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Patient-derived organoids provide a unique model system to explore disease-causing mutations ex vivo. By using organoids from duodenal or colonic biopsies of pediatric patients with intestinal epithelial disorders, we can directly assay the patient cells to tailor treatment to their unique disease state. The advent of organoid technology from patients with severe intestinal disorders such as Congenital Diarrhea Enteropathies (CoDE) and Very-Early-Onset Inflammatory Bowel Disease (VEO-IBD) has allowed for rapid advances in the understanding of and the treatment of these monogenic disorders. Still, the expansion of these lines for scalable studies is not trivial, and success rates of expansion are variable between groups, and even lab members within the same group. These protocols have been validated on patients with CoDE or VEO-IBD and age-matched control patients. Here, we present our recommended protocols for the cultivation of organoids from pediatric patients with CoDE and VEO-IBD. These protocols have been validated on organoids generated from the duodenum (duodenoids), ileum (ileoids), colon (colonoids) and iPSC-derived intestinal colonoids from pediatric healthy donors or donors with CoDE or VEO-IBD (Gwilt et al., 2023). Using our modified culture media, extended culture times from biopsy preparation and thawing frozen lines, gentle passaging techniques with the incomplete removal of the organoids from the matrigel, and modified monolayer protocols (Maeda et al., 2023; Maeda et al., 2022), we have been able to successfully culture and expand several lines for more than 5 years. The conditions and protocols used here provide a basis for reproducible phenotypes, scaling for larger functional studies on patient lines, and for reproducibility of results between several investigators. We provide a useful starting point and troubleshooting guidelines for the optimization of culturing organoids from any patient with novel disease pathology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bugda Gwilt, Thiagarajah. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations., Methods: All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated., Results: Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association., Conclusions: The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers., (© 2024. The Author(s).)

The exocrine pancreas is the main source of digestive enzymes which are released from secretory vesicles of acinar cells into the small intestine. Enzymes, including amylases, proteases and lipases, degrade the ingested food and thus determine the nutritional substrate for the gut microbiota. Acute (AP) and chronic pancreatitis (CP) are associated with a transitional or progressive exocrine pancreatic dysfunction, we analysed in the present study how an experimental induction of pancreatitis in mouse models affects the colonic and duodenal microbiome composition. Evaluation by 16 S rRNA gene sequencing revealed specific microbiome changes in colonic as well as in duodenal samples in different models of AP and CP. Mild acute pancreatitis, which is associated with a transient impairment of pancreatic secretion showed only minor changes in microbial composition, comparable to the ones seen in progressive dysfunctional mouse models of CP. The strongest changes were observed in a mouse model of severe AP, which suggest a direct effect of the immune response on gut microbiome in addition to a pancreatic dysfunction. Our data indicate that highly dysbiotic microbiome changes during pancreatitis are more associated with the inflammatory reaction than with a disturbed pancreatic secretion., (© 2024. The Author(s).)

BACKGROUND Pseudomelanosis duodeni (PD) is a rare incidental endoscopic finding characterized by flat, discrete speckles of dark pigment, usually in the proximal duodenum. PD is associated with chronic conditions, including end-stage renal disease, hypertension, and diabetes, and with certain medications, including oral iron supplements and sulfur-containing antihypertensives. CASE REPORT A 56-year-old woman presented with lower abdominal pain, intermittent rectorragia, and a history of peptic ulcer disease and iron-deficiency anemia, treated with oral iron supplements. She was hemodynamically stable, and laboratory test results were pertinent only for microcytic anemia. In the workup of iron-deficiency anemia, esophagogastroduodenoscopy was performed, showing findings suspicious for PD, which was confirmed by pathology. Colonoscopy revealed large internal hemorrhoids, and hemorroidectomy was scheduled during the same admission. Duodenum biopsies showed edematous villosities and large clusters of pigmented macrophages, with golden-brown cytoplasm positively stained with Perl's Prussian blue stain, indicating the presence of iron inside the macrophages. These findings confirmed the PD diagnosis. The pigment in PD is composed primarily of iron and sulfur, with iron being the main component, as seen in staining. In our case, we present findings of PD along with lower gastrointestinal bleeding manifesting as hemmoroidal bleeding. Giving the anatomical nature of hemorrhoids and that our patient was on oral iron therapy, the most likely mechanism behind the development of PD in our case was related to the oral iron therapy. CONCLUSIONS PD is a benign disorder of the duodenum. Further studies are needed to investigate its long-term outcomes and to formulate optimal management strategies.

Background: Conservative treatment of chronic pancreatitis has only a limited effect in most patients. Surgery offers very good long-term results, even in the early stages of the disease. Unfortunately, only a minority of patients undergo surgical treatment. The aim of this work was to summarise the current treatment options for patients with an inflammatory mass of the pancreatic head. Data from patients in our study demonstrates that the surgery is a safe method, and here we compare the perioperative and early postoperative outcomes of patients who underwent a pancreatoduodenectomy and duodenum-preserving pancreatic head resection for chronic pancreatitis., Methods: All patients who underwent a pancreaticoduodenectomy or a duodenum-preserving pancreatic head resection in our department between 2014 and 2022 were included in this study. Perioperative and early postoperative results were statistically analysed and compared., Results: Thirty-eight pancreaticoduodenectomies and 23 duodenum-preserving pancreatic head resections were performed. The overall mortality was 3%, whereas the in-hospital mortality after pancreaticoduodenectomy was 5%. The mortality after duodenum-preserving pancreatic head resection was 0%. No statistically significant differences in the hospital stay, blood loss, and serious morbidity were found in either surgery. Operative time was significantly shorter in the duodenum-preserving pancreatic head resection group., Conclusions: Both pancreatoduodenectomy and duodenum-preserving pancreatic head resection are safe treatment options. Duodenum-preserving pancreatic head resection showed a statistically significant superiority in the operative time compared to pancreaticoduodenectomy. Although other monitored parameters did not show a statistically significant difference, the high risk of complications after pancreaticoduodenectomy with a mortality of 5%; maintenance of the duodenum and upper loop of jejunum, and lower risk of metabolic dysfunctions after duodenum-preserving pancreatic head resection may favour duodenum-preserving pancreatic head resection in recommended diagnoses. Attending physicians should be more encouraged to use a multidisciplinary approach to assess the suitability of surgical treatment in patients with chronic pancreatitis., (© 2024. The Author(s).)

Objective: Gastrointestinal illnesses have been reported in relation to low disaccharidase activity, yet both the prevalence of disaccharidase deficiency and its association with gastrointestinal symptoms and irritable bowel syndrome (IBS) are largely unknown. We aimed to determine the association between low activity of disaccharidase enzymes on gastrointestinal symptoms and presence of IBS., Methods: Patients referred for gastroscopic examination due to gastrointestinal complaints were consecutively included. A pinch biopsy was taken from the distal part of duodenum, and disaccharidase activity was measured using the Dahlqvist method. Gastrointestinal symptom severity was measured using IBS-Symptom Severity Score (IBS-SSS)., Results: A total of 40 patients were included. Disaccharidase deficiency was detected in 24 patients (60%). Half of the patients ( n  = 21) had IBS according to Rome IV criteria. A majority (75%) of all patients reported moderate to severe gastrointestinal symptoms. Moderate to severe gastrointestinal symptoms were reported by 16 patients (67%) with disaccharidase deficiency and in 14 patients (88%) with normal disaccharidase activity. Lactase deficiency was detected in 22 patients (55%), maltase deficiency in 11 patients (28%), sucrase deficiency in 9 patients (23%), isomaltase deficiency in 13 patients (33%) and glucoamylase deficiency in 12 patients (30%). The activity of all enzymes was reduced in 8 patients (20%). Degree of disaccharidase deficiency was not associated with either the severity of gastrointestinal symptoms or the diagnosis of IBS. Enzymes levels were not associated with gastrointestinal symptom scores., Conclusion: Our findings did not reveal any association between biochemically measured disaccharidase deficiency and gastrointestinal symptoms or the presence of IBS.

Competing Interests: Conflicts of interest The authors declared that they have no conflicts of interest to this work.

Competing Interests: Declaration of competing interest The author has no financial or other conflicts of interest to disclose.

Background: Gastrointestinal dysfunction has emerged as a prominent early feature of Parkinson's Disease, shedding new light on the pivotal role of the enteric nervous system in its pathophysiology. However, the role of immune-cell clusters and inflammatory and glial markers in the gut pathogenetic process needs further elucidation., Objectives: We aimed to study duodenum tissue samples to characterize PD's enteric nervous system pathology further. Twenty patients with advanced PD, six with early PD, and 18 matched controls were included in the PADUA-CESNE cohort., Methods: Duodenal biopsies from 26 patients with early to advanced stage PD and 18 age-matched HCs were evaluated for the presence of surface markers (CD3+, CD4+, CD8+, CD20+, CD68+, HLA-DR), presence of misfolded alpha-synuclein and enteric glial alteration (GFAP). Correlation of immulogic pattern and clinical characteristic were analyzed., Results: The findings validate that in patients with Parkinson's Disease, the activation and reactive gliosis are linked to the neurodegeneration triggered by the presence of misfolded alpha-synuclein in the enteric nervous system. This process intensifies from the initial to the advanced stages of the disease. The clusters of T- and B-lymphocytes in the enteric system, along with the overall expression of HLA-DR in antigen-presenting cells, exceeded those in the control group. Conversely, no differences in terms of macrophage populations were found., Conclusions: These findings broaden our understanding of the mechanisms underlying the enteric nervous system's involvement in PD and point to the gastrointestinal system as a potential therapeutic target, especially in the early stages of the disease. Moreover, our results propose a role of T- and B-lymphocytes in maintaining inflammation and ultimately influencing alpha-synuclein misfolding and aggregation., Competing Interests: Declaration of competing interest The authors declare no disclosures or conflicts of interest related to the manuscript's content., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800 mg/kg), M(1600 mg/kg), H(3200 mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Calprotectin, a damage-associated molecular pattern protein of the S100/calgranulin family, is a potential marker of gastrointestinal inflammation in dogs and mainly originates from activated macrophages and granulocytes. Increased calprotectin concentrations are reported in feces and serum samples from dogs with chronic inflammatory enteropathy (CIE), but mucosal calprotectin expression has not been extensively investigated in canine CIE. Thus, we aimed to evaluate gastrointestinal mucosal concentrations of calprotectin in 62 dogs (44 dogs with CIE compared to 18 healthy Beagles) using a particle-enhanced turbidimetric immunoassay method. Additionally, we assessed the relationship of gastric, duodenal, jejunal, ileal, and colonic mucosal calprotectin levels with the clinical disease severity (canine clinical inflammatory bowel disease activity index, CIBDAI), histopathologic findings, clinical outcome, and serum albumin concentrations to further evaluate the potential of calprotectin as a biomarker for CIE., Results: Mucosal calprotectin concentrations in dogs with CIE were significantly higher in the duodenum (median: 276.2 μg/g) and colon (median: 298.2 μg/g) compared to healthy controls (median: 94.3 μg/g, P = 0.0039; and median: 112.0 μg/g, P = 0.0061). Similar numerical differences in the ileum and cecum were not statistically significant, and mucosal calprotectin concentrations correlated significantly among the different gastrointestinal segments. Histologic lesion severity was linked to mucosal calprotectin concentrations for inflammatory and structural histology criteria in the duodenum and colon (all P < 0.05). Higher mucosal calprotectin levels in the duodenum and across all segments correlated with lower serum albumin concentrations (both P < 0.05); duodenal mucosal calprotectin concentrations were more than sixfold higher in hypoalbuminemic dogs (median: 1441 µg/g, n = 4) than normoalbuminemic dogs (median: 227 µg/g, n = 40). There was no significant association of mucosal calprotectin levels with CIBDAI scores or individual clinical outcomes., Conclusions: These results show that duodenal and colonic mucosal calprotectin concentrations are increased in dogs with CIE, providing further supporting evidence for the diagnostic potential of fecal calprotectin (presumably reflecting mucosal) concentrations and in dogs with CIE. Further longitudinal research is needed to assess changes in mucosal calprotectin concentrations with clinical response to treatment vs. mucosal disease remission and to determine the clinical utility of fecal calprotectin concentrations to diagnose and monitor dogs with CIE in clinical practice., (© 2024. The Author(s).)

Introduction: Duodenal eosinophilia has been implicated in the pathophysiology of functional dyspepsia. In a retrospective observational study, we previously reported that duodenal eosinophilia (as defined by a mucosal count of greater than 15 eosinophils per 5 high power fields), was associated with symptomatic erosive gastroesophageal reflux disease (GERD), concomitant co-morbidities and Chinese ethnicity but not functional dyspepsia among 289 multiracial subjects undergoing diagnostic endoscopy in 2019 before the COVID-19 pandemic. We tested the reproducibility of those findings on a larger sample that included the original cohort and another 221 subjects who underwent endoscopy in 2022 after the easing of pandemic restrictions., Materials and Methods: Archived duodenal histology slides were assessed by a pathologist blind to demographic and clinical data gleamed retrospectively from clinical chart review. Logistic regression analysis was used to explore associations between duodenal eosinophilia and the variables age, gender, ethnicity, year of sampling (2019 vs 2022), concomitant co-morbidities, functional dyspepsia, symptomatic erosive GERD (Los Angeles Grades A to D), endoscopic oesophagitis, gallstone disease, Helicobacter pylori infection, irritable bowel syndrome and NSAID consumption. Three different thresholds for defining duodenal eosinophilia (>15, >22 and >30 eosinophils per 5 high power fields) were tested., Results: Year of sampling (2019, pre-pandemic) strongly predicted duodenal eosinophilia across all thresholds (OR 11.76, 13.11 and 21.41 respectively; p = 0.000). The presence of concomitant co-morbidities was a modest predictor across all thresholds whereas Chinese ethnicity only predicted at the lowest threshold. Absolute duodenal eosinophil counts predicted symptomatic erosive GERD (OR 1.03; p = 0.015) but not functional dyspepsia (OR 1.00; p = 0.896) after adjusting for age, gender, ethnicity, concomitant comorbidities and year of endoscopy. None of the subjects reached the threshold for the diagnosis of eosinophilic duodenitis., Conclusion: The cumulative impact of environmental exposures on duodenal eosinophil counts may be much greater than of putative factors linked to functional dyspepsia. A signal linking duodenal eosinophil counts and symptomatic erosive GERD was detected.

Background: Environmental enteric dysfunction (EED) is an inflammatory condition of the small intestine that is prevalent in children residing in low- and middle-income countries. EED is accompanied by profound histopathologic changes in the small bowel, loss of absorptive capacity, increased intestinal permeability, increased microbial translocation, and nutrient loss., Objectives: We sought to identify dysregulated genes and pathways that might underlie pediatric EED., Methods: RNA-sequencing libraries were generated from endoscopically obtained duodenal tissue from undernourished children with EED from 3 prospective cohorts of children with EED. The EED transcriptome was defined in comparison to North American children without EED. Weighted gene coexpression network analysis (WGCNA) was tested for gene modules associated with EED and its histologic features., Results: The 1784 upregulated genes in EED were highly enriched for immune and inflammatory processes, including IL-17 and JAK-STAT signaling, and cytokine-cytokine receptor interactions. The 1388 downregulated genes included genes corresponding to xenobiotic metabolism, detoxification, and antioxidant capacities. A gene coexpression module enriched for antimicrobial responses and chemokine activity was significantly associated with villous blunting, goblet cell depletion, and overall histologic severity of EED., Conclusions: The transcriptome signatures of EED include specific innate and adaptive immune responses that are consistently elevated across study centers, coupled with reduced detoxification and antioxidant capacities. These data may have implications for targeted interventions to improve EED outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is characterized by reduced absorptive capacity and barrier function of the small intestine, leading to poor ponderal and linear childhood growth., Objectives: To further define gene expression patterns that are associated with EED to uncover new pathophysiology of this disorder., Methods: Duodenal biopsies from cohorts of children with EED from Bangladesh, Pakistan and Zambia were analyzed by immunohistochemistry (IHC) to interrogate gene products that distinguished differentiation and various biochemical pathways in immune and epithelial cells, some identified by prior bulk RNA sequence analyses. Immunohistochemical staining was digitally quantified from scanned images and compared to cohorts of North American children with celiac disease (gluten-sensitive enteropathy) or with no known enteric disease and no pathologic abnormality (NPA) detected in their clinical biopsies., Results: After multivariable statistical analysis, we identified statistically significant (P < 0.05, 2-tailed t-test) elevated signals representing cluster of differentiation 45 (80%; 95% confidence interval [CI]: 24%, 127%), lipocalin 2 (659%; 95% CI: 198%, 1838%), and regenerating family 1 beta (221%; 95% CI: 47%, 600%) and lower signals corresponding to granzyme B (-74%; 95% CI: -82%, -62%), and sucrase isomaltase (-58%; 95% CI: -75%, -29%) in EED biopsies compared with NPA biopsies. Computerized algorithms also detected statistically significant elevation in intraepithelial lymphocytes (49%; 95% CI: 9%, 105%) and proliferation of leukocytes (267%; 95% CI: 92%, 601%) in EED biopsies compared with NPA biopsies., Conclusions: Our results support a model of chronic epithelial stress that decreases epithelial differentiation and absorptive function. The close association of several IHC parameters with manual histologic scoring suggests that automated digital quantification of IHC panels complements traditional histomorphologic assessment in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is a precursor of growth faltering in children living in impoverished conditions who are frequently exposed to environmental toxins and enteropathogens, leading to small bowel inflammatory, malabsorptive, and permeability derangements and low-grade chronic systemic inflammation., Objectives: We explored the association between anthropometrics and duodenal histologic features of EED among children from 3 lower middle-income country centers., Methods: In this cross-sectional study, Pakistani children (n = 63) with wasting, Bangladesh children (n = 116) with stunting or at risk for stunting (height-for-age Z score [HAZ] <-1 but ≥-2), and Zambian children (n = 108) with wasting or stunting received nutritional intervention. Children with anthropometric status refractory to intervention underwent endoscopy. Linear regression models included anthropometric around endoscopy, scores of histology parameters, and a global index score of EED-the total score percent-5 (TSP-5). Multivariable models were adjusted for center, age, sex, and histology slide quality., Results: Intersite variation was observed while exploring the association between anthropometrics and the TSP-5; for example, Pakistani children had the worst HAZ, yet their median TSP-5 score was lower than that of the other 2 centers. Even within each site, no overall pattern of higher TSP-5 score was observed with worsening HAZ. During univariate analysis, TSP-5 (coefficient: 0.01; 95% confidence interval [CI]: 0, 0.02), goblet cell depletion (coefficient: 0.22; 95% CI: 0.06, 0.37), and Paneth cell depletion (coefficient: 0.14; 95% CI: 0.01, 0.27) were associated with HAZ scores; however, they lost statistical significance in the multivariable models, with study center most strongly confounding the relationships seen in univariate models between anthropometry and histology., Conclusions: This study contributes a crucial negative finding that duodenal morphological features did not associate with anthropometric phenotypes; hence, anthropometric measurements may not be a suitable outcome measure for use in EED trials. Trial outcomes may need to be defined by combining the functional and structural elements of the gut to monitor EED., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder associated with growth impairment, delayed neurocognitive development, and impaired oral vaccine responses., Objectives: We set out to develop and validate a histopathologic scoring system on duodenal biopsies from a cohort study of children with growth failure in Bangladesh, Pakistan, and Zambia ("EED") with reference to biopsies from United States children with no clinically reported histologic pathology (referred to hereafter as "normal") or celiac disease., Methods: Five gastrointestinal pathologists evaluated 745 hematoxylin and eosin slide images from 291 children with EED (mean age: 1.6 y) and 66 United States children (mean age: 6.8 y). Histomorphologic features (i.e., villus/crypt architecture, goblet cells, epithelial and lamina propria acute/chronic inflammation, Brunner's glands, Paneth cells, epithelial detachment, enterocyte injury, and foveolar metaplasia) were used to score each histopathologic slide. Generalized estimating equations were used to determine differences between EED, normal, and celiac disease, and receiver operating characteristic curves were used to assess predictive value., Results: Biopsies from the duodenal bulb showed higher intramucosal Brunner's gland scores and lower intraepithelial lymphocyte scores than from the second or third parts of the duodenum (D2/3), so only D2/3 were included in the final analysis. Although 7 parameters differed significantly between EED and normal biopsies in regression models, only 5 (blunted villus architecture, increased intraepithelial lymphocytosis, goblet cell depletion, Paneth cell depletion, and reduced intramucosal Brunner's glands) were required to create a total score percentage (TSP-5) that correctly identified EED against normal biopsies (AUC: 0.992; 95% CI: 0.983, 0.998). Geographic comparisons showed more severe goblet cell depletion in Bangladesh and more marked intraepithelial lymphocytosis in Pakistan., Conclusions: This scoring system involving 5 histologic parameters demonstrates very high discrimination between EED and normal biopsies, indicating that this scoring system can be applied with confidence to studies of intestinal biopsies in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Environmental enteric dysfunction (EED), a chronic inflammatory condition of the small intestine, is an important driver of childhood malnutrition globally. Quantifying intestinal morphology in EED allows for exploration of its association with functional and disease outcomes., Objectives: We sought to define morphometric characteristics of childhood EED and determine whether morphology features were associated with disease pathophysiology., Methods: Morphometric measurements and histology were assessed on duodenal biopsy slides for this cross-sectional study from children with EED in Bangladesh, Pakistan, and Zambia (n = 69), and those with no pathologic abnormality (NPA; n = 8) or celiac disease (n = 18) in North America. Immunohistochemistry was also conducted on 46, 8, and 18 biopsy slides, respectively. Linear mixed-effects regression models were used to reveal morphometric differences between EED compared with NPA or celiac disease and identify associations between morphometry and histology or immunohistochemistry among children with EED., Results: In duodenal biopsies, median EED villus height (248 μm), crypt depth (299 μm), and villus:crypt (V:C) ratio (0.9) values ranged between those of NPA (396 μm villus height; 246 μm crypt depth; 1.6 V:C ratio) and celiac disease (208 μm villus height; 365 μm crypt depth; 0.5 V:C ratio). Among EED biopsy slides, morphometric assessments were not associated with histologic parameters or immunohistochemical markers, other than pathologist-determined subjective semiquantitative villus architecture., Conclusions: Morphometric analysis of duodenal biopsy slides across geographies identified morphologic features of EED, specifically short villi, elongated crypts, and a smaller V:C ratio relative to NPA slides, although not as severe as in celiac slides. Morphometry did not explain other EED features, suggesting that EED histopathologic processes may be operating independently of morphology. Although acknowledging the challenges with obtaining relevant tissue, these data form the basis for further assessments of the role of morphometry in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Over the past decade, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) proposed the option of diagnosing coeliac disease (CD) in children without duodenal biopsy. The aim of our study was to assess the diagnostic approach in newly diagnosed children with CD in Slovenia., Methods: In this prospective study, Slovenian paediatric gastroenterologists were invited to provide medical records of children under 19 years diagnosed with CD from March 2021 to October 2023. The analysis focused on tissue transglutaminase antibody (TGA) levels at diagnosis, diagnostic approach, adherence to ESPGHAN CD guidelines and diagnostic delays., Results: Data from 160 newly diagnosed CD patients (61.9% female; median age 8 years; 16.9% asymptomatic) were available for the analysis. No-biopsy approach was used in 65% (N = 104) of children and the majority (N = 101) fulfilled all the criteria for the no-biopsy approach. Of 56 children diagnosed using duodenal biopsy, a further 10 (17.8%) would have also been eligible for the no-biopsy approach based on the very high levels of TGA. Median diagnostic delay from first symptoms to confirmation of diagnosis was 6 months (min 0 months, max 87 months). Use of the no-biopsy approach has risen significantly since 2016 (37.8% vs. 65.0%; p = 0.001) and diagnostic delays have shortened (6 vs. 7 months; p < 0.05)., Conclusion: This prospective study highlights the frequent use of a no-biopsy approach for diagnosing CD in children in Slovenia, showing large adherence to ESPGHAN guidelines. Also, diagnostic delays have shortened over recent years, likely due to various awareness-raising projects on CD conducted during this period., (© 2024. The Author(s).)

A woman in her 20s presented with 6 weeks of fever, persistent vomiting and 28% loss of body weight. Symptoms were refractory to treatment with antiemetics and broad spectrum antibiotics.Further investigation via oesophageogastroduedenoscopy revealed a large gastric ulcer and pyloric stricture, causing gastric outlet obstruction (GOO). Biopsies of the stomach and duodenum showed plasma cell infiltration with a large proportion being IgG4 positive.Treatment with methylprednisolone, and later prednisolone, quickly improved inflammatory markers and symptoms. Balloon dilatation of the pyloric stricture also improved vomiting, allowing eventual re-establishment of oral nutrition. The patient made a full recovery with maintenance treatment on mycophenolate mofetil.IgG4-related disease (IgG4-RD) is a multisystem disorder with unpredictable presentation. The case highlights diagnostic challenges in IgG4-RD and identifies it as a rare differential in upper gastrointestinal symptoms. To our knowledge this is the first published case of IgG4-RD in the duodenum causing GOO., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Duodeno-duodenostomy (DD) has been proposed as a more physiological alternative to conventional duodeno-jejunostomy (DJ) for pancreas transplantation. Accessibility of percutaneous biopsies in these grafts has not yet been assessed. We conducted a retrospective study including all pancreatic percutaneous graft biopsies requested between November 2009 and July 2021. Whenever possible, biopsies were performed under ultrasound (US) guidance or computed tomography (CT) guidance when the US approach failed. Patients were classified into two groups according to surgical technique (DJ and DD). Accessibility, success for histological diagnosis and complications were compared. Biopsy was performed in 93/136 (68.4%) patients in the DJ group and 116/132 (87.9%) of the DD group ( p = 0.0001). The graft was not accessible for biopsy mainly due to intestinal loop interposition (n = 29 DJ, n = 10 DD). Adequate sample for histological diagnosis was obtained in 86/93 (92.5%) of the DJ group and 102/116 (87.9%) of the DD group ( p = 0.2777). One minor complication was noted in the DD group. The retrocolic position of the DD pancreatic graft does not limit access to percutaneous biopsy. This is a safe technique with a high histological diagnostic success rate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bassaganyas, Darnell, Soler-Perromat, Rafart, Ventura-Aguiar, Cuatrecasas, Ferrer-Fàbrega, Ayuso and García-Criado.)

Celiac disease (CeD) diagnosis is a complicated process, requiring a multi-step procedure and a high level of clinical knowledge. Some scientific societies, mainly from Europe and North America, have proposed appropriate guidelines for the diagnosis and management of CeD. Since duodenal biopsy is particularly challenging for children, guidelines of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, presented in 2012 and updated in 2020, have made it possible to avoid the biopsy in symptomatic pediatric patients with high levels of IgA anti-transglutaminase. Several parallel, similar studies in adults support the non-biopsy strategy. However, several pros and cons exist in applying such a strategy. The present narrative review reports the current evidence and the implication of omitting biopsy in the diagnosis of CeD in adults.

Diagnosis of biliopancreatic cancers by the available serum tumor markers, imaging, and histopathological tissue specimen examination remains a challenge. Circulating cell-free DNA derived from matched pairs of secretin-stimulated duodenal fluid (DF) and plasma from 10 patients with biliopancreatic diseases and 8 control subjects was analyzed using AmpliSeq™ HD technology for Ion Torrent Next-Generation Sequencing to evaluate the potential of liquid biopsy with DF in biliopancreatic cancers. The median cfDNA concentration was greater in DF-derived than in plasma-derived samples. A total of 13 variants were detected: 11 vs. 1 were exclusive for DF relative to the plasma source, and 1 was shared between the two body fluids. According to the four-tier systems, 10 clinical tier-I-II (76.9%), 1 tier-III (7.7%), and 2 tier-IV (15.4%) variants were identified. Notably, the 11 tier-I-III variants were exclusively found in DF-derived cfDNA from five patients with biliopancreatic cancers, and were detected in seven genes (KRAS, TP53, BRAF, CDKN2A, RNF43, GNAS, and PIK3CA); 82% of the tier-I-III variants had a low abundance, with a VAF < 6%. The mutational profiling of DF seems to be a reliable and promising tool for identifying cancer-associated alterations in malignant cancers of the biliopancreatic tract.

Pseudomelanosis duodeni is characterized by endoscopic findings of black or black-brown speckled pigmentation in the duodenal mucosa, usually diagnosed via biopsy. This report presents a case of a 75-year-old male presented with left lower abdominal pain, change in bowel habits, and decreased appetite. Gastroduodenoscopy and biopsies of the duodenum and antrum lead to the diagnosis of pseudomelanosis duodeni., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury 1-4 . Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8 + T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Patients on a gluten-free diet (GFD) whose celiac disease (CD) status is unknown may undergo gluten challenge (GC) to clarify their diagnosis. Though this is an established diagnostic practice, the proportion of patients undergoing GC who are diagnosed with CD is unknown., Aims: We aimed to analyze which factors were predictive of having CD in a cohort of patients who underwent GC followed by upper endoscopy with duodenal biopsy., Methods: We identified adult patients at a CD referral center who had been on a GFD and then underwent GC to determine a diagnosis of CD during the years spanning 2006 to 2020. We compared those patients found to have CD (defined as villus atrophy/Marsh 3) on duodenal biopsy with those who did not, using the chi square and Fischer exact tests., Results: We identified 206 patients who underwent GC. Of these 206, 30 (14%) were diagnosed with CD based on post-GC duodenal biopsy. 176 of the 206 (85%) patients reported various gastrointestinal symptoms, including bloating (39%), though these were more common in those without CD (any GI symptoms: 89% vs 67%, p 0.004; bloating: 43% vs 20%, p 0.019). Serology values, when normalized, including pre- and post-challenge TTG IgA (37% vs 1.7%, p 0.001; 23% versus 2.3%, p 0.001), DGP IgG and IgA (57% vs 2.8%, p 0.001; 37% vs 6.2%, p 0.001) were higher in the group of patients with CD., Conclusion: Among patients undergoing GC for diagnostic purposes, only 14% had evidence of villus atrophy corresponding with CD on duodenal biopsy. The presence of any elevated pre-challenge serology was associated with CD. Bloating in combination with low serologies may help risk stratify patients as being less likely to have CD upon GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Type 2 diabetes mellitus (T2DM) is increasing at an alarming rate, and only 50% of patients with T2DM achieve or maintain adequate glycemic control with pharmacological therapies. Metabolic surgery demonstrated superior efficacy compared to medical therapy but is unfeasible for most patients with T2DM. Duodenal mucosal resurfacing (DMR) by hydrothermal mucosal ablation, recellularization via electroporation therapy (ReCET), and photodynamic therapy are novel endoscopic procedures that use thermal, electrical, and photochemical energy, respectively, to ablate and reset dysfunctional duodenal mucosa. We assessed the data on the effects of these techniques on glycemic control and nonalcoholic fatty liver disease (NAFLD)., Methods: We systematically searched independently and in duplicate English and non-English language publications through January 31st, 2024. Outcomes assessed were an improvement in different metabolic health parameters and the safety of duodenal mucosal ablation (DMA) procedures. Outcomes were presented descriptively., Findings: We selected 12 reports reporting results from 3 randomized and 6 uncontrolled trials (seven evaluating DMR, two evaluating ReCET, all with a low risk of bias) for a total of 317 patients enrolled. DMA reduced HbA1c, fasting plasma glucose, and liver fat. When combined with newer antidiabetic drugs, it allowed insulin discontinuation in up to 86% patients. No major safety signal emerged., Conclusions: All DMA techniques improve glucose homeostasis; DMR and ReCET appear to be safe in patients with T2DM. If confirmed by future randomized trials and by trials with histological endpoints in NAFLD, then DMA appears to be a promising alternative or complement option to medications for T2DM and NAFLD treatment., Funding: This study received no funding., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The prevalence and the clinical significance of gastric foveolar metaplasia (GFM) of duodenal mucosa in pediatric patients are undetermined. The aim was to investigate the event of GFM in duodenal biopsies and its association with gastrointestinal tract disorders in pediatric patients., Methods: We performed a chart review of the characteristics and pathologic findings in patients with GFM described in the pathology reports during 2020 to 2022., Results: Sixty-five out of 3,857 patients (1.7%) had GFM observed in a total of 70/4,778 (1.5%) cases with duodenal biopsies. The ages ranged from 3 to 19 years. The duodenal bulb with GFM was identified in 65 out of 70 cases (92.9%). 17/70 (24.3%) biopsies had coexisting chronic duodenitis, and 52/70 (74.3%) had isolated GFM in duodenum. 48/70 (68.6%) cases had pathologic findings in other parts of the gastrointestinal tract, including 20 (28.6%) inflammatory bowel disease (IBD) and four (5.7%) H. pylori gastritis. Of all 4,778 cases, 136 (2.8%) and 92 (1.9%) cases were diagnosed as IBD and H. pylori gastritis, which had an odds ratio for GFM at 15.8 and 3.2 respectively ( p <0.05)., Conclusion: Both H. pylori gastritis and IBD are associated with GFM in pediatric patients, while isolated GFM itself in the duodenal bulb has limited clinical implications., (© 2024 by the Association of Clinical Scientists, Inc.)

Background: Pancreatoduodenectomy (PD) has a considerable surgical risk for complications and late metabolic morbidity. Parenchyma-sparing resection of benign tumors has the potential to cure patients associated with reduced procedure-related short- and long-term complications., Materials and Methods: Pubmed, Embase, and Cochrane libraries were searched for studies reporting surgery-related complications following PD and duodenum-preserving total (DPPHRt) or partial (DPPHRp) pancreatic head resection for benign tumors. A total of 38 cohort studies that included data from 1262 patients were analyzed. In total, 729 patients underwent DPPHR and 533 PD., Results: Concordance between preoperative diagnosis of benign tumors and final histopathology was 90.57% for DPPHR. Cystic and neuroendocrine neoplasms (PNETs) and periampullary tumors (PATs) were observed in 497, 89, and 31 patients, respectively. In total, 34 of 161 (21.1%) patients with intraepithelial papillar mucinous neoplasm exhibited severe dysplasia in the final histopathology. The meta-analysis, when comparing DPPHRt and PD, revealed in-hospital mortality of 1/362 (0.26%) and 8/547 (1.46%) patients, respectively [OR 0.48 (95% CI 0.15-1.58); p = 0.21], and frequency of reoperation of 3.26 % and 6.75%, respectively [OR 0.52 (95% CI 0.28-0.96); p = 0.04]. After a follow-up of 45.8 ± 26.6 months, 14/340 patients with intraductal papillary mucinous neoplasms/mucinous cystic neoplasms (IPMN/MCN, 4.11%) and 2/89 patients with PNET (2.24%) exhibited tumor recurrence. Local recurrence at the resection margin and reoccurrence of tumor growth in the remnant pancreas was comparable after DPPHR or PD [OR 0.94 (95% CI 0.178-5.34); p = 0.96]., Conclusions: DPPHR for benign, premalignant neoplasms provides a cure for patients with low risk of tumor recurrence and significantly fewer early surgery-related complications compared with PD. DPPHR has the potential to replace PD for benign, premalignant cystic and neuroendocrine neoplasms., (© 2024. The Author(s).)

Background and Aims: This pilot study aimed to evaluate safety and tissue sampling from subepithelial lesions (SEL) in the upper gastrointestinal tract with a novel electric motor driven endoscopic ultrasonography (EUS)-guided 17-gauge (G) size core needle biopsy (CNB) instrument., Methods: An investigator-led prospective open label, performance and safety control study, including seven patients (female n  = 4, median 71 y, range 28-75) with a determined SEL (median size 30 mm, range 17-150 mm) in the upper digestive tract (stomach n  = 6, duodenum n  = 1) were eligible and later followed up 14 days after index procedure. All investigations were completed according to protocol with three FNB 22-G passes with four fanning strokes and two EndoDrill ® 17-G passes with three fanning strokes., Results: Quality of samples as 'visible pieces' (>5 mm): FNB ( n  = 5/7) (fragmented/blood imbibed n  = 1, poor tissue quantity n  = 1) compared with 17-G CNB ( n  = 7/7). Histological result which led to final diagnosis (leiomyoma n  = 2, adenocarcinoma n  = 1, schwannoma n  = 1, neuroendocrine tumour n  = 1, desmoid tumour n  = 1 and gastrointestinal stromal tumour (GIST) n  = 1) could be obtained with the 17-G CNB instrument in all seven patients. FNB technique reached correct diagnosis in six patients. No serious adverse event were recorded., Conclusions: By using an electric driven 17-G biopsy device, a true cylinder of core tissue can be obtained in one single puncture from the area of interest reducing the need for a second sampling. The absolute benefit of EUS-guided CNB is that the sample can be handled and histologically prepared in the same manner as standard percutaneous core needle sample, e.g., breast and prostate cancer.

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten., (© 2024. The Author(s).)

Background and Aims: Cleanliness of the mucosa of the upper GI (UGI) tract is critical for performing a high-quality EGD. The aim of this study was to validate a recently developed UGI cleanliness scale (the Polprep: Effective Assessment of Cleanliness in Esophagogastroduodenoscopy [PEACE] system) in the detection of clinically significant lesions (CSLs) in the UGI tract., Methods: Patients who underwent a complete diagnostic EGD were prospectively enrolled from August 2021 to October 2022. The UGI tract (esophagus, stomach, and duodenum) cleanliness was scored from 0 to 3 for each segment. The primary outcomes were the detection of CSLs and PEACE scores., Results: Of 995 patients enrolled from 5 centers, adequate cleanliness (AQ; all scores ≥2) was found in 929 patients. In multivariate regression analysis, AQ was associated with the number of diagnosed CSLs (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.06-3.01; P = .03). Other factors related to CSL detection were duration of EGD (OR, 1.29, 95% CI, 1.23-1.35, P < .001), male sex (OR, 1.33, 95% CI, 1.04-1.71; P = .025), and EGD indication (dyspepsia, alarm symptoms, gastritis surveillance, other indications vs GERD) (OR, 0.43 [95% CI, 0.31-0.6, P < .001], OR, 0.44 [95% CI, 0.28-0.67, P < .001], OR, 0.44 [95% CI, 0.25-0.76; P = .004], and OR, 0.44 [95% CI, 0.31-0.62; P < .001], respectively). Twenty-seven patients were diagnosed with UGI neoplasia, all in patients with adequate cleanliness of the UGI tract., Conclusions: Adequate cleanliness of the UGI tract as assessed with the PEACE system was associated with a significantly higher detection rate of CSLs during EGD. The relationship of this scale with UGI neoplasia detection warrants further investigation., Competing Interests: Disclosure The following authors disclosed financial relationships: P. Sharma: consultant for Boston Scientific, Olympus, Salix Pharmaceuticals, Cipla, Medtronic, Takeda, Samsung Bioepis, and CDx; grant support from ERBE and Fujifilm. M. F. Kamiński: consultant for Olympus and Erbe; speaker for Boston Scientific, Ipsen, and Recordati; grant support from Olympus. All of the other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Current guidelines recommend multiple biopsies from the first (D1) and second (D2) part of duodenum to establish a diagnosis of celiac disease. In this meta-analysis we aimed to find whether D1 biopsy can increase the diagnostic yield of adult celiac disease., Methods: Literature databases were searched until January 2023 for studies reporting diagnosis of celiac disease in the adult population using D1 biopsy. Meta-analysis was done using a random-effects model. Heterogeneity was assessed by I 2 % and 95% prediction interval statistics. Measured outcomes were diagnostic yield with D1 and D2 biopsies and from 4 versus 2 biopsy samples., Results: A total of 16 studies were included in the final analysis. The pooled diagnostic rate of celiac disease from D1 biopsy was 77.4% [95% CI (64.7-86.5, I 2 94%)] and from D2 biopsy was 75.3% [60.8-85.7, I 2 96%]. The pooled rate of increase in diagnostic yield with D1 biopsy was 6.9% I [4.6-10.2, I 2 66%]. The pooled diagnosis rate with 2 biopsy samples were 77.3% [50-92, I 2 93%] and 86.4% I [58.4-96.7, I 2 87%] from D1 and D2 respectively, whereas that with 4 biopsy samples were 83.3% [49.8-96.2, I 2 76%] and 70.5% I [51-84.6, I 2 96%] from D1 and D2, respectively, the difference being non-significant., Conclusion: Our study demonstrates that taking 4 biopsy samples does not incur any additional diagnostic value over taking 2 biopsy samples from each duodenum segment. Although biopsy from the D1 and D2 has similar diagnostic yield in the adult population, there was an overall increase in diagnostic yield with D1 biopsy, especially in those with a patchy disease distribution., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The administration of dose-escalated radiation for pancreatic adenocarcinoma remains challenging because of the proximity of dose-limiting stomach and bowel, particularly the duodenum for pancreatic head tumors. We explore whether endoscopic injection of a temporary, absorbable hydrogel into the pancreatico-duodenal (PD) groove is safe and feasible for the purpose of increasing spatial separation between pancreatic head tumors and the duodenum., Methods and Materials: Six patients with localized pancreatic adenocarcinoma underwent endoscopic injection of hydrogel into the PD groove. Safety was assessed based on the incidence of procedure-related adverse events resulting in a delay of radiation therapy initiation. Feasibility was defined as the ability to create spatial separation between the pancreas and duodenum, as assessed on simulation CT., Results: All 6 patients were able to undergo endoscopic injection of hydrogel into the PD groove. No device-related events were experienced at any point in follow-up. Presence of hydrogel in the PD groove was apparent on simulation CT in all 6 patients. Mean space created by the hydrogel was 7.7 mm +/- 2.4 mm. In 3 patients who underwent Whipple resection, presence of hydrogel in the PD groove was pathologically confirmed with no evidence of damage to the duodenum., Conclusions: Endoscopic injection of hydrogel into the PD groove is safe and feasible. Characterization of the dosimetric benefit that this technique may offer in the setting of dose-escalated radiation should also be pursued, as should the ability of such dosimetric benefit to translate into clinically improved tumor control., Competing Interests: Disclosures Amol Kumar Narang reports grants or contracts from Boston Scientific, Nanocan, and Flavocure. Theodore S. Hong reports grants or contracts from National Cancer Institute and SU2C. Received consulting fees from Synthetic Biologics, Boston Scientific, Merck, Inviata, GSK, and NextCure. Participated on a Data Safety Monitoring Board or Advisory Board for Novocure and Galera. Has stock or stock options from Panther Therapeutics. Kai Ding reports support for the present manuscript from Augmenix and Boston Scientific. Grants or contracts with NIH. Joseph Herman reports grants or contracts from 1440 Canopy Cancer Collective. Royalties or licenses from Springer Publishing. Consulting fees from Histosonics and Boston Scientific. Support for attending meetings and/or travel from Histosonics and 1440 Canopy Cancer Collective. Patents planned, issued or pending with Oncospace. Has stock or stock options from Histosonics. Jeffrey Meyer reports support for the present manuscript from Boston Scientific. Royalties or licenses from Springer and UpToDate. Manoop S. Bhutani reports support for the manuscript from Boston Scientific. Grants or contracts from Nanobiotix-Research Grant and Trisalis. Consulting fees from Oncosil Inc and Starpax Medical. Kumar Krishnan reports consulting fees from Boston Scientific and Olympus Medical. Euin Ji Shin reports consulting fees from Boston Scientific. Payment for expert testimony from US Dept of Justice. Eugene J, Koay reports support for the present manuscript from Dept of Defense and the NIH. Grants or contracts from Philips Health care, GE Health care, Stand up to Cancer, Project Purple, Elekta, and Dept of Defense. Royalties or licenses from Taylor and Francis LLC. Consulting fees from RenovoRx, AstraZeneca, and Augmenix. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Apollo Cancer Hospitals in Chennai India, Bayer Health care, Philips Health care, and Aptitude Health. Patents planned, issued or pending for the design and fabrication of 3D printed oral stents for head and neck cancer. Leadership of fiduciary role in other board, society, committee or advocacy group, paid or unpaid with International Cholangiocarcinoma Research Network. Has stock or stock options with Quantum Aurea Capital., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Context.—: Changes in Paneth cell numbers can be associated with chronic inflammatory diseases of the gastrointestinal tract. So far, no consensus has been achieved on the number of Paneth cells and their relevance to celiac disease (CD)., Objectives.—: To compare crypt and Paneth cell granule areas between patients with CD and those without CD (non-CD) using an artificial intelligence-based solution., Design.—: Hematoxylin-eosin-stained sections of duodenal biopsies from 349 patients at the McGill University Health Centre were analyzed. Of these, 185 had a history of CD and 164 were controls. Slides were digitized, and NoCodeSeg, a code-free workflow using open-source software (QuPath, DeepMIB), was implemented to train deep learning models to segment crypts and Paneth cell granules. The total area of the entire analyzed tissue, epithelium, crypts, and Paneth cell granules was documented for all slides, and comparisons were performed., Results.—: A mean intersection-over-union score of 88.76% and 91.30% was achieved for crypt areas and Paneth cell granule segmentations, respectively. On normalization to total tissue area, the crypt to total tissue area in CD was increased and the Paneth cell granule area to total tissue area decreased when compared to non-CD controls., Conclusions.—: Crypt hyperplasia was confirmed in CD compared to non-CD controls. The area of Paneth cell granules, an indirect measure of Paneth cell function, decreased with increasing severity of CD. More importantly, our study analyzed complete hematoxylin-eosin slide sections using an efficient and easy to use coding-free artificial intelligence workflow., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: Reduced activity of the sucrase-isomaltase (SI) enzyme can cause gastrointestinal symptoms. Biochemical measurement of SI activity in small intestinal biopsies is presently considered the gold standard for the diagnosis of SI deficiency, but this invasive test is not suitable as a routine diagnostic tool., Aim: To evaluate a 13 C-sucrose-breath test ( 13 CSBT) as a diagnostic tool for SI deficiency in an adult population., Methods: 13 CSBT results were compared to sucrase activity measured in duodenal biopsies., Results: Forty patients with gastrointestinal symptoms were included in the study, 4 of whom had celiac disease and the rest ( n  = 36) had normal histological findings. Nine patients (22.5%) had low sucrase activity measured using duodenal biopsies. No correlation was observed between enzymatic sucrase activity and the 13 CSBT results. The 13 CSBT-curves for the celiac patients versus patients with normal duodenal histology demonstrated that the patients with celiac disease were within the lower range of the distribution., Conclusion: We observed a mismatch between the 13 CSBT results and the biochemically measured sucrase activity, suggesting that SI activity is not uniformly distributed throughout the small intestines. This methodological discrepancy should be acknowledged when diagnosing SI deficiency.

Background: Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal-jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats., Methods: High-fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro., Results: DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system-related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system-related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors., Conclusions: DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway-and not solely by improving blood glucose-to improve oxidative stress in the heart of diabetic cardiomyopathy rats., (© 2023 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Introduction: The diagnosis of eosinophilic gastrointestinal diseases is largely based on mucosal eosinophil counts, but thresholds and normal ranges beyond the esophagus are debated, calling for much-needed methodological standardization. We aimed to develop a standardized workflow for duodenal cell quantification and estimate duodenal eosinophil and mast cell numbers in healthy controls., Methods: Software-based histological cell quantification using free-sized or fixed-sized regions was developed and applied to digitized hematoxylin and eosin (H&E)-stained slides from 58 individuals (healthy controls [HCs] and patients with functional dyspepsia). Intraclass correlation coefficients (ICCs) compared inter-rater reliability between software-based and microscopic quantification. Reproducibility of the software-based method was validated in an independent cohort of 37 control and functional dyspepsia subjects. Eosinophil identification on H&E staining was compared to immunohistochemistry (IHC). Normal eosinophil (H&E) and mast cell (cKit) ranges were determined in 70 adult HCs., Results: Eosinophil quantification on digitized slides demonstrated excellent (ICC = 0.909) and significantly improved reproducibility over microscopic evaluation (ICC = 0.796, P = 0.0014), validated in an independent cohort (ICC = 0.910). Duodenal eosinophils were more abundant around crypts than in villi ( P < 0.0001), while counts were similar on matched H&E- and IHC-stained slides ( P = 0.55). Mean ± SD (95th percentile) duodenal eosinophils and mast cells in HC were 228.8/mm 2 ± 94.7 (402.8/mm 2 ) and 419.5/mm 2 ± 132.2 (707.6/mm 2 ), respectively., Discussion: We developed and validated a standardized approach to duodenal histological cell quantification, generalizable to various mucosal cell types. Implementation of software-based quantification identified 400 eosinophils/mm 2 and 700 mast cells/mm 2 as thresholds for abnormal duodenal infiltration., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length Z -score [WLZ]) failed to improve after a 2-month nutritional intervention underwent esophagogastroduodenoscopy (EGD). Paired duodenal luminal aspirates and duodenal mucosal biopsies were obtained from 43 children. Duodenal microbiota composition was characterized by sequencing bacterial 16S rRNA gene amplicons. Levels of bacterial taxa (amplicon sequence variants [ASVs]) were referenced to anthropometric indices, histopathologic severity in biopsies, expression of selected genes in the duodenal mucosa, and fecal levels of an immunoinflammatory biomarker (lipocalin-2). A "core" group of eight bacterial ASVs was present in the duodenal samples of 69% of participants. Streptococcus anginosus was the most prevalent, followed by Streptococcus sp., Gemella haemolysans , Streptococcus australis , Granulicatella elegans , Granulicatella adiacens, and Abiotrophia defectiva . At the time of EGD, none of the core taxa were significantly correlated with WLZ. Statistically significant correlations were documented between the abundances of Granulicatella elegans and Granulicatella adiacens and the expression of duodenal mucosal genes involved in immune responses (dual oxidase maturation factor 2, serum amyloid A, and granzyme H). These results suggest that a potential role for members of the oral microbiota in pathogenesis, notably Streptococcus , Gemella, and Granulicatella species, warrants further investigation.IMPORTANCEUndernutrition among women and children is a pressing global health problem. Environmental enteric dysfunction (EED) is a disease of the small intestine (SI) associated with impaired gut mucosal barrier function and reduced capacity for nutrient absorption. The cause of EED is ill-defined. One emerging hypothesis is that alterations in the SI microbiota contribute to EED. We performed a culture-independent analysis of the SI microbiota of a cohort of Pakistani children with undernutrition who had failed a standard nutritional intervention, underwent upper gastrointestinal tract endoscopy, and had histologic evidence of EED in their duodenal mucosal biopsies. The results revealed a shared group of bacterial taxa in their duodenums whose absolute abundances were correlated with levels of the expression of genes in the duodenal mucosa that are involved in inflammatory responses. A number of these bacterial taxa are more typically found in the oral microbiota, a finding that has potential physiologic and therapeutic implications., Competing Interests: The authors declare no conflict of interest.

Chronic inflammatory enteropathy (CIE) is a common condition in dogs causing recurrent or persistent gastrointestinal clinical signs. Pathogenesis is thought to involve intestinal mucosal inflammatory infiltrates, but histopathological evaluation of intestinal biopsies from dogs with CIE fails to guide treatment, inform prognosis, or correlate with clinical remission. We employed single-cell RNA sequencing to catalog and compare the diversity of cells present in duodenal mucosal endoscopic biopsies from 3 healthy dogs and 4 dogs with CIE. Through characterization of 35,668 cells, we identified 31 transcriptomically distinct cell populations, including T cells, epithelial cells, and myeloid cells. Both healthy and CIE samples contributed to each cell population. T cells were broadly subdivided into GZMA high (putatively annotated as tissue resident) and IL7R high (putatively annotated as non-resident) T cell categories, with evidence of a skewed proportion favoring an increase in the relative proportion of IL7R high T cells in CIE dogs. Among the myeloid cells, neutrophils from CIE samples exhibited inflammatory (SOD2 and IL1A) gene expression signatures. Numerous differentially expressed genes were identified in epithelial cells, with gene set enrichment analysis suggesting enterocytes from CIE dogs may be undergoing stress responses and have altered metabolic properties. Overall, this work reveals the previously unappreciated cellular heterogeneity in canine duodenal mucosa and provides new insights into molecular mechanisms which may contribute to intestinal dysfunction in CIE. The cell type gene signatures developed through this study may also be used to better understand the subtleties of canine intestinal physiology in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Manchester, Ammons, Lappin and Dow.)

Background: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD., Methods: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease., Findings: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms., Interpretation: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Crohn's disease is an inflammatory condition of the intestine characterized by largely unknown etiology and a relapse remission cycle of disease control. While possible triggers have been identified, research is inconsistent on the precise cause of these relapses, especially in the under-researched pediatric population. We hypothesized that patients in remission would have persistent microbial and inflammatory changes in small intestinal tissue that might trigger relapse. To this end, we analyzed intestinal biopsy samples from six patients with pediatric Crohn's disease in remission and a control group of 16 pediatric patients with no evident pathogenic abnormality. We identified compositional microbiota differences, including decreases in the genera Streptococcus and Actinobacillus as well as increases in Oribacterium and Prevotella in patients with controlled Crohn's disease compared to controls. Further, a histologic analysis found that patients with controlled Crohn's disease had increased epithelial integrity, and decreased intraepithelial lymphocytes compared with controls. Additionally, we observed increased peripheral CD4 + T cells in patients with pediatric Crohn's disease. These results indicate that markers of intestinal inflammation are responsive to Crohn's disease treatment, however the interventions may not resolve the underlying dysbiosis. These findings suggest that persistent dysbiosis may increase vulnerability to relapse of pediatric Crohn's disease. This study used a nested cohort of patients from the Bangladesh Environmental Enteric Dysfunction (BEED) study (ClinicalTrials.gov ID: NCT02812615 Date of first registration: 24/06/2016)., (© 2024. The Author(s).)

Tributyltin (TBT) is a biocide used in the formulation of antifouling paints and it is highly harmful. Despite the ban, the compound persists in the environment, contaminating marine foodstuffs and household products. Therefore, considering the route of exposure to the contaminant, the gastrointestinal tract (GIT) acts as an important barrier against harmful substances and is a potential biomarker for understanding the consequences of these agents. This work aimed to evaluate histological and neuronal alterations in the duodenum of male Wistar rats that received 20 ng/g TBT and 600 ng/g via gavage for 30 consecutive days. After the experimental period, the animals were euthanized, and the duodenum was intended for neuronal histochemistry (total and metabolically active populations) and histological routine (morphometry and histopathology). The results showed more severe changes in neuronal density and intestinal morphometry in rats exposed to 20 ng/g, such as total neuronal density decrease and reduction of intestinal layers. In rats exposed to 600 ng/g of TBT, it was possible to observe only an increase in intraepithelial lymphocytes. We conclude that TBT can be more harmful to intestinal homeostasis when consumed in lower concentrations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Narrow-band imaging (NBI) is a readily accessible imaging technique that enhances mucosal visualisation, allowing for a more accurate assessment of duodenal villi. However, its role in the diagnosis of coeliac disease (CD) in clinical practice remains limited., Methods: We systematically searched several databases in June 2023 for studies evaluating the diagnostic accuracy of NBI for detecting duodenal villous atrophy (VA) in patients with suspected CD. We calculated the summary sensitivity, specificity, and likelihood ratios using a bivariate random-effects model. The study followed PRISMA guidelines and was registered at PROSPERO (CRD42023428266)., Results: A total of 6 studies with 540 participants were included in the meta-analysis. The summary sensitivity of NBI to detect VA was 93% (95% CI, 81% - 98%), and the summary specificity was 95% (95% CI, 92% - 98%). The area under the summary receiver operating characteristic curve was 0.98 (95% CI, 96 - 99). The positive and negative predictive values of NBI were 94% (95% CI, 92% - 97%) and 92% (95% CI, 90% - 94%), respectively., Conclusion: NBI is an accurate non-invasive tool for identifying and excluding duodenal VA in patients with suspected CD. Further studies using a validated classification are needed to determine the optimal role of NBI in the diagnostic algorithm for CD., Competing Interests: Conflict of interest None declared., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Many antibody responses induced by infection, vaccination or autoimmunity show signs of convergence across individuals with epitope-dependent selection of particular variable region gene segments and complementarity determining region 3 properties. However, not much is known about the relationship between antigen-specific effector cells and antigen-specific precursors present in the naïve B-cell repertoire. Here, we sought to address this relationship in the context of celiac disease, where there is a stereotyped autoantibody response against the enzyme transglutaminase 2 (TG2). By generating TG2-specific monoclonal antibodies from both duodenal plasma cells and circulating naïve B cells, we demonstrate a discord between the naïve TG2-specific repertoire and the cells that are selected for autoantibody production. Hence, the naïve repertoire does not fully reflect the epitope preference and gene usage observed for memory B cells and plasma cells. Instead, distinct naïve B cells that target particular TG2 epitopes appear to be selectively activated at the expense of TG2-binding B cells targeting other epitopes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nonampullary duodenal epithelial tumors are rare, but their prevalence is increasing. Various gastrointestinal cancers have been associated with microbiomes. We evaluated the characteristics of the salivary and duodenal microbiomes of patients with nonampullary duodenal epithelial tumors., Methods: Saliva and biopsy samples from the duodenal bulb and descending portion were obtained from 15 patients with nonampullary duodenal epithelial tumors and 10 controls. Next-generation sequencing was performed to identify bacteria for comparison., Results: Saliva samples had higher Amplicon Sequence Variants (ASVs) and more observed species than duodenal samples. Saliva samples from patients with nonampullary duodenal epithelial tumor were dominated by Bacteroidetes and Prevotella, whereas Proteobacteria and Neisseria were dominant in the control samples. The relative abundance of bacteria was higher in patients with nonampullary duodenal epithelial tumors. Most bacteria were classified as bacteria of oral origin. Oribacterium and Stomatobaculum were significantly higher in the saliva, duodenal bulb, and descending portion of patients with nonampullary duodenal epithelial tumors., Conclusion: Patients with nonampullary duodenal epithelial tumors had different salivary and duodenal microbiomes than controls. Bacteria types differed between groups at each site, and most bacteria of oral origin were more abundant in patients with nonampullary duodenal epithelial tumors., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Villus height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocytes (IEL) are key measures of histology of the small intestine in celiac disease. Although the field of celiac disease has advanced, there remains no broadly accepted measure of mucosal injury. We assessed whether a composite Vh:Cd and IEL scale (VCIEL) can improve accuracy and statistical precision for assessing histology, compared with individual measures., Methods: The formulation of the VCIEL composite histologic scale was based on combining the Vh:Cd and IEL measurements for individual patients with equal weighting, by converting each scale to a fraction of their standard deviation and summing the results. The VCIEL formula was applied to several clinical trials and the results for Vh:Cd and IEL were compared with those for VCIEL with regards to clinical significance (effect size) and statistical significance., Results: For the ALV003-1021 trial, we observed an effect size and P value (analysis of covariance) of 1.37 and 0.038 for ΔVh:Cd, 1.17 and 0.005 for ΔIEL, and 1.86 and 0.004 for ΔVCIEL. For the similar gluten-challenge IMGX003-NCCIH-1721 trial, the corresponding results were 0.76 and 0.057 for ΔVh:Cd, 0.98 and 0.018 for ΔIEL, and 1.14 and 0.007 for ΔVCIEL. Similar improvements with the use of VCIEL over individual Vh:Cd and IEL measures were observed for other studies, including a nontherapeutic gluten challenge study., Conclusions: The composite VCIEL scale combining Vh:Cd and IEL values seems to improve accuracy and statistical precision compared with either component alone., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3 + lymphocytes, CD68 + , CD11c + myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)