirming the indispensable role of vagal efferent signalling. EA provides a novel molecular mechanism for improving gastrointestinal motility in DGP via a peripheral stimulation (ST36), spinal afferent (L4-L6), brainstem integration (NTS), vagal efferent (gastric) circuit.

Depression is a common mood disorder characterized by persistent sadness, loss of interest or pleasure, and a range of cognitive and physical symptoms such as gastrointestinal dysfunction that significantly impair daily functioning. Electroconvulsive Therapy (ECT) remains the treatment of choice and a critical last-resort intervention for patients with severe, treatment-resistant depression, particularly those at high risk of suicide. Evidence suggests that the gut-brain axis, a complex bidirectional communication network, plays a key role in the development of these multifaceted symptoms. This study explores the possibility that ECT may exert its therapeutic effects by modulating gastrointestinal function. In clinical investigation, a notable proportion of patients with major depressive disorder experienced significant alleviation of gastrointestinal symptoms, particularly constipation, following ECT. In preclinical research, Electroconvulsive Shock (ECS) is commonly applied to animal models as an experimental analogue to explore the mechanisms and efficacy of ECT. Complementary experiments in mice revealed that daily ECS not only reversed depressive-like behaviors but also restored colonic motility. This effect was closely associated with the normalization of neural activity in the hypothalamic paraventricular nucleus (PVN), a key brain region involved in autonomic nervous regulation. Importantly, these benefits were abolished by subdiaphragmatic vagotomy, underscoring the pivotal role of the vagus nerve in mediating gut-brain interactions. These findings offer insights into the neural pathways underpinning the gut-brain connection, highlighting the potential of ECT not only as a last line of defense against severe depression but also as a means to address associated gastrointestinal dysfunction.

Feeding is essential for both host-organism survival and gut-microbiota maintenance. Our research focuses on how kynurenic acid (KYNA), a gut-microbiota metabolite, regulates appetite during fasting. We find that fasting significantly raises KYNA levels in the intestine, which increases short-term food intake by inhibiting vagal afferent nerve in the nodose ganglion (NG) and activating AgRP neurons in arcuate nucleus (ARCAgRP). The orexigenic effects of KYNA are abolished by subdiaphragmatic vagotomy (sdVx), chemogenetic activation/inhibition of glutamatergic NG/ARCAgRP neurons, inhibiting the nucleus of the solitary tract (NTS) to ARCAgRP inputs, or knockdown of GPR35 (a KYNA receptor) in the intestinal vagal afferent nerve. Our data support a model in which KYNA acts through the GPR35 receptor to inhibit vagal afferent signaling and subsequently activate ARCAgRP neurons, which leads to increased food intake. These findings reveal a mechanism by which gut microbiota controls appetite during fasting, highlighting the complex relationship between microbial and host feeding behavior.

Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation.

Chronic exposure to a Western diet (WD) elicits hippocampal (HPC)-dependent memory impairment. One potential unexplored mechanism for these effects involves impaired vagus afferent nerve (VAN) signaling, as VAN signaling promotes HPC function, and WD consumption blunts the capacity of vagally-mediated gut signals to communicate to the brain. The medial septum (MS) is an anatomical relay between the brainstem and the HPC, and the MS extensively innervates the HPC with acetylcholine (ACh)-releasing fibers. Thus, we hypothesized that VAN signaling engages the HPC via MS ACh release, and further, that impairments in this signaling pathway underlie WD-associated HPC dysfunction. Using in vivo fiber photometry and fluorescent ACh sensors (iAChSnFR) in adult (Postnatal day 56-75) male Sprague Dawley rats, we demonstrate that HPC ACh binding is elevated immediately following consumption of a meal (n=10). Additional results revealed that these meal-induced elevations in HPC ACh binding were eliminated in animals who underwent a surgical subdiaphragmatic vagotomy (SDV), thus identifying a role for vagal signaling in mediating postprandial HPC ACh signaling (n=5-6/group). To explore how a WD affects this outcome, we recorded HPC ACh release in animals chronically exposed to a WD during development (Post-natal days 26-56) while consuming a meal during adulthood. Results reveal that, similar to SDV rats, meal-induced elevations in HPC ACh binding were eliminated in the WD group (n=6-8/group). Further, Western blot analyses revealed comparable reductions in HPC protein expression of vesicular ACh transporter, an indicator of ACh HPC tone, in SDV and WD rats relative to controls. Collectively, our findings identify ACh signaling as a neural substrate for gut-originating VAN potentiation of HPC function, and that impairments in this signaling pathway may underlie WD-induced HPC dysfunction. NIH funding: •DK104897 •DK123423 •DK118402 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

3,4-Methylenedioxymethamphetamine (MDMA) is a widely recognized entactogen frequently used recreationally. It is known for its interaction with the serotonin and oxytocin systems, which underlie its entactogenic effects in humans. Recently, we demonstrated that the gut-brain axis, mediated by the subdiaphragmatic vagus nerve, contributes to MDMA-induced resilience enhancement in rodents. This study investigates whether subdiaphragmatic vagotomy (SDV) affects plasma oxytocin levels and the expression of oxytocin and c-Fos in the hypothalamus following a single oral dose of MDMA in rats. SDV significantly reduced baseline plasma oxytocin levels and oxytocin expression in the paraventricular and supraoptic nuclei of the hypothalamus. Furthermore, SDV markedly attenuated MDMA-induced increases in plasma oxytocin and the expression of oxytocin and c-Fos in these hypothalamic regions. These findings suggest that the subdiaphragmatic vagus nerve plays a critical role in brain-body communication, mediating MDMA's pharmacological effects on the oxytocin system.

Patients with acute lung injury (ALI) often experience psychiatric and neurological symptoms; however, the precise underlying mechanisms remain unclear. Given that white matter loss (demyelination) contributes to these symptoms, we investigated whether lipopolysaccharide (LPS)-induced ALI leads to brain demyelination via a vagus nerve-dependent lung-brain axis. A single intratracheal injection of LPS caused severe lung injury and demyelination in the corpus callosum (CC) of mouse brains. Subdiaphragmatic vagotomy did not affect LPS-induced lung injury or demyelination in the CC. Interestingly, cervical vagotomy significantly attenuated LPS-induced hypo-locomotion, plasma interleukin-6 levels, and demyelination in the CC of ALI mice without influencing lung injury. These findings demonstrate that ALI can induce demyelination in the CC of the mouse brain via a cervical vagus nerve-dependent lung-brain axis, highlighting the critical role of this pathway in the psychiatric and neurological symptoms observed in ALI patients.

Parkinson's disease (PD) is a common neurodegenerative disease worldwide. Current treatment methods for PD are unable to halt disease progression. The gut microbiota contributes to the neurodevelopment of PD; however, the gut-brain connections and underlying neural bases that regulate this complex behavior are not yet clear. Enterococcus faecalis (EF) is a common commensal bacterium of the gut and a common pathogen associated with hospital-acquired infections. Here, we demonstrated the significant therapeutic effects of a non-pathogenic strain of EF (EF ATCC19433) on PD. In this study, we established a mouse model of PD by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that EF treatment alleviated behavioral impairment, dopaminergic neuronal loss, blood-brain barrier damage, and neuroinflammation induced by MPTP in the mice. Additionally, 16S rRNA sequencing revealed that dysbiosis of PD-related microbial communities induced by MPTP was reversed by EF treatment. Moreover, EF treatment relieved gastrointestinal dysfunction in the mice. The therapeutic efficacy of EF in MPTP-induced PD mice is markedly diminished when the activity of EF is lost. Further mechanistic studies indicated that the neuroprotective effects of EF in PD were associated with the vagus nerve pathway. Following the surgical severance of the vagus nerve through subdiaphragmatic vagotomy, the protective effects of EF on PD were markedly diminished. Our study suggests that EF can alleviate neurofunctional impairments and gastrointestinal disorders associated with PD, indicating that gut-derived microbes influence brain function through the vagus nerve pathway.