New insights into the characterization of the mechanism of action of hyoscine butylbromide in the human colon ex vivo.

INTRODUCTION: Hyoscine butylbromide (HBB) is one of the most used antispasmodics in clinical practice. Recent translational consensus has demonstrated a similarity between human colonic motor patterns studied ex vivo and in vivo, suggesting ex vivo can predict in vivo results. It is unclear whether the mechanism of action of antispasmodics can predict different use in clinical practice. The aim of the present study is to bridge this gap dissecting HBB's role in excitatory and inhibitory neural pathways. METHODS: 309 colon samples from 48 patients were studied in muscle bath experiments. HBB was tested on: 1-spontaneous phasic contractions (SPCs); 2-carbachol-induced contractility; electrical field stimulation (EFS)-induced selective stimulation of 3-excitatory and 4-inhibitory pathways and 5- SPCs and EFS-induced contractions enhanced by neostigmine. Atropine, AF-DX116 (M2 blocker) and DAU-5884 (M3 blocker) were used as comparators. RESULTS: In the presence of tetrodotoxin (TTX), HBB and atropine 1 µM reduced SPCs. HBB and atropine concentration-dependently reduced carbachol- and EFS-induced contractions. Inhibitory effects of DAU-5884 on EFS-induced contractions were more potent than of AF-DX116. HBB did not affect the off-response associated to neural inhibitory responses. Neostigmine enhanced both SPCs and EFS-induced contractions. In the presence of TTX and ω-conotoxin (GVIA), neostigmine still enhanced SPCs. Addition of HBB and atropine reduced these responses. CONCLUSIONS: This study demonstrates that HBB inhibits neural cholinergic contractions associated to muscarinic (mainly M3) receptors. HBB has a potential role in reducing colonic spasm induced by the release of acetylcholine from enteric motor neurons and from an atypical source including a potential non-neuronal origin.

Organization of neurogastroenterology and motility units with a multidisciplinary, patient-centered perspective.

Neurogastroenterology and Motility is a subspecialty of Gastroenterology dedicated to the management of gastrointestinal (GI) motor diseases and disorders of gut- brain interaction (DGBI). Both types of conditions may impair the nutritional status of the patients. In the case of motility disorders, because a deficient gastrointestinal motility may impair the correct digestion and absorption of foods. In DGBI because development of gastrointestinal symptoms may impair the correct nutrition of the patient. In both cases, different studies have shown that patients start restrictive diets by their own, without supervision of a dietician, leading to nutritional deficits in many cases. Likewise, psychological factors like stress situations or anxiety may trigger gastrointestinal symptoms in these patients, mainly in those with DGBI. Recent studies comparing a patient-centered approach that includes medical treatment, dietary modifications, and behavioural interventions with the gastroenterologist-only standard care, have shown a greater proportion of symptom improvement, psychological state and quality of life, as well as reduced costs in patients allocated to the multidisciplinary treatment. In conclusion, there is growing evidence in favour of dietary and behavioural interventions by specialized professionals, coupled with an appropriate medical evaluation and treatment by a gastroenterologist. Hence, the importance to develop reference units in which comprehensive and individualized management can be offered. Multidisciplinary models improve clinical outcomes and patient satisfaction, which should result in a reduction of direct and indirect costs. .

Current insights on chronic intestinal dysmotility: pseudo-obstruction and enteric dysmotility.

Chronic intestinal dysmotility is a rare and debilitating digestive disorder characterized by symptoms of mechanical obstruction without an organic lesion. It has diverse causes and involves various pathological mechanisms. Small bowel manometry is the preferred diagnostic method, particularly for patients with severe and progressive symptoms. The condition can be categorized as intestinal pseudo-obstruction and enteric dysmotility, both entities share abnormal small bowel motility, but with important differences in prognosis and management.

Sobrecrecimiento bacteriano intestinal. Documento de posicionamiento ASENEM-SEPD / Small intestinal bacterial overgrowth. A position paper of ASENEM-SEPD

El sobrecrecimiento bacteriano intestinal (SIBO, por sus siglas en inglés) es una entidad descrita desde hace varias décadas, pero que en los últimos años ha cobrado un especial interés por parte de los profesionales médicos y por la población general, probablemente por el aumento de la disponibilidad de pruebas diagnósticas y por la extensa difusión que se le ha dado a esta enfermedad a través de los medios de comunicación y redes sociales. En vista de la gran cantidad de información disponible en la actualidad y en ocasiones discrepante, entre la Sociedad Española de Patología Digestiva (SEPD) y la Asociación Española de Neurogastroenterología y Motilidad (ASENEM) hemos realizado un documento de posicionamiento para establecer líneas de diagnóstico y tratamiento del SIBO con la información científica actualizada.(AU)

Small intestinal bacterial overgrowth. A position paper of ASENEM-SEPD.

Small intestinal bacterial overgrowth (SIBO) is a condition that was described decades ago and has recently aroused special interest among both medical professionals and the general population, likely because of increased availability of diagnostic testing and extensive coverage by the media and social networks. In view of the large amount of-often conflicting-information available, the need has arisen to develop a joint position paper of the Sociedad Española de Patología Digestiva (SEPD) and Asociación Española de Neurogastroenterología y Motilidad (ASENEM) to discuss up-to-date scientific information.

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.

Anatomical landmarks localization for capsule endoscopy studies.

Wireless Capsule Endoscopy is a medical procedure that uses a small, wireless camera to capture images of the inside of the digestive tract. The identification of the entrance and exit of the small bowel and of the large intestine is one of the first tasks that need to be accomplished to read a video. This paper addresses the design of a clinical decision support tool to detect these anatomical landmarks. We have developed a system based on deep learning that combines images, timestamps, and motion data to achieve state-of-the-art results. Our method does not only classify the images as being inside or outside the studied organs, but it is also able to identify the entrance and exit frames. The experiments performed with three different datasets (one public and two private) show that our system is able to approximate the landmarks while achieving high accuracy on the classification problem (inside/outside of the organ). When comparing the entrance and exit of the studied organs, the distance between predicted and real landmarks is reduced from 1.5 to 10 times with respect to previous state-of-the-art methods.

End to End Colonic Content Assessment: ColonMetry Application.

The analysis of colonic contents is a valuable tool for the gastroenterologist and has multiple applications in clinical routine. When considering magnetic resonance imaging (MRI) modalities, T2 weighted images are capable of segmenting the colonic lumen, whereas fecal and gas contents can only be distinguished in T1 weighted images. In this paper, we present an end-to-end quasi-automatic framework that comprises all the steps needed to accurately segment the colon in T2 and T1 images and to extract colonic content and morphology data to provide the quantification of colonic content and morphology data. As a consequence, physicians have gained new insights into the effects of diets and the mechanisms of abdominal distension.

Clinical significance of small bowel manometry patterns suggestive of intestinal obstruction.

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.

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.

Nutritional challenges in patients with gastroparesis.

PURPOSE OF REVIEW: Our purpose was to review the most recent publications on nutritional management in gastroparesis, and their relevance for global management of gastroparesis. RECENT FINDINGS: 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. SUMMARY: 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. VIDEO ABSTRACT: http://links.lww.com/COCN/A17.

Effect of colonic distension on small bowel motility measured by jejunal high-resolution manometry.

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.

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.

The role of liver steatosis as measured with transient elastography and transaminases on hard clinical outcomes in patients with COVID-19.

Liver injury has been widely described in patients with Coronavirus disease 2019 (COVID-19). We aimed to study the effect of liver biochemistry alterations, previous liver disease, and the value of liver elastography on hard clinical outcomes in COVID-19 patients. We conducted a single-center prospective observational study in 370 consecutive patients admitted for polymerase chain reaction (PCR)-confirmed COVID-19 pneumonia. Clinical and laboratory data were collected at baseline and liver parameters and clinical events recorded during follow-up. Transient elastography [with Controlled Attenuation Parameter (CAP) measurements] was performed at admission in 98 patients. All patients were followed up until day 28 or death. The two main outcomes of the study were 28-day mortality and the occurrence of the composite endpoint intensive care unit (ICU) admission and/or death. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at admission in 130 patients (35%) and 167 (45%) patients, respectively. Overall, 14.6% of patients presented the composite endpoint ICU and/or death. Neither ALT elevations, prior liver disease, liver stiffness nor liver steatosis (assessed with CAP) had any effect on outcomes. However, patients with abnormal baseline AST had a higher occurrence of the composite ICU/death (21% versus 9.5%, p = 0.002). Patients ⩾65 years and with an AST level > 50 U/ml at admission had a significantly higher risk of ICU and/or death than those with AST ⩽ 50 U/ml (50% versus 13.3%, p < 0.001). In conclusion, mild liver damage is prevalent in COVID-19 patients, but neither ALT elevation nor liver steatosis influenced hard clinical outcomes. Elevated baseline AST is a strong predictor of hard outcomes, especially in patients ⩾65 years.

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.

Sex Differences and Commonalities in the Impact of a Palatable Meal on Thalamic and Insular Connectivity.

The neural mechanisms underlying subjective responses to meal ingestion remain incompletely understood. We previously showed in healthy men an increase in thalamocortical, and a decrease in insular-cortical connectivity in response to a palatable meal. As sex is increasingly recognized as an important biological variable, we aimed to evaluate sex differences and commonalities in the impact of a well-liked meal on thalamic and anterior insular connectivity in healthy individuals. Participants (20 women and 20 age-matched men) underwent resting-state magnetic resonance imaging (rsMRI) before and after ingesting a palatable meal. In general, the insula showed extensive postprandial reductions in connectivity with sensorimotor and prefrontal cortices, while the thalamus showed increases in connectivity with insular, frontal, and occipital cortices, in both women and men. However, reductions in insular connectivity were more prominent in men, and were related to changes in meal-related sensations (satiety and digestive well-being) in men only. In contrast, increases in thalamic connectivity were more prominent in women, and were related to changes in satiety and digestive well-being in women only. These results suggest that brain imaging may provide objective and sex-specific biomarkers of the subjective feelings associated with meal ingestion.

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.