Neurogastroenterology and Motility最新文献

Objective: Transcutaneous auricular vagus nerve stimulation (taVNS) has been reported to ameliorate symptoms of both functional dyspepsia (FD) and depression/anxiety, while the central mechanism underlying taVNS effects on depression and anxiety in FD remains unclear. The aim of this study was to investigate taVNS-induced depression-like behavioral changes and cerebral activity alterations in a rodent model of FD.

Methods: Neonatal Sprague-Dawley (SD) rats were gavaged with iodoacetamide (IA) to induce a FD model. taVNS was performed for 30 min once daily for 14 days consecutively. The open field test (OFT) and forced swimming test (FST) were conducted to assess depression-like behaviors. The amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo) were derived from resting-state functional magnetic resonance imaging. Correlations between differential ALFF and ReHo values and depression-like behaviors were analyzed to identify taVNS-related central changes.

Results: taVNS increased both horizontal and vertical scores in the OFT and reduced the immobility time of the FST. After taVNS intervention, the ALFF and ReHo values of the right brainstem were decreased. Conversely, the ALFF values of the left molecular layer of the cerebellum and the ReHo values of the right entorhinal cortex were increased. The horizontal score of the OFT was negatively correlated with the ALFF of the right brainstem. Both the vertical score of the OFT and the immobility time of the FST were negatively correlated with the ReHo values of the entorhinal cortex.

Conclusion: taVNS alleviates depressive state in FD rats, possibly mediated by enhancing local neural coordination in the right entorhinal cortex and suppressing spontaneous neural activity in the right brainstem. These findings support further exploration of taVNS as a candidate approach for FD-related depression.

Background and aim: Achalasia's insidious onset and nonspecific presentation contribute to diagnostic delays, often exceeding 20 months from symptom onset to confirmation. The four-domain CARS endoscopic score (Content, Anatomy, Resistance, Stasis) may expedite risk stratification. We performed a meta-analysis to assess diagnostic accuracy, interobserver reliability, and treatment-monitoring potential.

Methods: We searched PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov through June 2025. Study-level 2 × 2 contingency data were then synthesized using bivariate random-effects models to derive pooled sensitivity, specificity, positive predictive value, and negative predictive value, generate HSROC curves, and construct Fagan nomograms at 5% and 25% pre-test probabilities.

Results: We screened 49 studies and ultimately included five studies encompassing 1112 patients with a mean age of 54.5 years and overall achalasia prevalence of 31.7%. For a CARS threshold ≥ 4, pooled sensitivity was 0.73 (95% CI 0.69-0.78), specificity 1.00 (0.99-1.00), positive predictive value 0.99, and negative predictive value 0.88; employing a dual-threshold strategy (CARS = 0 to rule out; ≥ 4 to rule in) further improved sensitivity to 0.95 (0.92-0.98), specificity to 0.99 (0.97-1.00), positive predictive value to 0.99, and negative predictive value to 0.96. The HSROC AUC approached 0.99, and moreover interobserver agreement was almost perfect with a pooled Cohen's κ = 0.84 (95% CI 0.76-0.91).

Conclusions: CARS reliably stratifies patients into low-risk (CARS = 0), moderate-risk (1-3), and high-risk (≥ 4) groups facilitating deferred testing, targeted manometry, or prompt invasive evaluation while demonstrating excellent interobserver agreement, underscoring its clinical utility.

Trial registration: PROSPERO number: CRD420251007005.

Background: This study aims to evaluate transverse rectal diameter (TRD) as a predictor of clinical severity and response to conventional treatment in children with chronic functional constipation (CFC).

Methods: This longitudinal prospective study enrolled 105 children aged 4-17 years with CFC at Fondazione Policlinico A. Gemelli (Rome, Italy) from December 2021 to April 2025. We used the Constipation Scoring System (CSS), pelvic ultrasound (TRD, anterior wall thickness [WT], detrusor thickness [DT]), and follow-up assessments at 2, 4, and 6 months. Patients without TRD or CSS improvement at 6 months underwent high-resolution anorectal manometry (HR-ARM). Statistical analysis included generalized linear mixed-effects models.

Results: Children with megarectum (TRD ≥ 3 cm) showed higher CSS scores (p = 0.002), TRD (p = 0.001), WT (p = 0.021), and longer constipation duration (p = 0.005) compared to controls. TRD positively correlated with age (p = 0.008) and CSS (β = 1.41, p = 0.043). A significant reduction in TRD and WT was observed at 2 months posttreatment (p < 0.001). Nine patients who failed to improve had type I dyssynergia confirmed on HR-ARM. DT showed no significant correlation with clinical severity.

Conclusion: TRD measured by pelvic ultrasound is a reliable noninvasive marker for assessing severity and monitoring treatment response in pediatric CFC. Persistence of rectal dilatation may suggest underlying defecatory dyssynergia and guide further evaluation. Integration of TRD into routine practice could improve personalized, outpatient-based care. Further multicentric studies are needed to validate TRD as a predictive biomarker in long-term management.

Background: The reference standard for the assessment of esophageal motility and sphincter function is high-resolution esophageal manometry (HRM). Diagnostic values for HRM are determined by the Chicago Classification (CC v4.0), which is based almost entirely on distal esophageal function without measures to address the proximal esophageal segment. Therefore, we sought to determine normal HRM values for proximal esophageal function when obtained in the standard HRM positions (supine and upright).

Methods: Healthy, asymptomatic adults (≥ 18 years) were recruited. All participants completed a standard protocol. CC v4.0 measurements, along with a proximal contractile integral (PCI) (millimeters mercury-seconds-centimeters[mmHg-s-cm]), temporal measures of proximal and distal contractility (seconds), and lengths of proximal and distal esophagus (centimeters), were performed. Summary statistics, tests of normality, and paired two-sided t-tests were performed.

Results: HRM data from 30 participants were included. Mean supine PCI was 423.9 mmHg-s-cm with a mean contraction time of 3.2 s and a mean length of 5.5 cm. The mean upright PCI was 183.9 mmHg-s-cm with a mean contraction time of 2.2 s, and a mean length of 4.5 cm. All proximal values were significantly different comparing the two positions (PCI p < 0.0001; time p < 0.0001; length p < 0.0001). All distal measurements fell within the ranges of normal, and all measures for contractile integral, contraction time, and contraction length were statistically significantly different (p < 0.0001 for all) comparing proximal versus distal measurements.

Conclusions: These preliminary data represent our first attempt to quantify normal proximal esophageal function using HRM measurements of contractile vigor, contraction length, and time.

Background and aims: Enteroendocrine cells (EECs) lining the gastrointestinal (GI) wall sense chemical and mechanical changes in the gut, secreting an array of hormones and neurotransmitters in response. Enterochromaffin (EC) cells synthesize and secrete serotonin and represent approximately half of all EECs. EEC signals are transmitted to the brain via activation of afferent nerve fibers terminating in the GI tract. EECs grow neurite-like processes termed by some as "neuropods." These are proposed to contact intrinsic and extrinsic afferent nerves innervating the gut wall as the site of formation of a neuroepithelial circuit that signals from gut to both enteric and central nervous systems.

Methods: This study focused on investigating, along the length of the mouse GI tract, the spatial relationship between EC cells and sensory nerve fibers, all of which contain the neuropeptide CGRP. This was analyzed using confocal laser scanning microscopy and Imaris 3-dimensional image analysis. Our aim was to determine the potential relevance of cell processes as the sites of neurotransmission on EC cells.

Results: We found the number of contacts between EC cells and CGRP fibers increases along the GI tract, with maximal contacts occurring in the distal colon. These contacts localized primarily on the cell body, and not on processes. Further, a high degree of variability in EC cell architecture, including the frequency and size of processes was seen.

Conclusions: These findings do not support the notion that EEC processes are a primary cell location at which a neuroepithelial circuit is formed but do indicate that the likelihood of such contact points occurring increases in more distal areas of the GI tract.

Background: The UCon neurostimulator is a novel device providing dorsal genital nerve (DGN) stimulation for treating fecal incontinence (FI)/fecal urgency (FU). The primary aim was to explore its safety and secondarily its performance, hypothesizing that DGN stimulation would be feasible and safe, while reducing FI/FU.

Method: This was a prospective two-center feasibility study conducted in Denmark. Adults ≥ 18 years, with FI ≥ 1/week, and/or strong FU ≥ 3/week, and a St. Mark's Incontinence Score ≥ 9 were eligible. DGN stimulation was self-administered at home daily for 4 weeks in either a time-limited (30 min/day) or urge/on-demand (60 s upon urgency) modality. Safety was assessed through patient-reported adverse and device-related events. Efficacy was evaluated by comparing baseline data with the last 14 days of the intervention using symptom diaries, the St. Mark's Incontinence Score, and bowel-related quality-of-life measures.

Results: Forty patients consented (39 women), median age 62 years (Q1-Q3: 54-69), and 26 patients completed the study. An adverse and device-related median of 1.5 events per patient was reported, but these were mild and transient. Among patients completing the 4-week intervention, 74% (n = 19) with FI and 43% (n = 14) with strong FU achieved ≥ 50% symptom reduction (p = 0.005 and p ≤ 0.001, respectively). St. Mark's Incontinence Score (n = 26) reduced significantly from 16.0 (13-18) to 11.5 (9-15) (p ≤ 0.001).

Conclusion: Using the UCon neurostimulator in a home setting is safe and feasible. A 4-week stimulation period demonstrated significant positive results in treating FI and FU.

Clinical trials registration: The conducted research was preregistered at ClinicalTrials.gov with the following link: (https://ClinicalTrials.gov/study/NCT05368246?cond=UCon&rank=5).

Background: Irritable bowel syndrome (IBS) is characterized by recurrent visceral pain associated with low-grade gut inflammation. Electroacupuncture (EA) at acupoint ST36 (Zusanli) is reputed to alleviate gastrointestinal disorders, but its effects on IBS-related visceral hypersensitivity and inflammation remain to be fully elucidated. This study evaluated whether EA at ST36 attenuates visceral pain and modulates key inflammatory mediators in the IBS rat model.

Methods: Forty male rats were randomly assigned to Control, IBS model, IBS + EA, and IBS + Sham groups (n = 10 each). IBS was induced by intracolonic acetic acid enema combined with daily restraint stress for 1 week, validating the IBS-D model. EA was applied at bilateral ST36 (2/100 Hz alternating frequency, ~0.5 mA, 20 min) every other day for 2 weeks; sham treatment used superficial needling with no electrical current. Visceral pain was assessed by abdominal withdrawal reflex (AWR) scores and electromyographic responses to graded colorectal distension. Colonic tissues were analyzed for pro-inflammatory cytokines (interleukin-1β, IL-6, tumor necrosis factor-α) by ELISA and for the expression of pain or inflammation-related proteins (TRPV1 and nuclear factor kappa B, NF-κB) by Western blot analyses.

Results: IBS model rats exhibited pronounced visceral hypersensitivity, with AWR scores significantly elevated (e.g., score 3 threshold volume reduced by ~40% vs. controls, p < 0.01). EA at ST36 markedly alleviated visceral pain, increasing pain threshold and reducing AWR scores by ~30%-50% compared to untreated IBS (p < 0.05). EA also significantly downregulated colonic IL-1β, IL-6, and TNF-α levels (by 45%-60% vs. IBS, p < 0.01) and reduced TRPV1 and NF-κB expression toward normal levels.

Conclusion: EA at ST36 produced significant analgesic and anti-inflammatory effects in IBS model rats. Visceral hypersensitivity was blunted and colonic inflammatory biomarkers (cytokines, TRPV1, NF-κB) were suppressed by EA, suggesting that EA at ST36 modulates neuro-immune pathways to relieve IBS-related pain. These findings support the therapeutic potential of ST36-targeted electroacupuncture for managing IBS visceral pain via inflammatory mechanism attenuation.

Background: Polyethilenglicole (PEG), bisacodyl, prucalopride, and linaclotide were demonstrated to be superior to placebo for the treatment of chronic constipation. In a recent study, we reported the actions of PEG, bisacodyl, and prucalopride on colonic motor patterns. The aim of the present study was to evaluate the effect of linaclotide as compared to placebo on colonic motility assessed with high-resolution manometry (HRM).

Methods: In 10 volunteers (30.3 ± 10.6 years), two colonic HRM studies (40 solid-state sensors, 2.5 cm spaced) were performed at least 10 days apart. After 90 min of basal recording, linaclotide 290 μg or placebo was administered orally in double-blind, randomized, cross-over fashion, and the recording continued for 180 min before and after a standardized meal. Colonic motility index (MI) of the right, left colon, and rectum, expressed as a ratio of the baseline value, was compared between treatments by means of a mixed model analysis. The number of high-amplitude propagated sequences, of long-distance propagating sequences, and of pan-colonic pressurizations was compared between treatments.

Results: Linaclotide induced more long-distance propagating sequences than placebo (34.9 ± 41.2 vs. 3.0 ± 5.2, p = 0.026), especially during the meal and post-meal phases of the recording. The total number of pancolonic pressurizations did not differ between treatments. However, a significant increase in the mean number of pre-prandial pancolonic pressurizations was observed following linaclotide administration (p = 0.043). No treatment effect was found on the change in colonic MI from the baseline in any region of the colon.

Conclusions: In healthy controls, acute administration of linaclotide increases the total number of long-distance propagating sequences and the pre-prandial pancolonic pressurizations.

Background: Electroacupuncture (EA) therapy shows promising efficacy in irritable bowel syndrome (IBS). This study integrated nontargeted metabolomics with transcriptomics to investigate the immune-inflammatory mechanisms underlying the effects of EA therapy in male IBS rats.

Method: IBS was induced in rats using water avoidance stress (WAS), and EA was applied at ST25 and BL25 acupoints. The IBS model was evaluated alongside assessments of depressive behavior. Visceral sensation was quantified using the abdominal withdrawal reflex (AWR) and the area under the EMG curve of abdominorectal muscles. The intestinal barrier integrity was analyzed by measuring ZO-1 and MUC2 levels, while inflammation was assessed through IL-1β and TNF-α measurements. Colon samples underwent nontarget metabolomics and transcriptomics analyses, and DEGs were validated using RT-PCR and WB to identify potential pathways. Networks of DEGs and differential metabolites were subsequently constructed to elucidate their interactions.

Result: EA treatment increased the expression of ZO-1 and MUC2, inhibited the IL-1β and TNF-α, and alleviated visceral hypersensitivity and depressive behavior. Transcriptomics identified 13 DEGs, indicating that EA modified the gene expression levels of Lck, Cd28, Il16, Nfatc2, Ccl17, Pik3cd, Zap70, Lat, Cd40, Cxcl10, Tlr9, Tnfsf8, and Tnfsf11. The underlying mechanism may involve the inhibition of PD-1/PD-L1, TCR and NF-κB signaling pathways. Metabolomics identified 14 differential metabolites, suggesting that EA may correct metabolic disturbances.

Conclusion: EA alleviates intestinal damage, inflammation, and behavioral symptoms in male IBS rats, potentially through modulation of immune-inflammatory pathways and metabolic homeostasis. This study focused on male rats; future research including females may clarify sex-related differences in EA.

Background: Chronic cough is a frequent and troublesome extraesophageal manifestation of GERD, with poor response rates to proton pump inhibitors (PPIs) and limited diagnostic tools to predict treatment efficacy. The Lyon score, a novel composite metric integrating reflux parameters, has shown promise in typical GERD but remains untested in chronic cough.

Aim: To evaluate the ability of the Lyon score to predict symptomatic response to double-dose PPI therapy in patients with suspected GERD-related cough.

Methods: We retrospectively analyzed 232 adult patients with chronic cough undergoing upper endoscopy, high-resolution manometry, and 24 h impedance-pH monitoring. PPI response was defined as ≥ 50% reduction in cough severity after ≥ 8 weeks of double-dose PPI therapy.

Results: Among 232 patients, 94 (40.5%) responded to PPIs. Responders had significantly higher Lyon scores (median 7.5 vs. 2.5, p < 0.0001). The Lyon score showed strong predictive performance (AUC 0.769), superior to AET (AUC 0.718) and reflux episodes (AUC 0.602), and comparable to MNBI < 1500 Ω (AUC 0.798). A Lyon score ≥ 5 had 64% sensitivity and 83% specificity. MNBI < 1500 Ω yielded 67% sensitivity and 79% specificity. The combination Lyon score or MNBI < 1500 Ω achieved optimal diagnostic accuracy (sensitivity 79%, specificity 71%, Youden index 0.50), significantly outperforming the combination Lyon score or AET > 6% (p < 0.0001). AET > 6% remained highly specific (93%) but had poor sensitivity (43%).

Conclusion: The Lyon score is a useful tool to identify GERD-related chronic cough responsive to PPI therapy. The presence of low MNBI further improves the prediction of PPI response, supporting integration in reflux work-up for chronic cough.