Neurogastroenterology and Motility最新文献

Background: Impaired gastric accommodation is one of the most frequent symptoms of functional dyspepsia. The safety and efficacy of conventional treatments remain to be proven and alternative herbal therapies have been proposed to alleviate gastrointestinal symptoms. This preclinical study examined the role of herbal Amara extract (containing Artemisia absinthium, Centaurium erythraea, Cichorium intybus, Gentiana lutea, Juniperus communis, Achillea millefolium, Peucedanum ostruthium, Salvia officinalis, and Taraxacum extracts) on gastric (fundus) accommodation and the possible implication of muscarinic receptors in its regulation.

Methods: The effect of Amara extract on fundus motility was investigated in organ baths of smooth muscle strips isolated from the fundus of guinea pigs, and the role of the muscarinic receptor pathway was evaluated using functional and radioligand binding assays in cell lines expressing the M2 or M3 muscarinic receptor.

Key results: Amara extract inhibited carbachol-induced contraction of guinea pig smooth muscle strips in a dose-dependent manner. This relaxant effect was not affected by the M3 antagonist J-104129. Amara extract also inhibited M2, but not M3, receptor activity in CHO-K1 cells (IC₅₀ 219 μg mL^-1), and specifically bound the M2 receptor (IC₅₀ 294 μg mL^-1). Of the nine herbal components of Amara extract, Juniperus communis, P. ostruthium, and Salvia officinalis inhibited M2 receptor activity (IC₅₀ 32.0, 20.8, and 20.1 μg mL^-1, respectively), and P. ostruthium was sufficient to reverse carbachol-induced ex vivo contraction of guinea pig fundic smooth muscles.

Conclusion and inferences: Amara extract relaxes gastric smooth muscles by inhibiting the M2 muscarinic receptor. This study suggests the potential benefit of Amara extract for patients with impaired gastric accommodation.

Background and aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF₁) agonist, cortagine.

Methods: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle. The visceromotor responses (VMR) were assessed to a first CRD (baseline) before injections, and to a second CRD 15 min after the last treatment. Brain, jejunum, and proximal colon were collected from treated and naïve rats for levels quantification of three fatty acid amides (FAAs) [anandamide (arachidonyl-ethanolamide, AEA), oleoyl-ethanolamide (OEA) and palmitoyl-ethanolamide (PEA)], and 2-AG. In separate animals, defecation/diarrhea were monitored after URB597 and cortagine.

Key results: URB597 inhibited cortagine-induced increased VMR at 40 mmHg (89.0 ± 14.8% vs. 132.5 ± 15.6% for vehicle SC, p < 0.05) and 60 mmHg (107.5 ± 16.1% vs. 176.9 ± 24.4% for vehicle SC, p < 0.001) while not influencing basal VMR. In URB597 plus cortagine group, FAAs levels increased in the brain and intestinal tissue while 2-AG did not change. URB597 did not modify cortagine-induced defecation/diarrhea versus vehicle.

Conclusions and inferences: URB597 shows efficacy to elevate brain and intestinal FAAs and to counteract the colonic hypersensitivity induced by peripheral activation of CRF₁ signaling supporting a potential strategy of FAAH inhibitors to alleviate stress-related visceral hypersensitivity.

This paper introduces a metric capable of tracking a hypothetical brainstem "switching" mechanism involved in regulating the afferent influence of blood pressure on the vagal efferent control of heart rate. In theory, this metric could be applied to evaluate the "efficiency" of brainstem pathways involved in common mechanisms of autonomic function involving the vagal influences on the gut as well as the heart. Thus, by exploring the dynamic "efficiency" of the brainstem feedback circuit linking heart rate to posture, a clinically relevant index of vagal flexibility might be extracted that would provide a generalizable window into the vagal regulation of both the heart and gut. Recent research supports this contention and has documented that this metric, VE, appears to covary with disorders of the gut. Clinical application of this metric might identify individual vulnerabilities that frequently reflect symptoms assumed to have features of a dysregulated autonomic nervous system (i.e., dysautonomia). If this is confirmed by additional research, then this objective measure of neural regulation of autonomic function might provide insight into the pathogenesis of disorders of gut-brain interaction.

Background: High-resolution Manometry (HRM) is the most sensitive and specific test available for clinical assessment of hiatal hernia (HH), a common condition defined as the separation between the Lower Esophageal Sphincter (LES) and crural diaphragm (CD). While the link between HH and Gastroesophageal Reflux Disease (GERD) is established, the potential association of HH with esophageal dysmotility, independently from GERD, is uncertain. This study aimed to analyze if HH, with or without GERD, can associate with esophageal motility disorders.

Methods: Consecutive patients without previous esophageal surgery who underwent HRM between 2018 and 2022 were enrolled. All patients with symptoms suggestive of GERD underwent impedance-pH testing off-therapy. HH was defined as a separation >1 cm between LES and CD, and esophagogastric junction (EGJ) morphology was classified as: Type I, when there was no separation between LES and CD; Type II, in case of minimal separation (>1 and <3 cm); Type III, when ≥3 cm of separation was present. Demographic and clinical characteristics were collected at baseline, including Age, Gender, Alcohol-, Coffee- and Smoke-habits, GERD diagnosis and symptoms' duration. Two cohorts of patients, with and without HH, were retrospectively individuated, and their association with Ineffective Peristalsis, Hypercontractile Esophagus and Outflow Obstruction was analyzed with univariate and multivariate Logistic regressions using the statistical software R.

Key results: 848 consecutive patients were enrolled, and 295 cases of HH (34.8%), subdivided into 199 (23.5%) Type II- and 96 (11.3%) Type III-EGJ patients, were identified. Ineffective peristalsis was diagnosed in 162 (19.1%) subjects, Hypercontractile esophagus in 32 (3.8%), and Outflow Obstruction in 91 (10.7%), while GERD was present in 375 (44.2%) patients. HH was significantly associated with Ineffective Peristalsis (p < 0.001) and GERD (p < 0.001). Furthermore, HH resulted to be a risk factor for Ineffective peristalsis (OR 2.0, 95% CI 1.4-2.8, p < 0.001) both when the analysis was conducted in all the 848 subjects, independently from GERD, and when it was carried out in patients without GERD (OR 2.3, 95% CI 1.02-5.3, p = 0.04). The risk for Ineffective Peristalsis increased 1.3 times for every centimeter of HH. No statistically significant association was found between HH and Outflow obstruction or Hypercontractile Esophagus.

Conclusions & inferences: An increasing separation between the LES and CD may lead to a gradual and significant elevation in the risk of Ineffective Peristalsis. Interestingly, this association with HH is true in patients with and in those without GERD, suggesting that the anatomical alteration seems to play a major role in motility change.

Confocal laser endomicroscopy (CLE) is a novel technique allowing real time in vivo microscopy during standard endoscopy. Recently, acute mucosal alterations after food administration visualized by CLE have been linked to symptoms in irritable bowel syndrome (IBS). Interestingly, the observed reactions occurred in subjects without demonstrable allergic sensitization to food-this is in line with mechanistic research showing local but not systemic allergic sensitization to foods in an animal model for IBS. Here, European experts conducting CLE with food administration provide a narrative review of the available literature and propose practical guidance on the use of this technique. CLE allows physicians to observe acute mucosal reactions after the application of food to the duodenal mucosa in patients with functional gastrointestinal disorders. Some open-label interventions show a symptomatic benefit when patients exclude the nutrient that triggered an acute mucosal reaction. However, many technical, mechanistic, and clinical questions remain unanswered to date. Technically, the interobserver variability and learning curve requires systematic evaluation and criteria or cutoffs for alterations require validation. Mechanistic studies are needed to enhance our understanding of the mechanisms underlying observed alterations. Finally, rigorous blinded controlled studies are needed to assess a link of these observed alterations with symptom generation. CLE offers a platform allowing scientific insights related to food induced acute mucosal alterations. However, many questions remain unanswered, and more research is warranted to understand the role of acute mucosal alterations visualized upon food administration in IBS pathophysiology and treatment.

Background: An impaired intestinal barrier with the activation of corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models.

Methods: The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague-Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)- and CRF-induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163.

Key results: Intraperitoneal PD149163 (160, 240, 320 μg kg^-1) prevented LPS (1 mg kg^-1, subcutaneously)-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg^-1, intraperitoneally). Peripheral atropine, bicuculline (a GABA_A receptor antagonist), sulpiride (a dopamine D₂ receptor antagonist), astressin₂-B (a CRF receptor subtype 2 [CRF₂] antagonist), and intracisternal SB-334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model.

Conclusions and inferences: PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D₂, GABA_A, orexin, CRF₂, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms.

Background: Behavioral therapy has proved effective as rumination therapy. Our objective was to treat rumination patients using multidisciplinary behavioral therapy aimed at reducing ≥2 of the rumination score.

Methods: All patients fulfilled Rome IV criteria for rumination and were referred to speech therapy for psychoeducation, diaphragmatic breathing exercises and guided eating, physiotherapy for exercises to relax the thoracic and abdominal muscles, and consultation with the psychologist and the dietitian. Symptoms, depression, anxiety, health-related quality of life (HRQoL), and functional capacity were evaluated by questionnaires (Rome IV, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), 15D, and World Health Organization Disability Assessment Schedule (WHODAS) 2.0) at baseline and at 6-month control. Esophageal manometry was performed at 6-month control.

Key results: The study enrolled 11 patients (19-64 years, 10 female). Rumination score: 6.5 (5-8) at baseline, 4.0 (3-5) at the 6-month control, p = 0.005. BDI/8 (6-13), BAI/15 (8-29) at baseline; BDI/7 (4-8), BAI/15 (7-27) at the 6-month control, NS. 15D score: 0.800 at baseline, 0.845 at the 6-month control, NS. WHODAS 2.0 score: 15 (7-33) at baseline, 11 (7-26) at the 6-month control, NS. Rumination could be evoked in manometry in six of nine (67%) patients at 6-month control.

Conclusions and inferences: Behavioral multidisciplinary therapy significantly reduces the self-assessed frequency of rumination. These patients have more depression, anxiety and a lower HRQoL compared to the normal population.

Background: The functional relationship of striated esophagus (St.Eso) motor function with pharyngeal deglutitive biomechanical events has not been systematically studied. The aim of this study was to determine the spatio-temporal characteristics of St.Eso function and its correlation with pharyngeal biomechanics and bolus transport.

Methods: We studied 50 healthy volunteer subjects (age range: 21-82 years, 31 female) by digital videofluoroscopy. All subjects were studied in a seated, upright position. Thirteen of these 50 volunteers also underwent high-resolution manometry (HRM) concurrent with fluoroscopy. We used laryngeal excursion as a surrogate for St.Eso excursion.

Key results: Median duration of St.Eso excursion was 2.35 [1.93,2.85, 5th and 95th percentile] seconds. Mean maximum extent of St.Eso excursion was 2.84 ± 0.72 cm. We identified four distinct periods in deglutitive St.Eso motor function: P1. Anterosuperior ascent without bolus or peristaltic activity, P2. Non-peristaltic bolus receiving at the apogee of St.Eso excursion concurrent with UES opening and pharyngeal peristalsis P3. Peristaltic bolus transport as St.Eso descends and P4. Continued peristalsis in resting position.

Conclusions and inferences: 1. St.Eso motor function spans both pharyngeal and esophageal phases of swallowing for receiving and transporting the bolus, 2. Pressure signatures in HRM recordings currently attributed to St.Eso deglutitive motor activity does not represent the entirety of St.Eso peristalsis, only the part that occurs in its resting position. St.Eso peristalsis that occurs during its descent is recorded by pressure sensors initially in the pharynx. This finding needs to be considered when interpreting HRM recordings of the pharynx and proximal esophagus.