Neurogastroenterology and Motility最新文献

Investigations into mechanisms of cyclic(al) vomiting syndrome (CVS) began at the bedside more than a century ago. The modern era started with the formation of the Cyclic Vomiting Syndrome Association in 1993 that helped initiate robust efforts in education, advocacy, family physician conferences, scientific symposia, dedicated clinical programs, therapeutic guidelines, and research. Even today, bedside clues continue to emerge with the recent description of cannabinoid hyperemesis syndrome (CHS) and subsequent evidence of a perturbed endocannabinoid system. The clinical picture of CVS has evolved from that of a straightforward emetic disorder related to migraine requiring short-term antiemetics or prophylactic anti-migraine therapy, to a complicated, heterogenous one with multiple comorbid associations (anxiety, dysautonomia) and endophenotypes (migraine, Sato, CHS). This expanded view has important therapeutic implications which necessitate managing the comorbidities which can in turn impact the disease itself and proffered promising evidence that behavioral management (meditation) and vagal neuromodulation appear efficacious with few untoward effects, perhaps by reestablishing autonomic (parasympathetic) balance. The pathophysiologic picture now appears to be inscribed on an autonomic polyvagal design but multiple additional pathways interact, some confirmed (NK1, CB1, HPA axis, PPM1D gene, biological calendar, estrogen), and others, possible (TRPV-1, CGRP, GDF-15, mitochondrial dysfunction, impaired cation transport). CVS and its cousin CHS continue to challenge clinicians and perplex investigators and in the current era require not only a critical mass of specific pathway expertise but also syncretic biopsychosocial thinking to integrate these disparate threads. We may have reached such a tipping point at this Symposium.

Background: The human colon receives 2 L of fluid daily. Small changes in the efficacy of absorption can lead to altered stool consistency with diarrhea or constipation. Drugs and formulations can also alter colonic water, which can be assessed using the magnetic resonance imaging (MRI) longitudinal relaxation time constant, T1. We explore the use of regional T1 assessment in evaluating disorders of colonic function.

Methods: Individual participant data analysis of data from 12 studies from a single center of patients with constipation, irritable bowel syndrome with diarrhea (IBS-D), and healthy volunteers (HV). T1 was quantified by measuring the signal from the tissue at different times after a pulse which inverts the magnetization.

Key results: When diarrhea was induced by a macrogol laxative T1 in the ascending colon, T1AC was negatively correlated with stool bacterial content, r² = 0.78, p < 0.001. T1AC was increased by another laxative, rhubarb. Patients with IBS-D had elevated fasting T1AC (0.78 ± 0.28 s, N = 67) compared to HV (0.62 ± 0.21 s, N = 92) while those with constipation lay within the normal range (HV 10-90th centiles 0.33-0.91 s). Fasting T1AC in IBS-D was reduced by mesalazine treatment. T1 in the descending colon was consistently lower than T1AC, with a bigger reduction in patients with constipation than HV. Pre-feeding dietary fiber (bran, nopal, and psyllium) was associated with fasting T1AC at or above the normal 90th centile.

Conclusions and inferences: T1 is an MRI parameter which could be used to monitor effectiveness of novel agents designed to alter colonic water content and stool consistency.

Background: Disorders of gut-brain interactions (DGBI) affect more women, and marital quality may have been a factor that explains clinical manifestations of DGBI-however, the mechanism is unclear. This study aimed to elucidate supported relationships between DGBI with marital quality and clinical attributes in married Malay women.

Methods: This cross-sectional study involved married Malay women with functional dyspepsia (FD), irritable bowel syndrome (IBS), and FD-IBS overlap per Rome IV criteria. Multivariate analysis of variance (MANOVA) and Pearson correlation analysis were performed to determine the association between DGBI, marital quality, and clinical attributes of catastrophizing, psychological dysfunction, and quality of life. Path analysis models were developed, tested, and fitted to elucidate relationships that satisfied significance testing and fit indices (termed supported relationship).

Key results: Of 1130 screened participants, 513 were analyzed. The prevalence of FD, IBS, and FD-IBS overlap was 33.9% (n = 174), 29.5% (n = 151), and 36.6% (n = 188), respectively. Of 17 variables in MANOVA, significant differences in variables were observed for FD vs. FD-IBS overlap (10), IBS versus FD (10), and IBS versus FD-IBS overlap (5). Pearson correlation matrices found significant correlations for 15 of 17 variables. After testing and fitting, the third path model (Model 3) was deemed the final model. Model 3 suggested that relationships between DGBI and marital and clinical attributes were complex and bidirectional. The number of supported relationships were 50, 43, and 39 for FD-IBS overlap, FD, and IBS, respectively.

Conclusions and inferences: Relationships between DGBI, marital quality, and clinical attributes among married Malay women are complex and bidirectional.

Introduction: Colonic manometry (CM) is a diagnostic procedure used to evaluate pediatric patients with refractory constipation, fecal incontinence, Hirschsprung disease, and pediatric intestinal pseudo-obstruction. Pan-colonic high-amplitude propagated contractions (HAPCs), measured by CM, reflect an intact neuromuscular function of the colon. Current guidelines recommend starting CM with fasting recording for 1-2 h, but no prior evaluation has determined the diagnostic yield of the fasting phase. We aimed to determine the utility of the fasting phase during CM studies.

Methods: We evaluated CM studies conducted at a tertiary pediatric center (2018-2022). Fasting phases of normal CM studies were evaluated.

Key results: In 433 included studies 241 (55.7%) females, median age (9.7 years), the average fasting recording lasted 126 min. A total of 193 (44.6%) studies exhibited fasting HAPCs, with 123 (28.4%) being pan-colonic. The presence of pan-colonic HAPCs was based solely on the fasting phase in 11 (2.5%) studies. Patients with fasting pan-colonic HAPCs were younger (median age of 6.9 vs. 9.8 years, p = 0.0001) and had a higher rate of postprandial HAPCs (69.1% vs. 25.2%, p < 0.0001). Most fasting pan-colonic HAPCs presented during the first 60 min (94/123, 76.4%). All studies demonstrated HAPCs after stimulation with bisacodyl. In analyzing just the initial 30 min of fasting on CM, only 2 (0.5%) studies would have been misclassified as abnormal, with no bisacodyl administration in these studies.

Conclusions & inferences: Shortening the fasting phase minimally affects next-day CM results and could reduce patient inconvenience, hospital-related costs, and potential side effects.

Introduction: Postoperative ileus (POI) is an iatrogenic disorder marked by temporary impaired gastrointestinal (GI) motility post-abdominal surgery. Surgical handling of the intestine activates resident macrophages (Mfs), leading to inflammatory cytokine release and leukocyte recruitment into the muscularis, which compromises intestinal contractility. The mechanisms behind this activation are unclear. Recent studies suggest peritoneal Mfs, particularly large peritoneal macrophages (LPMs), might play a role in sterile intestinal inflammation by rapidly recruiting to the serosal layer of the gut and aiding in tissue damage resolution.

Methods: To identify immune cells involved in the early phase of POI, single-cell RNA sequencing (scRNA-seq) was conducted. The migration of LPMs post-surgery was studied using adoptive transfer techniques. LPMs were depleted via intraperitoneal injection of clodronate liposomes. Subsequently, flow cytometry, quantitative PCR (qPCR), and immunofluorescence were performed to assess the impact of LPM depletion and analyze cell populations and inflammatory effects.

Results: (1) Intestinal manipulation (IM) leads to the accumulation of monocytes, neutrophils, mature Mfs, CD8+ T cells, and LPMs within 2 h post-surgery. (2) Heparin treatment does not affect gut transit or reduce IL-6, IL-1a, and IL-1b expression in the early phase of POI. (3) Depletion of LPMs via clodronate liposome does not prevent monocyte, neutrophil, and Mfs infiltration in the muscularis externa, nor does it improve gut transit or reduce cytokine expression. (4) LPMs migrate to the serosa after IM but do not enter the muscularis externa.

Conclusion and inferences: LPMs adhere to the intestinal serosa following intestinal manipulation but do not migrate into the intestinal muscularis or participate in the inflammatory response and delayed transit. Consequently, LPMs are not involved in the pathogenesis of POI.

Background: The enteric nervous system plays a key role in the coordination of gastrointestinal motility together with sympathetic, parasympathetic, and extrinsic sensory pathways. In some cases, abnormalities in neural activity in these pathways contribute to disorders of gut motility. Where this is associated with damage or death of enteric neurons, usually detected by microscopy, this is considered a gut neuropathy.

Purpose: This review summarizes recent advances in the identification of neuropathies in a range of gastrointestinal motility disorders.

Background: Intestinal ischemia affects the functioning of the Enteric Nervous System (ENS). Pannexin-1 channel participates in cell communication and extracellular signaling. Probenecid (PB) is a pannexin-1 channel inhibitor, which can be a potential treatment for intestinal ischemia.

Aim: Study the effects of ileal ischemia and reperfusion (I/R) and PB treatment on myenteric neurons and in rats.

Methods: Male Wistar rats were used for I/R induction, the ileal vessels were occluded for 45 min and reperfusion was performed after this time. The Sham groups underwent all surgical procedures without obstruction of the ileal vessels. Animals were euthanized 24 h or 14d post-I/R. The PB group received an injection of PB post-I/R. Ileal segments were collected for immunofluorescence analyses to identify neurons calretinin immunoreactive (-ir) and pannexin-1-ir. Neuronal density (cells/field), area (μm²), intestinal motility, and ultrastructural analyses were performed.

Key results: The pannexin-1 channel was double-labeled with calretinin-ir neurons. Neuronal density reduced by 21% reduction in calretinin-ir neurons in the I/R 24 h group and recovered 26% in the PB 24 h group. In the 14d group, there was a 23% reduction in calretinin-ir neurons in the I/R 14d group and a recovery of 26% in the PB 14d group. The analysis of the contraction after electrical simulation was lower in the I/R 14 d group and recovered in the PB 14d.

Conclusions and inferences: Intestinal I/R affects myenteric neurons and causes morphological and functional changes. PB was able to attenuate the effects of I/R and could constitute a therapeutic tool for intestinal I/R.

Introduction: High-resolution manometry (HRM) allows assessment of esophagogastric junction (EGJ) disruption. While type 3 EGJ predicts definitive gastroesophageal reflux disease (GERD), type 2 EGJ is less clearly implicated in GERD pathogenesis. This study aimed to characterize physiologic findings in type 2 EGJ to determine if the HRM-based Milan Score can define GERD within type 2 EGJ.

Methods: 535 patients with suspected GERD who underwent HRM and reflux monitoring were retrospectively analyzed. Clinical, HRM, and reflux study data were compared between the EGJ morphology subtypes, with objective GERD defined according to Lyon Consensus 2.0. The Milan Score, a novel metric that integrates ineffective esophageal motility, EGJ-contractile integral, EGJ morphology, and straight leg raise response, was abnormal when ≥ 137 (risk rate 50% for GERD). Receiver operating characteristic (ROC) curve analysis was performed to assess the accuracy of the Milan Score to predict objective GERD.

Results: Type 3 EGJ was associated with the highest rate of objective GERD, followed by type 2 and type 1 EGJ (p < 0.001), with a corresponding stepwise increase in AET from type 1 to 3 EGJ (p < 0.001). Type 2 EGJ with Milan Score < 137 resembled type 1 EGJ (objective GERD in 23.6% vs. 33.2%, p = 0.09), and type 2 EGJ with score ≥ 137 resembled type 3 EGJ (objective GERD in 88.2% vs. 78.8%, p = 0.11). On ROC analysis, the Milan Score had an area under the curve of 0.858.

Conclusion: While type 2 EGJ includes varying GERD severity, the Milan Score can segregate patients at risk for objective GERD.

Background: Irritable Bowel Syndrome (IBS) is a prevalent condition characterized by dysregulated brain-gut interactions. Despite its widespread impact, the brain mechanism of IBS remains incompletely understood, and there is a lack of objective diagnostic criteria and biomarkers. This study aims to investigate brain network alterations in IBS patients using the functional connectivity strength (FCS) method and to develop a support vector machine (SVM) classifier for distinguishing IBS patients from healthy controls (HCs).

Methods: Thirty-one patients with IBS and thirty age and sex-matched HCs were enrolled in this study and underwent resting-state functional magnetic resonance imaging (fMRI) scans. We applied FCS to assess global brain functional connectivity changes in IBS patients. An SVM-based machine - learning approach was then used to evaluate whether the altered FCS regions could serve as fMRI-based markers for classifying IBS patients and HCs.

Results: Compared to the HCs, patients with IBS showed significantly increased FCS in the left medial orbitofrontal cortex (mOFC) and decreased FCS in the bilateral cingulate cortex/precuneus (PCC/Pcu) and middle cingulate cortex (MCC). The machine-learning model achieved a classification accuracy of 91.9% in differentiating IBS patients from HCs.

Conclusion: These findings reveal a unique pattern of FCS alterations in brain areas governing pain regulation and emotional processing in IBS patients. The identified abnormal FCS features have the potential to serve as effective biomarkers for IBS classification. This study may contribute to a deeper understanding of the neural mechanisms of IBS and aid in its diagnosis in clinical practice.

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.