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Constipation; Intestinal manometry; Intestinal neuropathy Restrenyiment; Manometria intestinal; Neuropatia intestinal Estreñimiento; Manometría intestinal; Neuropatía intestinal Introduction Minute rhythm and prolonged simultaneous contractions are patterns of postprandial small bowel contractile activity that historically have been considered as suggestive of mechanical intestinal obstruction; however, these patterns have been also encountered in patients with motility-like symptoms in the absence of bowel obstruction. The objective of this study was to determine the current diagnostic outcome of patients with these intestinal manometry patterns. Methods Retrospective study of patients with chronic digestive symptoms evaluated by intestinal manometry at our center between 2010 and 2018. Results The minute rhythm (MRP) or prolonged simultaneous contractions (PSC) postprandial patterns were detected in 61 of 488 patients (55 MRP and 6 PSC). Clinical work-up detected a previously non-diagnosed partial mechanical obstruction of the distal intestine in 10 (16%) and a systemic disorder causing intestinal neuropathy in 32 (53%). In the remaining 19 patients (31%, all with MRP), the origin of the contractile pattern was undetermined, but in 16, substantial fecal retention was detected within 7 days of the manometric procedure by abdominal imaging, and in 6 of them colonic cleansing completely normalized intestinal motility on a second manometry performed within 39 ± 30 days. Conclusion and Inference Currently, the most frequent origin of MRP and PSC encountered on small bowel manometry is intestinal neuropathy, while a previously undetected mechanical obstruction is rare. Still, in a substantial proportion of patients, no underlying disease can be identified, and in them, colonic fecal retention might play a role, because in a subgroup of these patients, manometry normalized after colonic cleansing. Hence, colonic preparation may be considered prior to intestinal manometry. This work was supported by the Instituto de Salud Carlos III and co-financed by the European Union (FEDER/FSE) [PI17/01794]; Spanish Ministry of Economy and Competitiveness (Dirección General de Investigación Científica y Técnica) [SAF 2016-76648-R]; Ciberehd is funded by the Instituto de Salud Carlos III. LA was supported by the Instituto de Salud Carlos III (CM20/00182).

Our purpose was to review the most recent publications on nutritional management in gastroparesis, and their relevance for global management of gastroparesis.The last months, several reviews on gastroparesis have been published as well as excellent reviews on the nutritional management of patients suffering this condition. In these publications, the relevance of nutrition in management of gastroparesis has been highlighted. However, alarming studies have been published from several authors from Europe and the United States showing that a majority of patients did not follow any dietary advice from a specialist in nutrition, most patients start restrictive diets by their own, and that as much as 60% of patients have a caloric-deficient diet. In addition, recent studies show that some of the recommendations, like a radical exclusion of fibers from the diet, may be reconsidered taking into account the potential beneficial effects of fibers in global health.Nutritional interventions are one of the cornerstones in management of gastroparesis. Consequently, an interdisciplinary approach, with managing teams composed by gastroenterologist and specialist in nutrition should be the correct strategy to achieve the best outcomes in symptom control and prevention of complications related to nutritional deficits.http://links.lww.com/COCN/A17.

Colonic distension; High-resolution manometry; Small bowel motility Distensió colònica; Manometria d'alta resolució; Motilitat de l'intestí prim Distensión colónica; Manometría de alta resolución; Motilidad del intestino delgado Background Abnormal motility patterns in the jejunum can be detected in patients with prominent colonic content, and these abnormalities may be due to either a primary jejunal dysfunction or a reflex distortion. The objective of the present study was to determine the effect of colonic distension on small bowel postprandial motility using high-resolution manometry. Methods Single center, controlled, parallel, randomized, single blind study in healthy subjects testing the effect of colonic filling vs sham infusion on the responses to a meal in 16 healthy subjects. Nutrients were continuously infused in the proximal jejunum (2 Kcal/min) during the 2-h study period to induce a steady-state postprandial motor pattern. Jejunal motility was measured by water-perfused, high-resolution manometry. After 1 h postprandial recording (basal period), gas was infused during 7.5 min via a rectal tube (720 mL or sham infusion), and jejunal motility was recorded for another hour. Key Results Jejunal postprandial motility during the basal period was characterized by two overlapping components: a) continuous segmental activity (non-propagated or shortly propagated) and b) intercurrent propagated fronts (3.8 ± 1.1 fronts of 2-5 clustered contractions/h >10 cm propagation). As compared to sham infusion, colonic gas filling: a) inhibited continuous segmental contractile activity (by 17 ± 4%; p = 0.044 vs control group) and b) stimulated intermittent propagated fronts (up to 9.0 ± 2.2 fronts/h; p = 0.017 vs control group). Conclusions and Inferences Long retrograde reflexes induced by colonic distension distort the balance between segmental and propagated activity, and may affect the normal response of the jejunum to food ingestion. Jejunal manometry in patients may be artifacted by colonic overload.

Microanatomical dissection; Mitochondrial disorders; MtDNA depletion Disección microanatómica; Trastornos mitocondriales; Agotamiento del ADNmt Dissecció microanatòmica; Trastorns mitocondrials; Esgotament de l'ADNmt 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. The work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca-Dipartimenti eccellenti on the Project Personalized medicine. LC and VC are supported by the Italian Ministry of Health (Ricerca Corrente 2021 funding). RDG is supported by funds from the University of Ferrara.

Altres ajuts: acords transformatius de la UAB 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.

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/mm(2) 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.

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.

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.

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).

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 baseline 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., 19 pages, 13 figures, 9 tables, Accepted in Computerized Medical Imaging and Graphics

Background We have previously shown that meal ingestion induces cognitive perception (sensations) with a hedonic dimension (well-being) that depends on the characteristics of the meal and the appropriateness of the digestive response. The aim of the present study is to identify metabolomic biomarkers of the cognitive response to meal ingestion. Methods In 18 healthy subjects, the response to a test meal (Edanec, 1 kcal/mL) ingested until maximum satiation (50 mL/min) was assessed. Perception measurements and blood samples were taken before, at the end of the meal, and 20 min after ingestion. The cognitive response and the hedonic dimension were measured on 10 cm scales. Metabolomic analysis was performed using nuclear magnetic resonance (NMR) spectroscopy and values of triglycerides, insulin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were determined using conventional laboratory techniques. Key Results Ingestion up to maximum satiation induced sensation of fullness and decreased digestive well-being. The total amount ingested by each subject correlated with the basal sensation of hunger, but not with other sensations or blood metabolite levels. Immediately after ingestion, satiation correlated with an increase in glucose (R = 0.49; p = 0.038) and valine levels (R = 0.48; p = 0.043). Twenty-minutes after finalizing ingestion, triglyceride levels had significantly increased which correlated with the recovery in well-being (R = 0.48; p = 0.046) and the decrease in desire to eat a food of choice (R = −0.56; p = 0.016). The increase in lipids inversely correlated with abdominal discomfort (R = −0.51; p = 0.032). Conclusions & Inferences Cognitive and hedonic responses to meal ingestion correlate with changes in circulating metabolites, which may serve as objective biomarkers of perception.

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.

Gas-bloat syndrome refers to a three-faceted clinical picture: the patient feels bloated; the abdomen distends; and the individual may verbalize the discomfort as suffering from “too much gas.” Nowadays, it is more often designated and classified as functional bloating by the Rome criteria (with or without abdominal distension). The gas-bloat syndrome is produced by several interacting mechanisms including excess accumulation of intra-luminal air and/or fluid in the gut, visceral hypersensitivity, and abnormal viscera-somatic reflexes that reshape the abdominal cavity creating the appearance of distension. The diagnosis is largely clinical, but specialized imaging, breath tests, and more sophisticated motility tests may be helpful in selected cases. Treatment is tailored to symptom severity and patient concerns, ranging from simple reassurance to dietary modification and pharmacotherapy to help clear retained stool in patients with constipation, reduce gas production, decrease visceral hypersensitivity, and correct abnormal chest-diaphragm-abdominal muscle activity by biofeedback.

BACKGROUND: Chronic-intestinal-pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent sub-occlusive episodes. Although neuro-muscular-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 neuro-epithelial 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), as well as 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.

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.

Prebiotics and diets low in fermentable oligo-, di-, mono-saccharides and polyols (low-FODMAP diet) might reduce symptoms in patients with functional gastrointestinal disorders, despite reports that some nonabsorbable, fermentable meal products (prebiotics) provide substrates for colonic bacteria and thereby increase gas production. We performed a randomized, parallel, double-blind study of patients with functional gastrointestinal disorders with flatulence. We compared the effects of a prebiotic supplement (2.8 g/d Bimuno containing 1.37 g beta-galactooligosaccharide) plus a placebo (Mediterranean-type diet (prebiotic group, n = 19) vs a placebo supplement (2.8 g xylose) plus a diet low in FODMAP (low-FODMAP group, n = 21) for 4 weeks; patients were then followed for 2 weeks. The primary outcome was effects on composition of the fecal microbiota, analyzed by 16S sequencing. Secondary outcomes were intestinal gas production and digestive sensations. After 4 weeks, we observed opposite effects on microbiota in each group, particularly in relation to the abundance of Bifidobacterium sequences (increase in the prebiotic group and decrease in the low-FODMAP group; P = .042), and Bilophila wadsworthia (decrease in the prebiotic group and increase in the low-FODMAP group; P = .050). After 4 weeks, both groups had statistically significant reductions in all symptom scores, except reductions in flatulence and borborygmi were not significant in the prebiotic group. Although the decrease in symptoms persisted for 2 weeks after patients discontinued prebiotic supplementation, symptoms reappeared immediately after patients discontinued the low-FODMAP diet. Intermittent prebiotic administration might therefore be an alternative to dietary restrictions for patients with functional gut symptoms. ClinicalTrials.gov no.: NCT02210572.