Neurogastroenterology & Motility

Objectives. To compare the efficacy and safety of invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). Materials and Methods. This prospective interventional trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM via an implanted device or ENM via surface electrodes. Stimulation was delivered at 14 Hz, 210 s pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Results. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; P = .0018). Treatment success was observed in 80% of ENM and 83% of SNM patients (P = 1.00). No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27% vs SNM 17%; P = .50). Conclusions. Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach.

BackgroundChronic gastroduodenal symptoms are challenging to diagnose and treat. Body surface gastric mapping provides non-invasive biomarkers of gastric function, but the requirement of a standard meal for postprandial assessment can be difficult for severely symptomatic patients. AimsTo assess the impact of reduced meal sizes and fasting on body surface gastric mapping metrics to determine clinical interpretability under non-standard nutritional loads. MethodsHealthy controls (n=60) underwent a 4.5-hour Gastric Alimetry test. Three age, sex, and BMI-matched groups (n=20 each) were compared: Standard Meal (482 kCal), Nutrient bar + Water (250 kcal), and Fasted (no meal). Principal Gastric Frequency, Gastric Alimetry Rhythm Index, BMI-Adjusted Amplitude, and fed:fasted Amplitude Ratio were analyzed against normative intervals. ResultsMeal status significantly affected amplitude-based metrics; the Standard Meal group exhibited higher BMI-Adjusted Amplitude (p<0.001) and fed:fasted Amplitude Ratio (p=0.001) than Fasted and Bar + Water groups. Frequency and rhythm-based metrics were resilient; Principal Gastric Frequency (p=0.245) and Gastric Alimetry Rhythm Index (p=0.336) showed no significant differences across conditions. While amplitude deviations were common in the Fasted group (20% fell below the normative range), Gastric Alimetry Rhythm Index and Principal Gastric Frequency remained within normal reference ranges for 95% of participants across all conditions. ConclusionsWhile consuming <50% of the standard meal significantly reduces gastric amplitude, gastric rhythm remains stable. Principal Gastric Frequency and Gastric Alimetry Rhythm Index function as reliable biomarkers of gastric myoelectrical function regardless of nutritional state.

ObjectiveTo establish a fetal lamb model of complex gastroschisis and characterize the impact on the intestines over time. Summary Background DataGastroschisis is a congenital abdominal wall defect and in its complex form is associated with serious morbidity. Robust large-animal models may help understanding are lacking. MethodsAt gestational day 75, gastroschisis was induced by creating a 1-cm abdominal wall defect reinforced by a silicone ring. Fetuses were assessed either at term or at mid-gestation (13-21 days post-induction). The primary outcome was complex gastroschisis occurrence, defined by bowel stenosis, atresia, volvulus, perforation or necrosis; otherwise classified as simple. At mid-gestation, occurrence was compared between early (13-16 days) and late (17-21 days) intervals. Secondary outcomes included prenatal ultrasound findings, in vivo bowel motility and morphology, ex-vivo bowel contractility, amniotic fluid composition, and histology across complex, simple, and normal groups. ResultsGastroschisis was induced in 32 fetuses. At term (n=14), all survivors (7/14; 50%) had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses and smooth muscle remodeling. At mid-gestation (n=18), complex gastroschisis occurred more frequently in the late than in the early group (71% vs. 11%; p=0.035). Mid-gestation gastroschisis fetuses showed greater intra-abdominal bowel dilatation on ultrasound and higher amniotic fluid digestive enzyme levels compared with non-operated littermates, with the greatest dilation observed in complex gastroschisis. ConclusionsThis model consistently reproduces complex gastroschisis in term survivors. After induction, complex gastroschisis occurrence increases with disease duration and is accompanied by structural and functional bowel changes.

Background: Jejunal diverticulitis is an uncommon but increasingly recognized cause of acute abdomen. It can present with a range of CT findings, including peridiverticular inflammation, bowel wall thickening, and fecalized small bowel content, with perforation or abscess occurring as complications in roughly 6% of cases. Case reports note varied presentations with jejunal and ileal involvement, treatment ranging from nonoperative management with antibiotics to urgent surgical intervention. Though rare, small bowel diverticulitis, particularly involving the jejunum, can result in significant morbidity, including peritonitis and sepsis, requiring heightened clinical suspicion in elderly or immunocompromised patients. Methods: We conducted a single center retrospective review of patients diagnosed with jejunal diverticulitis in a single academic center's Emergency General Surgery registry between December 2017 and December 2024. Of 42 patients initially identified, 34 had confirmed diagnoses on chart review. Data abstracted included age, sex, imaging modality, presence of perforation, serial physical exams, lab values (CBC, lactate), ICU admission, length of stay (LOS), antibiotic duration, operative status and timing, distance of residence from our institution, disposition after index admission, and readmission within one year. Results: Of the 34 confirmed cases, 24 (71%) were perforated: 2 presented with small bowel obstruction, 16 with abscesses and/or contained perforations, and 1 with both. 19 of the 24 perforated patients required operative intervention: 9 proceeded directly to the OR, 3 on hospital day one, and 2 as late as hospital day six. Among non-operative patients treated with antibiotics alone, the average LOS was 6 days (range: 2-23). Two patients were readmitted within one year: neither had undergone surgery during their index admission and neither were related to their index admission. Overall, three patients died: two during the index admission (both perforated and operated on) and one on readmission. Conclusion: Compared to the 6% complication rate reported in prior literature, our series demonstrates a notably higher rate of perforation (71%) among patients diagnosed with jejunal diverticulitis. Operative intervention was common, though a subset of patients was successfully managed non-operatively with antibiotics. Mortality was limited to patients with significant comorbidities and complex presentations. These findings underscore the heterogeneity in presentation and outcomes and highlight the need for a standardized approach. Development of practice guidelines incorporating clinical, radiographic, and laboratory parameters may improve diagnostic accuracy and guide timely, evidence-based management of this rare but serious condition.

Background & AimsDiabetes mellitus has been associated with both intestinal barrier dysfunction and peripheral neuropathy leading to increased risk of infection. The mucus layer forms a physical barrier against pathogens and is a critical component of the intestinal barrier that may be impaired in diabetes. This study aimed to assess how diabetes impacts goblet cells (GCs), mucus layer integrity, and innervation in the colon. MethodsFluorescence microscopy was used to investigate GCs, the mucus layer, and innervation in the colon of db/db mice. Custom open-access image analysis pipelines were developed to quantify GC numbers, location and content, mucus thickness, bacterial colonization, and innervation density in intestinal tissue sections. We also treated mice with the clinically used glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide to assess its capacity to reverse pathological changes to GCs and the mucus layer in a model of established type 2 diabetes (T2DM). ResultsThe mucus layer was significantly thinner in the colon of db/db mice with established diabetes and bacteria more readily colonized the epithelium and crypts. Intercrypt GC numbers were significantly reduced in db/db mice. However, there were significantly more GCs per crypt, and crypts were elongated in the db/db colon. Innervation was reduced in the mucosa and external muscle of the colon, consistent with diabetic neuropathic changes. Liraglutide treatment increased the size of GCs but had no effect on GC numbers, mucus thickness, or innervation in this model of established T2DM. ConclusionsMucus barrier dysfunction and GC hyperplasia is evident in the db/db colon. Increased microbial penetrability through the mucus layer suggests potential implications for the increased risk of gastrointestinal infection in diabetes.

Background: Irritable bowel syndrome (IBS) is characterized by heterogeneous symptom trajectories and high treatment discontinuation rates. Traditional analyses examine longitudinal outcomes and time-to-event endpoints separately, potentially missing informative dropout and the association between symptom dynamics and treatment persistence. Objective: To jointly model patient-reported IBS symptom trajectories and time-to-treatment discontinuation using shared random effects, characterizing the association between individual symptom dynamics and treatment persistence in a large Canadian prospective cohort. Methods: We analyzed 2,847 adults with Rome IV diagnosed IBS enrolled in the Canadian Gut Project (2018 to 2024) across 14 gastroenterology centres in Alberta, British Columbia, and Ontario. The longitudinal submodel used linear mixed-effects regression for the IBS Severity Scoring System (IBS-SSS) measured at baseline and months 3, 6, 12, 18, and 24. The survival submodel used a Weibull proportional hazards model for time-to-treatment discontinuation. The joint model linked both processes through shared random effects (random intercept and slope), estimated via maximum likelihood with adaptive Gauss-Hermite quadrature (15 nodes). We conducted sensitivity analyses using Bayesian estimation, alternative association structures (current value, time-dependent slopes), and multiple imputation for intermittent missingness. Results: Mean baseline IBS-SSS was 298.4 (SD 72.1). Over 24 months, 1,042 participants (36.6%) discontinued treatment. The longitudinal submodel revealed a mean IBS-SSS decline of -8.7 points/month (95% CI: -10.2, -7.1) with substantial between-person heterogeneity in both intercepts (STD = 4,218.3) and slopes (STD = 12.4). The association parameter linking the shared random intercept to the hazard of discontinuation was = 0.0034 (95% CI: 0.0021, 0.0047; p < 0.001), indicating that each 10-point increase in individual-specific baseline severity increased the hazard of discontinuation by 3.5%. The shared slope association parameter was 2 = -0.187 (95% CI: -0.264, -0.110; p < 0.001), demonstrating that individuals with steeper symptom improvement had lower discontinuation hazards. IBS-D subtype (HR = 1.41; 95% CI: 1.18, 1.69), concurrent anxiety (HR = 1.28; 95% CI: 1.09, 1.50), and social media health information use (HR = 0.82; 95% CI: 0.71, 0.95) were significant predictors in the survival submodel. Conclusion: Joint longitudinal-survival modelling reveals that IBS symptom trajectories and treatment discontinuation are dynamically linked through individual-level latent processes. Higher baseline severity and slower improvement trajectories significantly predict earlier discontinuation. These findings support personalized treatment monitoring approaches that use real-time symptom trajectory data to identify patients at risk of discontinuation.

Background/ObjectivesGlucagon-Like Peptide-1 (GLP-1) is a key incretin hormone that regulates glucose homeostasis and energy metabolism. Impaired GLP-1 signaling contributes to the development of obesity, metabolic syndrome, and type 2 diabetes. Emerging evidence indicates that gut microbiota-derived components can influence GLP-1 secretion, highlighting the therapeutic potential of microbial modulators. Akkermansia muciniphila, a next-generation probiotic associated with improved metabolic health, remains underexplored for its capacity to stimulate GLP-1 release. This study aimed to investigate the GLP-1- stimulatory effects of live and pasteurized (dead) A. muciniphila strains in human enteroendocrine cells. MethodsHuman enteroendocrine L-cells (NCI-H716) were treated with varying doses of live and dead A. muciniphila from Vidya Herbss proprietary VHAKM strain and a commercially available marketed strain (dead form). Following incubation, GLP-1 levels were quantified from culture supernatants using enzyme-linked immunosorbent assay (ELISA). Comparative analyses assessed differences in GLP-1 secretion between strains and treatment forms. ResultsBoth live and pasteurized VHAKM strains significantly increased GLP-1 secretion compared to untreated controls. The live VHAKM strain exhibited higher GLP-1 stimulatory activity than its pasteurized counterpart and the marketed strain. The results suggest a strain-specific and viability-dependent modulation of GLP-1 secretion in human L-cells. ConclusionsThis study demonstrates that A. muciniphila VHAKM enhances GLP-1 secretion in a strain- and form-dependent manner, with live cells showing superior efficacy. These findings provide foundational insights for developing microbiome-targeted interventions to boost endogenous GLP-1 levels and improve metabolic health outcomes.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a genetic connective tissue disorder characterized by hypermobile joints, chronic pain, fatigue, brain fog, orthostatic intolerance, and GI symptoms and dysmotility. Its heterogeneous presentation contributes to poor quality of life, inappropriate interventions, and prolonged diagnostic delays, often up to 10 years. This study primarily aimed to determine if physiological signals captured by a medical-grade wrist wearable could characterize autonomic patterns in hEDS and relate them to symptoms. Individuals with hEDS (n=30) and healthy controls (n=28) wore a medical grade smartwatch for 30 days, collecting continuous heart rate variability, activity, oxygen saturation, and blood pressure, alongside initial baseline symptom and quality-of-life surveys. Individuals with hEDS showed greater instability and variability in both systolic and diastolic blood pressure as well as the HRV metric LF/HF ratio, in comparison to healthy controls (p-values: 0.04, 0.02, 0.02). During sleep, metrics of parasympathetic activity (HRV measures: HF power, pNN50, RMSSD) trended lower in hEDS than healthy in comparison. As expected, survey domains assessing physiologic symptoms and quality-of-life were significantly worse in the hEDS cohort (p-values < 0.05). Notably, autonomic metrics correlated with GI symptoms in the hEDS cohort (Spearman's {rho} range: 0.38-0.60), and psychological symptoms in the healthy cohort (Spearman's {rho} range: -0.47-0.41). Principal component analysis (PCA) of physiologic and symptom features clearly separated groups, supporting distinct physiologic profiles. Combination of GI symptom index and wearable monitoring show promise as a hybrid screening approach that could substantially shorten the time to diagnosis in this population.

BackgroundIrritable bowel syndrome (IBS) contributes disproportionately to gastrointestinal-related emergency department (ED) utilization in South Korea, yet evidence on population-level interventions informed by patient-generated digital discourse remains limited. Recent social media analyses have identified dominant thematic concerns among IBS patients, including dietary triggers, symptom management, psychosocial burden, and information-seeking, suggesting actionable targets for digital self-management tools. ObjectiveTo evaluate the population-level impact of the Jang Geongang (, "Gut Health") digital self-management platform, whose content architecture was informed by topic modeling of IBS-related social media discourse, on IBS-attributed ED visits and unplanned hospitalizations, using a controlled interrupted time series (CITS) design. MethodsWe analyzed monthly aggregate claims data from South Koreas National Health Insurance Service (NHIS) spanning January 2018 to December 2024 (84 monthly observations). The Jang Geongang platform was launched in four pilot metropolitan areas (Seoul, Incheon, Daejeon, Gwangju) in July 2021, with eight non-pilot metropolitan areas serving as concurrent controls. Segmented regression with Newey-West heteroskedasticity and autocorrelation consistent (HAC) standard errors was used to estimate changes in level and trend of IBS-attributed ED visits per 100,000 insured population. Sensitivity analyses included autoregressive integrated moving average (ARIMA) transfer function models, varying pre-intervention windows, and leave-one-out control exclusion. ResultsThe CITS model estimated an immediate level change of -3.42 IBS-attributed ED visits per 100,000 (95% CI: -5.18 to -1.66, p < 0.001) following platform launch, and a change in monthly trend of -0.19 visits per 100,000 per month (95% CI: -0.31 to -0.07, p = 0.003), compared to control areas. By December 2024, the cumulative estimated reduction was 10.5 ED visits per 100,000 (23.8% relative reduction). Effects were concentrated in younger adults (19-39 years; level change: -5.14, p < 0.001) and IBS-D subtype visits (level change: -4.87, p < 0.001). ARIMA transfer function models corroborated these findings (immediate impact: -3.28, p = 0.001). Unplanned hospitalizations showed a smaller but significant reduction (level change: -0.84 per 100,000, p = 0.018). ConclusionsA digital self-management platform designed using social media derived IBS patient discourse insights was associated with sustained population-level reductions in IBS-attributed emergency utilization. Controlled interrupted time series analysis provides robust evidence for the public health impact of translating social media analytics into scalable digital health interventions.

OBJECTIVE This study investigates the long-term impacts of childhood exposure to voiding cystourethrogram (VCUG), a diagnostic procedure for vesicoureteral reflux. Primary outcomes include long-term health outcomes, mental health disorders, healthcare avoidance, and participation in risky behaviors compared to a control group. METHODS A 9-month retrospective cohort study was conducted with adults who received most of their medical care in the U.S. Respondents self-reported health metrics, behaviors, and outcomes via a 20-minute survey. Respondents were divided into two groups: those who remembered undergoing at least one VCUG in childhood (VCUG group), and those who did not (control group). RESULTS Of 334 respondents, 204 (61%) were in the VCUG group (mean age: 29, 70% female) and 130 (39%) were controls (mean age: 34, 70% female). Notable findings include: 47% of VCUG respondents were diagnosed with depression compared to 27% of controls. 15% of female-born VCUG respondents reported they would never visit a gynecologist compared to 2% of controls. 34% of VCUG respondents smoked regularly compared to 5% of controls, and 11% of VCUG respondents regularly missed work compared to 1% of controls. These findings highlight the need for further research and clinical consideration of VCUG's long-term consequences. CONCLUSIONS This study suggests that the effects of childhood VCUG extend into adulthood. Our findings underscore the need to reassess informed consent protocols and consider full-scale studies to minimize bias.

BackgroundIdiopathic epilepsy (IE) is the most common chronic nervous system disorder of dogs, and its cause is poorly understood. Emerging evidence suggests that microbiome alterations can occur with IE via the microbiota-gut-brain axis. Therefore, we analyzed the fecal microbiomes of 98 dogs (49 IE, 49 control) in a pairwise case-control observational study using 16S rRNA gene sequencing. ResultsAlthough the microbial community was mostly similar between groups, IE was associated with a modest but significant shift in Weighted-Unifrac distance (P = 0.042). We used six differential abundance (DA) methods to identify differentially abundant amplicon sequencing variants (ASVs) between IE and control groups. Notably, one Collinsella ASV was found to be significantly more abundant in IE dogs by all six methods. The gut microbial compositions varied drastically across households (accounting for about 69% of the total variation), but did not have significant differences between sex, age, or breed. Phenobarbital administration in IE dogs had a significant effect on seizure control, and was not associated with changes in the microbiome. ConclusionOur findings suggest a relationship between gut microbiomes and IE. However, the specific mechanism needs to be further investigated.

Background: Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC. Methods: A retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens. Results: Overall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. Conclusion: Among CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.

Lipodystrophies are a group of disorders featuring reduced adipose tissue mass or function, which often leads to significant metabolic disease, reduced lifespan and impaired quality of life. Individuals with congenital generalised lipodystrophy (CGL) have severely reduced adipose tissue mass. The loss of healthy systemic lipid storage typically causes hepatic steatosis and lipoatrophic diabetes. In addition, adipocyte-secreted hormones including leptin and adiponectin are dramatically reduced. Leptin has critical roles regulating appetite and broader effects on lipid and glucose metabolism. Daily injection with recombinant leptin is currently the only specific, approved treatment for CGL. The consequences of adiponectin loss in these patients are not fully understood. Likewise, the potential therapeutic benefit of adiponectin delivery is unclear. Here we examine the effect of delivering leptin or adiponectin by adeno-associated virus (AAV) as potential gene therapy treatment for metabolic disease in CGL using a well-characterised murine model of the condition. AAV-mediated leptin delivery significantly improved hepatic steatosis and hyperinsulinemia. However, adiponectin delivery did not lead to any observed beneficial effects. This demonstrates the potential of gene therapy approaches for long-term delivery of leptin in individuals with lipodystrophy, without the need for continuous supply of perishable therapeutics and painful daily injections.

Background: Creatine monohydrate (typically 5 to 20 g/day) has a well-established safety profile across diverse populations. Creatine hydrochloride (CR-HCl) is a highly soluble creatine formulation that may allow effective supplementation at substantially lower doses (750 mg to 3 g/day); however, controlled human safety data specific to CRHCl remain limited. Objective: To evaluate the short-term laboratory safety and tolerability of low dose CRHCl supplementation administered for 28 days in healthy adults. Methods: This single center, single arm, singl blind pilot safety study enrolled 11 healthy adults (10 females, 1 male; mean age 44.6 plus/minus 7.2 years). Participants consumed 750 mg/day CRHCl for 28 consecutive days while maintaining their usual diet and physical activity patterns. Fasting blood and urine samples were collected at baseline and Day 28. Laboratory assessments included hematological, lipid, and clinical chemistry biomarkers. Pre and post changes were evaluated using paired parametric and nonparametric tests, baseline-adjusted regression models, bootstrap confidence intervals, and false discovery rate (FDR) correction. Results: All participants completed the intervention. No clinically meaningful changes were observed in lipid parameters, hematologic indices, renal markers, or most chemistry analytes after adjustment for multiple comparisons. Fasting glucose increased modestly (8.1 mg/dL) prior to multiplicity adjustment but was not statistically significant after FDR correction and remained within reference ranges. Serum bicarbonate decreased slightly (2.4 mmol/L); although statistically detectable in parametric analysis, values remained within physiological limits and were not consistently supported by nonparametric testing.

Objectives: Acute gastroenteritis is a leading cause of pediatric emergency department (ED) visits. While ondansetron reduces vomiting, intravenous rehydration, and hospital admissions, its efficacy when initiated at triage remains unclear. We aimed to evaluate whether triage nurse-initiated administration of ondansetron in children with suspected gastroenteritis reduces the proportion of patients requiring observation following initial physician assessment. Methods: We conducted a randomized, double-blind, placebo-controlled trial in a tertiary pediatric ED in Canada. Children aged 6 months to 17 years presenting with morae than 3 episodes of vomiting in the preceding 24 hours (including 1 within 2 hours of arrival), were eligible. At triage, we randomized participants to receive liquid ondansetron or a color- and taste-matched placebo. The primary outcome was the proportion of patients requiring observation after the first physician evaluation. Secondary outcomes included post-intervention vomiting, ED length of stay, patient comfort, and 48-hour return visits. The trial was registered at ClinicalTrials.gov (NCT03052361). Results: Recruitment was stopped prematurely due to the COVID-19 pandemic. Ninety-one participants were randomized to ondansetron (n= 44) or placebo (n= 47). Overall, 40 patients (45%) were discharged immediately after the initial physician assessment, with no difference between the ondansetron and placebo groups (44% vs. 45%; absolute difference -1%, 95% CI: -20% to 19%). No significant differences were observed in all secondary outcomes. Conclusion: In this trial, triage nurse-initiated ondansetron administration did not reduce the need for ED observation in children with presumed gastroenteritis. While being underpowered, this study could inform researchers planning larger clinical trials.

1.Fermentable fibres such as inulin can support metabolic health but may exacerbate gastrointestinal symptoms in individuals with irritable bowel syndrome (IBS) due to rapid fermentation and gas production. The gel-forming fibre psyllium improves IBS symptoms, although the underlying mechanisms remain unclear. We hypothesised that fibre gelation alters fermentation by modulating microbial access to substrates. To test this, we compared psyllium with methylcellulose, a chemically modified, gel-forming fibre, to determine the effects of gelation on inulin fermentation. Inulin alone or combined with psyllium or methylcellulose was fermented for 48 hrs in a colonic fermentation model inoculated with healthy human faeces. Gas production, metabolite profiles, microbial community composition and microbial localisation within fibre gels were assessed. Bioactivity of fermentation products was evaluated in STC-1 cells. Psyllium co-fermentation significantly accelerated fermentation and enhanced production of metabolites, while methylcellulose had minimal effects. Psyllium maintained higher diversity and enriched polysaccharide-degrading taxa including Bacteroides and Phoecaeicola species, which were strongly associated with metabolic activity. Bacterial penetration into the psyllium matrix was observed but not into methylcellulose. Fermentation products from psyllium but not methylcellulose stimulated GLP-1 and 5-HT secretion in STC-1 cells. These findings demonstrate that delayed-onset fermentable gel-forming fibres enhance microbial access to entrapped substrates, driving metabolic and hormonal responses.

BackgroundPeri-synaptic astrocyte processes (PAPs) play a fundamental role in synapse formation and function. Central afferent synapse loss and astrocyte dysfunction greatly impede sensory-motor circuitry in spinal muscular atrophy (SMA) disease progression, however mechanisms underpinning tripartite synapse dysfunction remains to be fully elucidated. The aims of this study were to further define PAP and motor neuron synaptic defects in human SMA disease pathology and implement a therapeutic intervention strategy to improve motor neuron function. MethodsWe derived astrocyte monocultures and motor neuron astrocyte co-cultures from healthy and SMA patient induced pluripotent stem cell (iPSC) lines to assess intrinsic astrocyte filopodia defects and phenotypes occurring at the synapse-PAP interface, respectively, using cell surface capture mass spectrometry proteomics, confocal and super resolution microscopy, synaptogliosome isolation, and electrophysiology. ResultsSMA astrocytes demonstrated intrinsic filopodia actin defects featuring low abundance of actin-associated cell surface N-glycoproteins, and decreased filopodia density and CDC42-GTP levels after actin remodeling stimulation. This phenotype is likely driven by the significant reduction of CD44 and phosphorylated ezrin, radixin and moesin ERM proteins (pERM) within SMA astrocyte filopodia. The dual combination of SMN1 gene therapy and forskolin treatment, an adenylyl cyclase activator leading to increased cyclic adenosine monophosphate (cAMP) levels and actin signaling pathway stimulation, led to extensive branching and increased filopodia density of SMA astrocytes during actin remodeling. SMA patient-derived motor neuron and astrocyte co-cultures, particularly samples derived from male patient iPSC lines, demonstrated a significant decrease in synapse number, actin-associated pre-synaptic neurotransmitter release protein, synapsin I (SYN1), and PAP-associated expression of pERM and glutamate transporter, EAAT1. Our astrocyte-targeted SMN1 augmentation and forskolin treatment paradigm restored SYN1 protein levels within the SMA synaptogliosome, resulting in significant increases in motor neuron synapse formation and function, but did not fully restore PAP-associated proteins levels at the synapse. ConclusionsSMA astrocytes demonstrate intrinsic actin-associated defects within filopodia, which correlates with decreased pERM levels at tripartite motor neuron synapses. We also define a SMN- and cAMP-targeted treatment paradigm that significantly increases pre-synaptic neurotransmitter release protein levels to improved SMA motor neuron synapse formation and function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/714618v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1257ab8org.highwire.dtl.DTLVardef@19c0010org.highwire.dtl.DTLVardef@c84552org.highwire.dtl.DTLVardef@3f1e62_HPS_FORMAT_FIGEXP M_FIG C_FIG

Introduction: Pudendal nerve stimulation is a promising therapy for urinary incontinence, however stimulation can evoke off-target activity. We aimed to determine whether multi-contact cuff electrodes can selectively recruit motor fibers of the pudendal nerve trunk in preclinical feline and ovine models. Methods: Multi-contact cuff electrodes were implanted around the pudendal nerve in anesthetized felines and ovines. Structured variations in electrode contact configurations and stimulation amplitudes were applied to evoke external urethral sphincter (EUS) and external anal sphincter (EAS) pressure responses. We calculated selectivity indices, EUS Scores, and EAS Scores to quantify selective recruitment and the magnitude of evoked pressure changes. Results: We achieved selective motor activation, with preferential recruitment of the EUS or EAS in all three feline experiments and one of three ovine experiments. In felines, at least four electrode combinations selectively evoked EUS responses (EUS Score 0.5) and at least one combination targeted the EAS. In ovines, one EUS-selective and six EAS-selective combinations obtained comparable scores. In preliminary tests, we observed functional increases in leak point pressure and incontinence prevention with selective stimulation. Conclusions: This study shows that multi-contact cuff electrodes can selectively activate EUS and EAS motor fibers in the pudendal nerve. Future work should focus on optimizing stimulation parameters to enhance selectivity and assess the translational potential of this approach for restoring pelvic organ control.

BackgroundTourette Syndrome (TS) is a neurodevelopmental movement disorder involving involuntary motor and vocal tics believed to be characterised by disordered neural inhibition. Cortical representations have previously been manipulated by disruptions in the inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA). However, while facial tics are the most reported motor tic, it is unclear if facial sensorimotor representations differ in TS. MethodsSixteen individuals with Tourette Syndrome (TS) or chronic tic disorder and twenty typically developing (TD) control participants underwent 3-Tesla functional magnetic resonance imaging (fMRI). Blood-oxygenation level-dependent (BOLD) responses were measured during a block-design task comprising cued facial movements of common facial tics (blinking, grimacing and jaw clenching). Activations in bilateral pre- and post-central cortices and supplementary motor areas (SMA) were examined. Conjunction analyses identified voxels commonly and uniquely activated across movements within each group. ResultsBoth groups showed significant activations in the bilateral sensorimotor cortices and SMA in response to blink, grimace and jaw clench movements, with no significant between-group differences. Between-group similarities were lowest for unique blink maps. Common voxel maps also revealed low between-group similarity, with reduced sensorimotor activation and no shared SMA activation across movements in the TS group. ConclusionVoluntary facial sensorimotor representations do not differ between groups. However, low similarities between group unique blink maps may reflect greater prevalence of blinking tics in TS. Additionally, reduced overlap in sensorimotor activation and absent common SMA engagement across cued movements in the TS group may indicate altered motor integration or action initiation.

PurposeIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by impaired reproductive maturation, and approximately half of all cases lack an identified genetic cause. We investigated the genetic basis of IHH in two large cohorts to identify novel disease-causing genes. MethodsWe analyzed exome and genome sequencing data from 1,822 patients with IHH from two independent cohorts. Rare variants were filtered using pedigree-informed inheritance models. PLEKHA6 expression in the postmortem human hypothalamus were tested at the mRNA and protein level. Functional studies assessed kisspeptin secretion in cell-based assays. ResultsWe identified 18 distinct PLEKHA6 variants in 24 patients from 20 unrelated families (1.3% of cohort). Variants segregated with disease under autosomal recessive and autosomal dominant (with variable penetrance) inheritance patterns. PLEKHA6 was robustly expressed in the hypothalamus and showed clear colocalization with neurokinin B, which served as the marker for the GnRH pulse generator. Functional studies demonstrated that patient variants significantly impaired kisspeptin secretion. ConclusionPLEKHA6 is a novel IHH gene and the first reported regulator of kisspeptin secretion from the kisspeptin-neurokinin B-dynorphin (KNDy) neurons, which have recently been established as the GnRH pulse generator. These findings establish impaired kisspeptin release as a new disease mechanism in IHH and highlight the critical role of neuropeptide trafficking in reproductive function.