Distinctive gastrointestinal motor dysfunction in patients with MNGIE.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms. METHODS: Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022. KEY RESULTS: In this period, five patients diagnosed of MNGIE (age range 16-46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms. CONCLUSIONS AND INFERENCES: MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated.

Artificial intelligence to improve polyp detection and screening time in colon capsule endoscopy.

Colon Capsule Endoscopy (CCE) is a minimally invasive procedure which is increasingly being used as an alternative to conventional colonoscopy. Videos recorded by the capsule cameras are long and require one or more experts' time to review and identify polyps or other potential intestinal problems that can lead to major health issues. We developed and tested a multi-platform web application, AI-Tool, which embeds a Convolution Neural Network (CNN) to help CCE reviewers. With the help of artificial intelligence, AI-Tool is able to detect images with high probability of containing a polyp and prioritize them during the reviewing process. With the collaboration of 3 experts that reviewed 18 videos, we compared the classical linear review method using RAPID Reader Software v9.0 and the new software we present. Applying the new strategy, reviewing time was reduced by a factor of 6 and polyp detection sensitivity was increased from 81.08 to 87.80%.

Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant.

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.

Propagation patterns of jejunal motor activity measured by high-resolution water-perfused manometry.

BACKGROUND: The manometric diagnosis of severe intestinal dysmotility is performed at most institutions using catheters with 2-8 sensors 5-10 cm apart. The recent application of high-resolution manometry catheters with closely spaced sensors to other gut segments has been highly successful. The objective of the present study was to determine the feasibility of a jejunal high-resolution manometry method and to carry out a descriptive analysis of normal jejunal motor function. METHODS: A 36-channel high-resolution water-perfused manometry catheter (MMS-Laborie, Enschede, The Netherlands) was orally placed in the jejunum of 18 healthy subjects (10 men, eight women; 21-38 age range). Intestinal motility was recorded during 5 h, 3 during fasting, and 2 after a 450 kcal solid-liquid meal. Analysis of motility patterns was supported by computerized tools. KEY RESULTS: All healthy subjects except one showed at least one complete migrating motor complex during the 3 h fasting period. Phase III activity lasted 5 ± 1 min and migrated aborally at a velocity of 7 ± 3 cm/min. High-resolution spatial analysis showed that during phase III each individual contraction propagated rapidly (75 ± 37 cm/min) over a 32 ± 10 cm segment of the jejunum. During phase II, most contractile activity corresponded to propagated contractile events which increased in frequency from early to late phase II (0.5 ± 0.9 vs 2.5 ± 1.3 events/10 min, respectively; p < 0.001). After meal ingestion, non-propagated activity increased, whereas propagated events were less frequent than during late phase II. CONCLUSIONS & INFERENCES: Jejunal motility analysis with high-resolution manometry identifies propagated contractile patterns which are not apparent with conventional manometric catheters.

Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from patients with MNGIE. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown, and ischemic abnormalities in MNGIE.NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE.

WCE polyp detection with triplet based embeddings.

Wireless capsule endoscopy is a medical procedure used to visualize the entire gastrointestinal tract and to diagnose intestinal conditions, such as polyps or bleeding. Current analyses are performed by manually inspecting nearly each one of the frames of the video, a tedious and error-prone task. Automatic image analysis methods can be used to reduce the time needed for physicians to evaluate a capsule endoscopy video. However these methods are still in a research phase. In this paper we focus on computer-aided polyp detection in capsule endoscopy images. This is a challenging problem because of the diversity of polyp appearance, the imbalanced dataset structure and the scarcity of data. We have developed a new polyp computer-aided decision system that combines a deep convolutional neural network and metric learning. The key point of the method is the use of the Triplet Loss function with the aim of improving feature extraction from the images when having small dataset. The Triplet Loss function allows to train robust detectors by forcing images from the same category to be represented by similar embedding vectors while ensuring that images from different categories are represented by dissimilar vectors. Empirical results show a meaningful increase of AUC values compared to state-of-the-art methods. A good performance is not the only requirement when considering the adoption of this technology to clinical practice. Trust and explainability of decisions are as important as performance. With this purpose, we also provide a method to generate visual explanations of the outcome of our polyp detector. These explanations can be used to build a physician's trust in the system and also to convey information about the inner working of the method to the designer for debugging purposes.

Motor dysfunction of the gut in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Cystic fibrosis transmembrane conductance regulator is extensively expressed in the intestine and has an important role in the regulation of the viscosity and pH of gut secretions. Several studies have reported a delay in small bowel and colonic transit times in patients with CF which have been attributed to the secretory dysfunction. Our aim was to determine whether intestinal contractility is affected in these patients. METHODS: Consecutive patients with CF referred to our institution between 2014 and 2017 (n = 16) were prospectively investigated using automated non-invasive techniques for morpho-functional evaluation of the gut developed in our laboratory. On separate days, intraluminal images of the gut were obtained by capsule endoscopy and external images by abdominal MRI. Analysis of images (endoluminal and external) was performed with original, previously validated programs based on computer vision and machine learning techniques and compared with age- and sex-matched controls. KEY RESULTS: Patients with CF exhibited important reduction in contractile activity and increased retention of static turbid luminal content in the small bowel by endoluminal image analysis. Morpho-volumetric analysis of MRI images found increased ileo-colonic volumes in CF. Significant correlations between abnormalities detected by intraluminal and external imaging techniques were found. The presence and severity of digestive symptoms were not related to abnormal gut function. CONCLUSION AND INFERENCES: Impaired transit and pooling of gut contents in patients with CF is associated with impaired intestinal motility.

Enteric neuron density correlates with clinical features of severe gut dysmotility.

Gastrointestinal (GI) symptoms can originate from severe dysmotility due to enteric neuropathies. Current methods used to demonstrate enteric neuropathies are based mainly on classic qualitative histopathological/immunohistochemical evaluation. This study was designed to identify an objective morphometric method for paraffin-embedded tissue samples to quantify the interganglionic distance between neighboring myenteric ganglia immunoreactive for neuron-specific enolase, as well as the number of myenteric and submucosal neuronal cell bodies/ganglion in jejunal specimens of patients with severe GI dysmotility. Jejunal full-thickness biopsies were collected from 32 patients (22 females; 16-77 yr) with well-characterized severe dysmotility and 8 controls (4 females; 47-73 yr). A symptom questionnaire was filled before surgery. Mann-Whitney U test, Kruskal-Wallis coupled with Dunn's posttest and nonparametric linear regression tests were used for analyzing morphometric data and clinical correlations, respectively. Compared with controls, patients with severe dysmotility exhibited a significant increase in myenteric interganglionic distance (P = 0.0005) along with a decrease in the number of myenteric (P < 0.00001) and submucosal (P < 0.0004) neurons. A 50% reduction in the number of submucosal and myenteric neurons correlated with an increased interganglionic distance and severity of dysmotility. Our study proposes a relatively simple tool that can be applied for quantitative evaluation of paraffin sections from patients with severe dysmotility. The finding of an increased interganglionic distance may aid diagnosis and limit the direct quantitative analysis of neurons per ganglion in patients with an interganglionic distance within the control range.NEW & NOTEWORTHY Enteric neuropathies are challenging conditions characterized by a severe impairment of gut physiology, including motility. An accurate, unambiguous assessment of enteric neurons provided by quantitative analysis of routine paraffin sections may help to define neuropathy-related gut dysmotility. We showed that patients with severe gut dysmotility exhibited an increased interganglionic distance associated with a decreased number of myenteric and submucosal neurons, which correlated with symptoms and clinical manifestations of deranged intestinal motility.

Gut epithelial and vascular barrier abnormalities in patients with chronic intestinal pseudo-obstruction.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances. METHODS: To test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4, and zonula occludens-1 (ZO-1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full-thickness biopsies using Western blot. KEY RESULTS: Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype. CONCLUSIONS & INFERENCES: The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.

Metabolomic signature of the postprandial experience.

BACKGROUND: Ingestion of a meal up to maximal tolerance induces unpleasant fullness sensation and changes in circulating metabolites. Our aim was to evaluate the relation between postprandial sensations and the metabolomic responses to a comfort meal. METHODS: In 32 non-obese healthy men, homeostatic sensations (hunger/satiety, fullness), hedonic sensations (digestive well-being, mood), and the metabolomic profile in plasma (low-molecular weight metabolites and lipoprotein profiles) were measured before and 20 minutes after a comfort meal (warm ham and cheese sandwich and juice; total 300 mL; 425 kcal). Perception was measured on 10 cm scales and the metabolomic response by nuclear magnetic resonance spectroscopy. KEY RESULTS: The comfort meal induced homeostatic sensations (satiety and fullness) associated with a positive hedonic reward (enhanced digestive well-being and mood) and a clear change in the metabolomic profile with a sharp discrimination between the pre and postprandial state by a non-supervised principal component analysis. The change in circulating metabolites correlated with the postprandial sensations: the increase in alanine correlated with the increase in fullness (R = 0.50; P = 0.004) and well-being (R = 0.50; P = 0.004); the increase in glucose correlated with the sensation of fullness (R = 0.40; P = 0.023) and enhanced mood (R = 0.41; P = 0.020). CONCLUSION AND INFERENCES: Metabolomic changes in the response to a meal may provide an objective index of the postprandial experience, which may have clinical implications in the management of patients with poor meal tolerance or meal-related symptoms.

Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders.

Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.

Effect of prucalopride on intestinal gas tolerance in patients with functional bowel disorders and constipation.

BACKGROUND AND AIM: Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation. METHODS: Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2 mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires. RESULTS: During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (≥ 200 mL) while on placebo. However, in those patients who had increased symptoms during the gas test (≥ 3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3 ± 0.5 mean score vs 3.5 ± 0.3 on placebo; P = 0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo. CONCLUSION: Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86).

The dysfunctional gut.

After many decades debating whether the clinical manifestations of patients with functional digestive symptoms originate "in their minds" or "in their guts," arguments remain strong on both sides of the controversy. However, advances in understanding of gut physiology and pathophysiology, and persuasive evidence on the bidirectionality of the regulatory traffic between the enteric and central nervous systems, are helping to characterize clinical situations in which we can legitimately speak of gut dysfunction, as opposed to others where symptoms are not associated with apparent or detectable gut disturbances and may truly represent somatization of an affective disorder. In this review, we describe available clinically applicable technology, albeit in specialized clinical research units, that may be used to discern whether or not challenging patients have gut sensory or motor disturbances. The practical yield of applying such methods to diagnostic investigation may be substantial, because it establishes a plausible mechanism of disease that may be used in patient management and patient persuasion, to remove uncertainties and to prevent futile repetition of conventional diagnostic tests. By evolving from symptom analysis to mechanism-based diagnosis, our gastroenterology community may progress toward the goal of delivering the full diagnostic spectrum from altered morphology to disturbed function.

Colonic responses to gas loads in subgroups of patients with abdominal bloating.

OBJECTIVES: We sought to evaluate colonic gas accommodation, ileocecal competence, and colonic clearance in subgroups patients with abdominal bloating. METHODS: Thirty-six patients complaining of abdominal bloating (12 constipation-predominant irritable bowel syndrome (IBS-C), 12 diarrhea-predominant irritable bowel syndrome (IBS-D), and 12 functional bloating) and 18 healthy controls were studied. Abdominal perception and girth were measured during: (i) 1 h continuous infusion of gas at 24 ml/min into the rectum (accommodation period) and (ii) 30 min free rectal gas evacuation (clearance period). In eight patients and eight healthy subjects, the gas infused was labeled with radioactive xenon (74 MBq (133)Xe), and gas distribution was determined by scintigraphy. RESULTS: Colonic gas accommodation produced significantly more abdominal symptoms and distension in patients than in healthy subjects (3.8+/-0.2 vs. 2.4+/-0.3 perception score; P<0.001; 10.9+/-0.6 vs. 8.3+/-0.5 mm girth increment; P=0.009). Scintigraphy showed no differences in colonic gas distribution and no ileal gas reflux, but patients exhibited impaired gas clearance from the proximal colon (63%+/-10% clearance in 30 min vs. 80%+/-2% in health; P=0.042), resulting in more residual gas (506+/-46 vs. 174+/-47 ml; P<0.001), perception (1.9+/-0.2 vs. 1.0+/-0.2 score; P=0.015), and girth increment (4.2+/-0.7 vs. 2.2+/-0.5 mm; P=0.024); IBS-C patients exhibited increased sensation and objective distension, as opposed to sensation only in IBS-D and distension only in functional bloating. CONCLUSIONS: Patients with abdominal bloating have normal colonic accommodation and ileocecal competence but impaired gas clearance from the proximal colon after retrograde infusion, and the consequences of this dysfunction are related to bowel habit.

New insight into intestinal motor function via noninvasive endoluminal image analysis.

BACKGROUND & AIMS: Evaluation of small bowel motility by intestinal manometry is invasive and requires expertise for interpretation. Our aim was to use capsule technology for evaluation of small bowel motor function based on a fully computerized image analysis program. METHODS: Thirty-six consecutive patients with severe intestinal motor disorders (19 fulfilling manometric criteria of intestinal dysmotility and 17 not) and 50 healthy subjects received the endoscopic capsule (Pillcam; Given Imaging, Yokneam, Israel). Endoluminal image analysis was performed with a computer vision program specifically developed for the detection of contractile patterns (phasic luminal closure and radial wrinkles by wall texture analysis), noncontractile patterns (tunnel and wall appearance by Laplacian filtering), intestinal content (by color decomposition analysis), and endoluminal motion (by chromatic stability). Automatic classification of normal and abnormal intestinal motility was performed by means of a machine-learning technique. RESULTS: As compared with healthy subjects, patients exhibited less contractile activity (25% less phasic luminal closures, P < .05) and more noncontractile patterns (151% more tunnel pattern, P < .05), static sequences (56% more static images, P < .01), and turbid intestinal content (94% more static turbid images, P < .01). On cross validation, the classifier identified as abnormal all but 1 patient with manometric criteria of dysmotility and as normal all healthy subjects. Out of the 17 patients without manometric criteria of dysmotility, 11 were identified as abnormal and 6 as normal. CONCLUSIONS: Our study shows that endoluminal image analysis, by means of computer vision and machine-learning techniques, constitutes a reliable, noninvasive, and automated diagnostic test of intestinal motor disorders.