Histopathology underlying environmental enteric dysfunction in a cohort study of undernourished children in Bangladesh, Pakistan, and Zambia compared with United States children.

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.

The Environmental Enteric Dysfunction Biopsy Initiative (EEDBI) Consortium: mucosal investigations of environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is an asymptomatic acquired disorder characterized by upper small bowel inflammation, villus blunting, and gut permeability. It is a major contributor to poor growth in childhood as well as other highly consequential outcomes such as delayed neuorcognitive development. After decades of intermittent interest in this entity, we are now seeing a resurgence in the field of EED. However, recent studies have been hampered by a lack of investigation of the target tissue-the upper small bowel. In 2016, the EEDBI (Environmental Enteric Dysfunction Biopsy Initiative) Consortium was established as a common scientific platform across 3 independent EED biopsy cohort studies in Bangladesh, Pakistan, and Zambia. Two centers in the United States recruited comparison groups of children undergoing endoscopy for clinical indications. The EEDBI Consortium goal was to augment the contributions of the individual centers and answer high-level questions amenable to analysis and interpretation across the studies. Here, we describe the Consortium and its cohorts and recruitment procedures across studies. We also offer details applicable to all papers in this supplement, which describe EED mucosal histology, morphometry, immunohistochemistry, and transcriptomics as well as histology relationship to pathogens and biomarkers.

Enteric pathogens relationship with small bowel histologic features of environmental enteric dysfunction in a multicountry cohort study.

BACKGROUND: Environmental Enteric Dysfunction (EED) is an acquired disorder of asymptomatic altered gut function, the etiology of which is unknown. EED is postulated to be a major contributor to growth faltering in early childhood in regions where early-life enteropathogenic carriage is prevalent. Few studies have examined the critical organ (the upper small bowel) with enteropathogens in the evolution of small bowel disease. OBJECTIVES: The objective of this study was to determine if fecal enteropathogenic detection predicts subsequent EED histology. METHODS: Fecal samples were obtained from undernourished children aged <2 y without diarrhea enrolled in 3 cohort studies, who failed nutritional intervention and subsequently underwent endoscopy. Duodenal biopsies from 245 (Bangladesh n = 120, Pakistan n = 57, and Zambia n = 68) children were scored using a semiquantitative histologic grading protocol. Thirteen enteropathogens were sought in common across the 3 centers using TaqMan array cards (TAC) (Bangladesh and Pakistan) and the Luminex platform (Zambia). An additional 18 pathogens and 32 virulence loci were sought by TAC and included in sensitivity analyses restricted to TAC data. RESULTS: Multivariable linear regressions adjusting for study center, age at stool collection, and stool-to-biopsy interval demonstrated the following: 1) an association of norovirus and Shigella detection with subsequent enterocyte injury [ß 0.2 (95% CI: 0.1, 0.3); P = 0.002 and ß 0.2 (95% CI: 0.0, 0.3); P = 0.008, respectively], 2) association of Campylobacter with intraepithelial lymphocytes [ß 0.2 (95% CI: 0.0, 0.4); P = 0.046], and 3) association of Campylobacter and enterotoxigenic Escherichia coli with a summative EED histopathology index score [ß 4.2 (95% CI: 0.8, 7.7); P = 0.017 and ß 3.9 (95% CI: 0.5, 7.3); P = 0.027, respectively]. All but 2 of these associations (Shigella-enterocyte injury and Campylobacter-index score) were also demonstrated in TAC-only sensitivity analyses, which identified additional associations between other pathogens, pathogen burden, or virulence loci primarily with the same histologic parameters. CONCLUSIONS: The detection of some enteropathogens in asymptomatic infections is associated with subsequent EED histopathology. These novel findings offer a basis for future EED etiology and pathogenesis studies.

A fruit fly-based approach to unraveling enteropathy-causing pharmaceuticals.

Enteropathy is a gastrointestinal disorder characterized by inflammation in the small intestine and one of the causes of enteropathy is the side effects of certain drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of NSAIDs, such as indomethacin, could inhibit prostaglandin synthesis, leading to a decrease in mucus production and small intestine integrity. To test the effects of a drug, it is necessary to undergo preclinical testing using animal models. Commonly used animal models such as mice and rats have several drawbacks including high cost, ethical issues, and long lifespan. Therefore, alternatives such as using invertebrate animals like Drosophila melanogaster as a more economical in vivo platform with genetic similarity to mammals and devoid of ethical concerns are needed. The aim of this study was to evaluate Drosophila melanogaster as an in vivo model organism in testing the side effects of pharmaceuticals that cause enteropathy. In this study, flies aged 3-5 days were starved and then placed into treatment vials comprising untreated control and indomethacin-treated (3.75 mM, 7.5 mM, and 15 mM). Survival analysis was conducted during the treatment period, followed by a Smurf assay test after seven days of treatment. Subsequently, the expression of pro-inflammatory cytokine-related genes (drs and totA), mitochondria stability-related genes (tom40), and endogenous antioxidant-related genes (sod1, sod2, and cat) was performed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Our data indicated that indomethacin did not impact lifespan or cause intestinal damage. However, we observed increased expression of pro-inflammatory cytokine-related genes, including drs, and a twofold increase in totA gene expression. Furthermore, there was a significant upregulation of mitochondrial stability gene tom40, endogenous antioxidant genes sod1 and cat, and a threefold increase in sod2 at 15 mM indomethacin. Although no phenotypical changes in gut integrity were detected, the increased expression of pro-inflammatory cytokine genes suggests the occurrence of inflammation in the indomethacin-treated flies.

Evaluation of the fatty acid-based erythrocyte membrane lipidome in cats with food responsive enteropathy, inflammatory bowel disease and low-grade intestinal T-cell lymphoma.

Feline chronic enteropathies (FCE), include food-responsive-enteropathy (FRE), inflammatory bowel disease (IBD), and low-grade intestinal T-cell lymphoma (LGITL), and are common causes of chronic gastrointestinal signs in cats. Distinguishing between different subgroups of FCE can be challenging due to the frequent overlap of anamnestic, clinical, and laboratory data. While dysregulation in lipid metabolism has been reported in humans and dogs with chronic IBD, similar changes in cats are not yet completely understood. Assessing the fatty acid (FA) profile of red blood cell (RBC) membranes offers a valuable method for evaluating the quantity and quality of structural and functional molecular components in the membranes. Therefore, this study aimed to examine the FA composition of RBC membranes in FCE in comparison to healthy cats (HC). Gas-chromatography was used to quantitatively analyze a cluster of 11 FA, and based on these results, parameters of lipid homeostasis and enzyme activity indexes were calculated. A total of 41 FCE cats (17 FRE, 15 IBD, 9 LGITL) and 43 HC were enrolled. In FCE cats, the values of docosapentaenoic acid (p = 0.0002) and docosahexaenoic acid (p = 0.0246), were significantly higher, resulting in an overall increase in ω-3 polyunsaturated fatty acids (PUFA) (p = 0.006), and that of linoleic acid (p = 0.0026) was significantly lower. Additionally, FCE cats exhibited an increased PUFA balance (p = 0.0019) and Δ6-desaturase index (p = 0.0151), along with a decreased ω-6/ω-3 ratio (p = 0.0019). No differences were observed among cats affected by FRE, IBD and LGITL. Like humans and dogs, the results of this study indicate that FCE cats also display changes in their FA lipid profile at the level of the RBC membrane. The non-invasive analysis of RBC membrane shows promise as a potential tool for gaining a better understanding of lipid imbalances in this disease.

Cerebral involvement in sitosterolemia.

BACKGROUND: Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. METHODS: This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. RESULTS: The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. CONCLUSION: This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

Deciphering the spatiotemporal transcriptional landscape of intestinal diseases (Review).

The intestines are the largest barrier organ in the human body. The intestinal barrier plays a crucial role in maintaining the balance of the intestinal environment and protecting the intestines from harmful bacterial invasion. Single­cell RNA sequencing technology allows the detection of the different cell types in the intestine in two dimensions and the exploration of cell types that have not been fully characterized. The intestinal mucosa is highly complex in structure, and its proper functioning is linked to multiple structures in the proximal­distal intestinal and luminal­mucosal axes. Spatial localization is at the core of the efforts to explore the interactions between the complex structures. Spatial transcriptomics (ST) is a method that allows for comprehensive tissue analysis and the acquisition of spatially separated genetic information from individual cells, while preserving their spatial location and interactions. This approach also prevents the loss of fragile cells during tissue disaggregation. The emergence of ST technology allows us to spatially dissect enzymatic processes and interactions between multiple cells, genes, proteins and signals in the intestine. This includes the exchange of oxygen and nutrients in the intestine, different gradients of microbial populations and the role of extracellular matrix proteins. This regionally precise approach to tissue studies is gaining more acceptance and is increasingly applied in the investigation of disease mechanisms related to the gastrointestinal tract. Therefore, this review summarized the application of ST in gastrointestinal diseases.

Lesion size and location in deep infiltrating bowel endometriosis: Correlation with gastrointestinal dysfunction and pain.

INTRODUCTION: Presence of deep infiltrating bowel endometriosis (DE) is associated with occurrence of dyschezia and gastrointestinal symptoms. The degree of the disease, the lesion length, and the location, that is, lesion-to-anal-verge distance (LAVD) of DE, as well as the severity of the symptoms appear to be correlated. Nevertheless, it is not yet known to what extent the size and LAVD of bowel DE influence the severity of gastrointestinal symptoms. The present study aims to evaluate a possible correlation of lesion location (LAVD) and size (according to the #Enzian classification) with preoperative symptoms. MATERIAL AND METHODS: In this prospective study, premenopausal patients with histologically confirmed DE undergoing modified limited nerve-vessel sparing rectal segmental bowel resection or full-thickness discoid resection were evaluated. Extent of endometriosis was defined according to the #Enzian classification during surgery. The primary outcome measure was the correlation between lesion size and location with the GI function impairment reflected by presurgical lower anterior resection syndrome (LARS) scores; the secondary outcome was differences in presurgical numeric rating scale pain scores of dyschezia, dyspareunia, and dysmenorrhea as well as the impact of concomitant DE of other locations on symptom intensity. RESULTS: Of 162 consecutive patients, 151 were included in the final analysis. No significant correlation was observed between lesion size (#Enzian compartments C1/C2/C3) or LAVD and GI dysfunction reflected by LARS-like symptoms (p = 0.314 and p = 0.185, respectively) or pain symptoms (dyschezia, p = 0.440; dyspareunia, p = 0.136; and dysmenorrhea p = 0.221). Furthermore, no significant correlation was observed between lesion size and GI dysfunction when merging two severity grades (#Enzian compartments C1 plus C2 vs. C3; p = 0.611). In addition, LAVD did not affect the degree of dyschezia (p = 0.892), dyspareunia (p = 0.395), or dysmenorrhea (p = 0.705). Finally, the presence of concomitant DE lesions infiltrating the vagina/rectovaginal space (#Enzian compartment A) and/or sacrouterine ligaments/parametrium (#Enzian compartment B) did not alter the severity of preoperative dyschezia (p = 0.493) or dysmenorrhea (p = 0.128) but showed a trend toward affecting gastrointestinal function (p = 0.078) and was significantly associated with dyspareunia (p = 0.035). CONCLUSIONS: In present study, we could not find a correlation between colorectal DE lesion size and location (LAVD) and gastrointestinal function impairment or intensity of dyschezia and dysmenorrhea. Additional involvement of vagina/rectovaginal space (#Enzian compartment A) and/or sacrouterine ligaments/parametrium (#Enzian compartment B) exerts a significant impact on the degree of dyspareunia in women with colorectal DE.

Characterization of early-stage lesions and investigation on the role of mucosal trauma in hemorrhagic bowel syndrome in cattle.

Hemorrhagic bowel syndrome (HBS) is characterized by a dissecting intramucosal hematoma at the small bowel, causing obstruction and severe hemorrhage in dairy cattle. Recent investigation revealed the presence of early-stage lesions in cows affected by HBS. These are presumed to be the initial stage of the hematoma, as both share unique dissection of the lamina muscularis mucosae (LMM) as histological hallmark. Early-stage lesions of HBS have not been characterized in greater detail, and neither has the hypothesis of mucosal abrasion as etiology been explored. Therefore, the first objective of the present study was to characterize the morphology of early-stage lesions, by gross examination, histochemistry, immunohistochemistry and transmission electron microscopy. The second objective was to determine the effect of mucosal abrasion to the small intestine in an ex vivo model. A total of 86 early-stage lesions from 10 cows with HBS were characterized. No underlying alterations at the LMM were evident which could explain their occurrence. However, degeneration at the ultrastructural level of the LMM smooth muscle cells was present in 3 of 4 lesions, it is however unclear whether this is primary or secondary. Bacteriological examination did not reveal any association with a specific bacterium. Experimental-induced and early-stage lesions were gross and histologically evaluated and scored in three cows with HBS and seven controls. Experimentally induced lesions in both affected cows and controls, were histologically very similar to the naturally occurring early-stage lesions. Altogether, the results are suggestive for mucosal trauma to play a role in the pathogenesis of HBS.

Exploring the potential of human intestinal organoids: Applications, challenges, and future directions.

The complex and dynamic environment of the gastrointestinal tract shapes one of the fastest renewing tissues in the human body, the intestinal epithelium. Considering the lack of human preclinical studies, reliable models that mimic the intestinal environment are increasingly explored. Patient-derived intestinal organoids are powerful tools that recapitulate in vitro many pathophysiological features of the human intestine. In this review, the possible applications of human intestinal organoids in different research fields are highlighted. From physiologically relevant to intestinal disease modeling, regenerative medicine, and toxicology studies, the potential of intestinal organoids will be here presented and discussed. Despite the remarkable opportunities offered, limitations related to ethical concerns, tissue collection, reproducibility, and methodologies may hinder the full exploitation of this cell-based model into high throughput studies and clinical practice. Currently, distinct approaches can be used to overcome the numerous challenges found along the way and to allow the full implementation of this ground-breaking technology.

Clinical and genetic characteristics of Chinese patients diagnosed with chronic enteropathy associated with SLCO2A1 gene.

BACKGROUND AND AIMS: Chronic enteropathy associated with SLCO2A1 gene is a rare intestinal disease caused by loss-of-function SLCO2A1 mutations, with clinical and genetic characteristics remaining largely unknown, especially in Chinese patients. This study aims to reveal clinical and genetic features of Chinese CEAS patients, highlighting the previously unreported or unemphasized characteristics. METHODS: We enrolled 12 Chinese patients with chronic enteropathy associated with SLCO2A1 gene admitted to Peking Union Medical College Hospital from January 2018 to December 2022. Clinical and genetic data of these patients were collected and analyzed. RESULTS: 58.3% of patients were male, who also had primary hypertrophic osteoarthropathy, whereas female patients did not have primary hypertrophic osteoarthropathy. Apart from common symptoms associated with anemia and hypoalbuminemia, abdominal pain, ileus, diarrhea, and hematochezia were present. 4 of the 5 female patients had early-onset amenorrhea, though the causal relationship remained to be clarified. Endoscopy and computed tomography enterography revealed that lesions can occur in any part of the digestive tract, most commonly in the ileum. Pathology showed multiple superficial ulcers with adjacent vascular dilatation, and loss of SLCO2A1 expression, particularly in gastrointestinal vascular endothelial cells. Genetic analysis confirmed SLCO2A1 mutations in all patients and identified 11 new SLCO2A1 variants for CEAS. CONCLUSIONS: This study reports new clinical, pathological, and genetic findings in 12 Chinese patients with chronic enteropathy associated with SLCO2A1 gene. This study provides insights into the pathogenesis of this disease. However, studies with larger sample sizes and more in-depth mechanism research are still required.

Pathogenesis of chronic enteropathy associated with the SLCO2A1 gene: Hypotheses and conundrums.

Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.

Studying the cellular basis of small bowel enteropathy using high-parameter flow cytometry in mouse models of primary antibody deficiency.

Background: Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined. Methods: In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA-/-, Aicda-/-, CD19-/- and JH -/-) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy). Results: Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively. Conclusions: Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.

Modeling the cell biology of monogenetic intestinal epithelial disorders.

Monogenetic variants are responsible for a range of congenital human diseases. Variants in genes that are important for intestinal epithelial function cause a group of disorders characterized by severe diarrhea and loss of nutrient absorption called congenital diarrheas and enteropathies (CODEs). CODE-causing genes include nutrient transporters, enzymes, structural proteins, and vesicular trafficking proteins in intestinal epithelial cells. Several severe CODE disorders result from the loss-of-function in key regulators of polarized endocytic trafficking such as the motor protein, Myosin VB (MYO5B), as well as STX3, STXBP2, and UNC45A. Investigations of the cell biology and pathophysiology following loss-of-function in these genes have led to an increased understanding of both homeostatic and pathological vesicular trafficking in intestinal epithelial cells. Modeling different CODEs through investigation of changes in patient tissues, coupled with the development of animal models and patient-derived enteroids, has provided critical insights into the enterocyte differentiation and function. Linking basic knowledge of cell biology with the phenotype of specific patient variants is a key step in developing effective treatments for rare monogenetic diseases. This knowledge can also be applied more broadly to our understanding of common epithelial disorders.

Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem cell transplantation.

BACKGROUND: Endoscopic features of intestinal transplant-associated microangiopathy (iTAM) have not been comprehensively investigated. This study aimed to examine the endoscopic characteristics of patients diagnosed with iTAM. METHODS: This retrospective analysis included 14 patients pathologically diagnosed with iTAM after stem cell transplantation for hematolymphoid neoplasms (n = 13) or thalassemia (n = 1). The sex, age at diagnosis, endoscopic features, and prognosis of each patient were assessed. Serological markers for diagnosing transplant-associated thrombotic microangiopathy were also evaluated. RESULTS: The mean age at the time of iTAM diagnosis was 40.2 years. Patients diagnosed based on the pathognomonic pathological changes of iTAM presented with diverse symptoms at the times of endoscopic examinations, including diarrhea (n = 10), abdominal pain (n = 5), nausea (n = 4), appetite loss (n = 2), bloody stools (n = 2), abdominal discomfort (n = 1), and vomiting (n = 1). At the final follow-up, six patients survived, while eight patients succumbed, with a median time of 100.5 days (range: 52-247) post-diagnosis. Endoscopic manifestations included erythematous mucosa (n = 14), erosions (n = 13), ulcers (n = 9), mucosal edema (n = 9), granular mucosa (n = 9), and villous atrophy (n = 4). Erosions and/or ulcers were primarily observed in the colon (10/14, 71%), followed by the ileum (9/13, 69%), stomach (4/10, 40%), cecum (5/14, 36%), duodenum (3/10, 30%), rectum (4/14, 29%), and esophagus (1/10, 10%). Cytomegalovirus infection (n = 4) and graft-versus-host disease (n = 2) coexisted within the gastrointestinal tract. Patients had de novo prolonged or progressive thrombocytopenia (6/14, 43%), decreased hemoglobin concentration (4/14, 29%), reduced serum haptoglobin level (3/14, 21%), and a sudden and persistent increase in lactate dehydrogenase level (2/14, 14%). Peripheral blood samples from 12 patients were evaluated for schistocytes, with none exceeding 4%. CONCLUSIONS: This study provides a comprehensive exploration of the endoscopic characteristics of iTAM. Notably, all patients exhibited erythematous mucosa throughout the gastrointestinal tract, accompanied by prevalent manifestations, such as erosions (93%), ulcers (64%), mucosal edema (64%), granular mucosa (64%), and villous atrophy (29%). Because of the low positivity for serological markers of transplant-associated thrombotic microangiopathy in patients with iTAM, endoscopic evaluation and biopsy of these lesions are crucial, even in the absence of these serological features.

Neutrophil extracellular trap formation and its implications in nonsteroidal anti-inflammatory drug-induced small intestinal injury.

BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. METHODS: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. RESULTS: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1ß and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. CONCLUSION: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.

Capsule endoscopy and panendoscopy: A journey to the future of gastrointestinal endoscopy.

In 2000, the small bowel capsule revolutionized the management of patients with small bowel disorders. Currently, the technological development achieved by the new models of double-headed endoscopic capsules, as miniaturized devices to evaluate the small bowel and colon [pan-intestinal capsule endoscopy (PCE)], makes this non-invasive procedure a disruptive concept for the management of patients with digestive disorders. This technology is expected to identify which patients will require conventional invasive endoscopic procedures (colonoscopy or balloon-assisted enteroscopy), based on the lesions detected by the capsule, i.e., those with an indication for biopsies or endoscopic treatment. The use of PCE in patients with inflammatory bowel diseases, namely Crohn's disease, as well as in patients with iron deficiency anaemia and/or overt gastrointestinal (GI) bleeding, after a non-diagnostic upper endoscopy (esophagogastroduodenoscopy), enables an effective, safe and comfortable way to identify patients with relevant lesions, who should undergo subsequent invasive endoscopic procedures. The recent development of magnetically controlled capsule endoscopy to evaluate the upper GI tract, is a further step towards the possibility of an entirely non-invasive assessment of all the segments of the digestive tract, from mouth-to-anus, meeting the expectations of the early developers of capsule endoscopy.

Acetato de lanreotida e acetato de octreotida de liberação prolongada para o tratamento de pacientes com sintomas associados a tumores endócrinos gastroenteropancreáticos funcionais / Lanreotide acetate and extended-release octreotide acetate for the treatment of patients with symptoms associated with functional gastroenteropancreatic endocrine tumors

INTRODUÇÃO: Os tumores neuroendócrinos (TNE) são neoplasias, com origem mais comum no trato gastrointestinal, que podem cursar com liberação de hormônios associado a sintomas, levando a síndrome carcinoide, com incidência anual estimada em 0,25/1.000.000 na Europa (ano de 2008). As manifestações clínicas mais comuns incluem diarreia secretória e rubor súbito, mas a diarreia é considerada mais debilitante com potencial risco de morte. Quando o tratamento curativo com ressecção completa não é viável pela presença de doença metastática, o tratamento é direcionado para o controle dos sintomas da síndrome carcinoide e os análogos da somatostatina (octreotida ou lanreotida) são considerados terapia de primeira linha na SC. PERGUNTAS DE PESQUISA: O acetato de octreotida de liberação prolongada (octreotida LAR) e o acetato de lanreotida de liberação prolongada (lanreotida LP) são eficazes, seguros e custo-efetivos para o tratamento dos sintomas relacionados à SC associados ao TNE gastroenteropancreático funcional em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Foram selecionados três ensaios clínico

Influence of Feeding Time on a Non-steroidal Anti-inflammatory Drug-induced Small Intestinal Injury Mouse Model.

BACKGROUND/AIM: Non-steroidal anti-inflammatory drugs (NSAIDs), the most widely used pharmaceuticals, induce various adverse effects, including gastrointestinal injuries, such as ulcers and bleeding. Animal models of NSAID-induced small intestinal injury (NSI) have been extensively employed for the development of preventive and therapeutic agents. However, some experimental variations related to feeding times have been observed following NSI induction. This study aimed to investigate the impact of feeding time on an NSI mouse model. MATERIALS AND METHODS: The mice were divided into eight groups: normal, sham, and model groups (with feeding times of 2 h, 6 h, 10 h, 14 h, 18 h, and 22 h; n=10 in each group). The mice were fasted for 18 h before the injection of indomethacin (15 mg/kg, subcutaneously), except for the normal group. Food supply was halted at specific time points (2 h, 6 h, 10 h, 14 h, 18 h, and 22 h); however, the normal and sham groups were continuously fed throughout the experiment. The length of the small intestine was measured, and histological analysis was performed 24 h after induction. RESULTS: Up to 14 h after induction, NSI, indicated by small intestine shortening, remained consistent, with a reduction in length of approximately 10-20%. However, feeding for more than 14 h significantly exacerbated NSI, both anatomically and histologically. CONCLUSION: The ulcerative changes observed in the small intestine 14 h after indomethacin injection may be closely associated with the influence of food on NSI.

Identification of Terminal ßGlcNAc on Brachyspira Species in Human Intestinal Spirochetosis.

Human intestinal spirochetosis (HIS) is a colorectal bacterial infection caused by the Brachyspira species. Griffonia simplicifolia-II (GS-II) is a lectin specific to terminal α/ßGlcNAc residues. Here, we investigated terminal ßGlcNAc residues in the context of HIS infection using GS-II-horseradish peroxidase staining and HIK1083 immunostaining specific to terminal αGlcNAc residues. Fourteen of 15 HIS cases were GS-II-positive on the bacterial body. No cases showed HIK1083 positivity. The percentage of bacterial bodies staining positively for GS-II based on comparison with anti-Treponema immunostaining was ≤30% in seven cases, 30-70% in two, and >70% in six. Of 15 HIS cases analyzed, none were comorbid with tubular adenomas, and three were comorbid with sessile serrated lesions (SSLs). To determine the species of spirochete infected, the B. aalborgi-specific or B. pilosicoli-specific NADPH oxidase genes were amplified by PCR. After direct sequencing of the PCR products, all nine cases in which PCR products were observed were found to be infected with B. aalborgi alone. These results indicate that the HIS bacterial body, especially of B. aalborgi, is characterized by terminal ßGlcNAc and also indicate that terminal ßGlcNAc on the HIS bacterial body is associated with HIS preference for SSLs.