Duodenal mucosa of untreated celiac disease patients has altered expression of the GAS6 and PROS1 and the negative regulator tyrosine kinase TAM receptors subfamily.

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.

Role of adjuvant Crohn's disease exclusion diet plus enteral nutrition in asymptomatic pediatric Crohn's disease having biochemical activity: A randomized, pilot study.

BACKGROUND: Conventional therapy can result in remission in mild-moderate pediatric Crohn's disease (CD). However, some patients experience loss of response to biological drugs despite increased dosage. METHODS: We planned to determine that CD exclusion diet plus partial enteral nutrition offers additional benefits in asymptomatic children with CD having elevated fecal calprotectin. A randomized, open-label, pilot, controlled interventional study was conducted in children with CD while on medical treatment and elevated fecal calprotectin on routine testing. Patients continued their medications and were randomized into a group that received CD exclusion diet plus partial enteral nutrition for 12 weeks and one that continued a regular diet. RESULTS: Twenty-one patients participated: 11 received CD exclusion diet plus partial enteral nutrition and 10, regular diet. Median fecal calprotectin in the CD exclusion diet plus partial enteral nutrition decreased in 9/11 to 50% of baseline, remaining practically unchanged in the regular diet, except for two patients (p = 0.005). Body mass index z-score increased in the CD exclusion diet plus partial enteral nutrition. Only 1/11 patients in the CD exclusion diet plus partial enteral nutrition group, while 4/10 in the regular diet, experienced clinical relapse (p = 0.149). Only one patient in the CD exclusion diet plus partial enteral nutrition, while eight in the regular diet, were considered to need their biologic treatment intensified (p = 0.005); 2/11 in the CD exclusion diet plus partial enteral nutrition had the dose or frequency of the biologic reduced vs. none (0/10) in the regular diet group. The short Pediatric Crohn's Disease Activity Index and anthropometry showed no significant changes in either group. CONCLUSIONS: Diet therapy could be a useful addition to medications in children with CD in apparent remission, but elevated fecal calprotectin. TRIAL REGISTRATION: Clinical trial number: NCT05034458.

Food-sensitized pediatric patients show colonic cow's milk protein-specific Th2 cells.

Food allergies have become a health concern worldwide. Around 6% to 10% of children are allergic to cow's milk proteins. We have previously characterized colorectal polyps in patients sensitized to food allergens. These polyps are classified as inflammatory and present a type 2 environment, with elevated interleukin (IL)-13 and IL-4, and are a site of immunoglobulin E synthesis. In this study, we characterized and isolated cow's milk protein-specific T cell lines and T cell clones from the lamina propria of polyps from patients sensitized to these proteins. Isolated T cells responded to cow's milk proteins similarly to peripheral blood T cells, showing antigen-specific cell proliferation and Th2 cytokines release in vitro. T cell clones obtained were all CD4+ T cells and expressed the membrane TCRαß receptor and secreted higher IL-4, IL-5, and IL-13 amounts than unstimulated cells, whereas interferon γ secretion remained unchanged. Remarkably, the gut homing chemokine receptor CCR9 was augmented in cow's milk-specific peripheral and lamina propria T cells, and CCL25 was found to be expressed in the inflammatory polyp tissue and not in the adjacent mucosa. In conclusion, we isolated and characterized cow's milk-specific lamina propria CD4+ Th2 cells from colonic inflammatory polyps. CCR9 expression on these cells, along with increase secretion of CCL25 in the polyp, favors recruitment and cow's milk-specific allergic response within the inflammatory polyp tissue. Our findings may be critical to understand the underlying mechanism that promotes immunoglobulin E synthesis in the colon of cow's milk proteins allergic patients, contributing to the development of novel T cell-targeted immunotherapies.

Trastornos funcionales gastrointestinales. Cómo tratar sin medicar / Functional gastrointestinal disorders. How to manage them without medication

Los trastornos funcionales gastrointestinales (TFGI) se caracterizan por síntomas atribuibles al tracto gastrointestinal que no pueden ser explicados por anormalidades estructurales ni bioquímicas. Durante el primer año de vida, pueden generar mucho malestar en el lactante y preocupación en sus padres. Su diagnóstico se basa en criterios clínicos que expertos han determinado y en una historia clínica y un examen físico completo que descartan causas orgánicas. El objetivo de esta actualización es presentar estrategias para el manejo de los TFGI más frecuentes durante el primer año de vida: cólicos, regurgitaciones, disquecia y estreñimiento, bajo la visión de los nuevos conocimientos fisiopatológicos, que eviten los estudios y medicaciones innecesarias.

Functional gastrointestinal disorders (FGIDs) are characterized by symptoms attributable to the gastrointestinal tract that cannot be explained by the presence of structural or biochemical abnormalities. During the first year of life, FGIDs can cause great discomfort in infants and concern in their parents. The diagnosis of FGIDs is based on clinical criteria determined by experts and on a comprehensive case-taking process and physical exam to rule out organic causes. The objective of this update is to describe strategies for the management of the most frequent FGIDs during the first year of life: colics, regurgitations, dyschezia, and constipation, in light of new pathophysiological insights, to avoid unnecessary tests and medications.

Type-2 Cytokines Promote the Secretion of the Eosinophil-Attractant CCL26 by Intestinal Epithelial Cells in Food-Sensitized Patients.

Several inflammatory processes of the bowel are characterized by an accumulation of eosinophils at inflammation sites. The mechanisms that govern mucosal infiltration with eosinophils are not fully understood. In this work, we studied the colorectal polyp-confined tissue containing eosinophils and we hypothesized that intestinal epithelial cells are the cell source of eotaxin-3 or CCL26, a potent chemoattractant for eosinophils. We analyzed colorectal polyps (n=50) from pediatric patients with rectal bleeding by H&E staining and eosin staining, and different pro-inflammatory cytokines were assessed by RT-qPCR and ELISA. IgE and CCL26 were investigated by RT-qPCR, ELISA and confocal microscopy. Finally, the intracellular signaling pathway that mediates the CCL26 production was analyzed using a kinase array and immunoblotting in human intestinal Caco-2 cell line. We found a dense cell agglomeration within the polyps, with a significantly higher frequency of eosinophils than in control adjacent tissue. IL-4 and IL-13 were significantly up-regulated in polyps and CCL26 was elevated in the epithelial compartment. Experiments with Caco-2 cells showed that the type-2 cytokine IL-13 increased STAT3 and STAT6 phosphorylation and eotaxin-3 secretion. The addition of the blocking antibody Dupilumab or the inhibitor Ruxolitinib to the cytokine-stimulated Caco-2 cells diminished the CCL26 secretion to basal levels in a dose-dependent manner. In conclusion, our findings demonstrate a high frequency of eosinophils, and elevated levels of type-2 cytokines and eotaxin-3 in the inflammatory stroma of colorectal polyps from pediatric patients. Polyp epithelial cells showed to be the main cell source of CCL26, and IL-13 was the main trigger of this chemokine through the activation of the STAT3/STAT6/JAK1-2 pathway. We suggest that the epithelial compartment actively participates in the recruitment of eosinophils to the colonic polyp-confined inflammatory environment.

Alergia a la proteína de la leche de vaca; nuevos conocimientos desde una visión multidisciplinaria / Cow's milk protein allergy; new knowledge from a multidisciplinary perspective

En las últimas décadas, se ha observado una mayor prevalencia, persistencia y gravedad de la alergia a la proteína de leche de vaca (APLV). Se han postulado diversas hipótesis respecto a posibles mecanismos responsables, con énfasis en el papel de la microbiota en la inducción y el mantenimiento de la tolerancia inmunitaria, así como la importancia del establecimiento temprano de una microbiota saludable a través de la promoción de la lactancia materna, el parto por vía vaginal, el uso racional de antibióticos e inhibidores de la bomba de protones, junto con la introducción temprana y variada de alimentos. La utilización de probióticos y la inmunoterapia específica para alérgenos (ITA) emergen como las estrategias terapéuticas con más evidencia a favor para la adquisición de tolerancia. El objetivo de esta revisión ha sido describir la información actual respecto a los mecanismos inmunitarios involucrados en la APLV, el papel de la microbiota y las perspectivas futuras en el tratamiento.

In recent decades, a higher prevalence, persistence, and severity of cow's milk protein allergy (CMPA) have been observed. Different hypotheses have been proposed in relation to potential responsible mechanisms, with emphasis on the role of the microbiota in the induction and maintenance of immune tolerance as well as the importance of establishing a healthy microbiota in an early manner through the promotion of breastfeeding, vaginal delivery, rational use of antibiotics and proton pump inhibitors, along with an early introduction of varied foods. The use of probiotics and allergenspecific immunotherapy (AIT) come up as the treatment strategies with the greatest evidence in favor of tolerance acquisition. The objective of this review was to describe the information currently available about the immune mechanisms involved in CMPA, the role of microbiota, and future treatment perspectives.

IL-33 Alarmin and Its Active Proinflammatory Fragments Are Released in Small Intestine in Celiac Disease.

Initially described as Th2 promoter cytokine, more recently, IL-33 has been recognized as an alarmin, mainly in epithelial and endothelial cells. While localized in the nucleus acting as a gene regulator, it can be also released after injury, stress or inflammatory cell death. As proinflammatory signal, IL-33 binds to the surface receptor ST2, which enhances mast cell, Th2, regulatory T cell, and innate lymphoid cell type 2 functions. Besides these Th2 roles, free IL-33 can activate CD8+ T cells during ongoing Th1 immune responses to potentiate its cytotoxic function. Celiac Disease (CD) is a chronic inflammatory disorder characterized by a predominant Th1 response leading to multiple pathways of mucosal damage in the proximal small intestine. By immunofluorescence and western blot analysis of duodenal tissues, we found an increased expression of IL-33 in duodenal mucosa of active CD (ACD) patients. Particularly, locally digested IL-33 releases active 18/21kDa fragments which can contribute to expand the proinflammatory signal. Endothelial (CD31+) and mesenchymal, myofibroblast and pericyte cells from microvascular structures in villi and crypts, showed IL-33 nuclear location; while B cells (CD20+) showed a strong cytoplasmic staining. Both ST2 forms, ST2L and sST2, were also upregulated in duodenal mucosa of CD patients. This was accompanied by increased number of CD8+ST2+ T cells and the expression of T-bet in some ST2+ intraepithelial lymphocytes and lamina propria cells. IL-33 and sST2 mRNA levels correlated with IRF1, an IFN induced factor relevant in responses to viral infections and interferon mediated proinflammatory responses highly represented in duodenal tissues in ACD. These findings highlight the potential contribution of IL-33 and its fragments to exacerbate the proinflammatory circuit and potentiate the cytotoxic activity of CD8+ T cells in CD pathology.

Enfermedad celíaca y otras patologías relacionadas con el gluten / Celiac disease and other pathologies related to gluten

Se intentan aclarar los conceptos diferenciales de enfermedad celíaca, sensibilidad al gluten no celíaca y alergia al trigo. Se abordan las manifestaciones clínicas junto al Score clínico desarrollado en el Servicio para calcular matemáticamente la presencia de enfermedad celíaca. Finalmente, se aborda el tartamiento, seguimiento, y las nuevas patologías relacionadas a la enfermedad

¿Que se trago mi hijo? Urgencias en niños por ingestión de cuerpo extraño. Experiencia de seis años en un hospital pediátrico / What did my son drink? Emergency in children due to ingestion of foreign body. Six-year experience in a pediatric hospital

La ingestión de cuerpo extraño (CE) es la segunda causa de endoscopia de urgencia después de la hemorragia de vías digestivas; es un problema frecuente en la población pediátrica. Los niños pueden ingerir cualquier tipo de objeto, la mayoría de los cuales pueden pasar sin inconvenientes por el tracto gastrointestinal. No obstante, algunos pueden poner en riesgo la vida o acarrear complicaciones

Foreign body ingestion is the second cause of emergency endoscopy after bleeding from the digestive tract; It is a frequent problem in the pediatric population. Children can ingest any type of object, most of which can pass without inconvenience through the gastrointestinal tract; however, some can be life-threatening or complicating

Sensibilidad al gluten: presentación de tres casos / Gluten sensitivity: presentation of three cases

En los últimos años, ha cobrado mayor interés la existencia de un cuadro clínico muy similar al de la enfermedad celíaca, que no se ajusta a los cánones tradicionales de diagnóstico. Se trata de pacientes con una alta sospecha diagnóstica de enfermedad celíaca, que presentan serología y biopsia de intestino delgado normal. La literatura relata, desde la década del 80, la existencia de un síndrome que relaciona el gluten de la dieta con un efecto tóxico generador de síntomas gastrointestinales en presencia de una mucosa normal. A esta entidad se la denominó síndrome de Cooper-Cook. En los últimos años, ha habido numerosas publicaciones que hacen referencia a esta entidad, pero ahora bajo la denominación de sensibilidad al gluten. En el siguiente artículo, se presentan tres casos clínicos que hacen referencia a esta enfermedad.

In the last few years, the existence of a clinical profile similar to celiac disease has become important; this disease does not adapt to the traditional diagnosis canons. It is related to a number of patients who are diagnosed as having the celiac disease but present normal serology and small bowel's biopsy. Since the 80's, medical literature reports the existence of a syndrome that connects gluten diet with a toxic effect that produces gastrointestinal symptoms even though the mucosa remains normal. This disease is called the Cooper-Cook syndrome. Over the last few years, there have been lots of publications about this disease under the name "gluten sensitivity". In the following article, three clinical cases that refer to this condition are presented.

[Gluten sensitivity: presentation of three cases]. / Sensibilidad al gluten: presentación de tres casos.

In the last few years, the existence of a clinical profile similar to celiac disease has become important; this disease does not adapt to the traditional diagnosis canons. It is related to a number of patients who are diagnosed as having the celiac disease but present normal serology and small bowel's biopsy. Since the 80's, medical literature reports the existence of a syndrome that connects gluten diet with a toxic effect that produces gastrointestinal symptoms even though the mucosa remains normal. This disease is called the Cooper-Cook syndrome. Over the last few years, there have been lots of publications about this disease under the name "gluten sensitivity". In the following article, three clinical cases that refer to this condition are presented.

Role of CXCR3/CXCL10 axis in immune cell recruitment into the small intestine in celiac disease.

Lymphocytic infiltration in the lamina propria (LP), which is primarily composed of CD4(+) Th1 cells and plasma cells, and increased numbers of intraepithelial lymphocytes (IELs), is a characteristic finding in active celiac disease (CD). Signals for this selective cell recruitment have not been fully established. CXCR3 and its ligands, particularly CXCL10, have been suggested to be one of the most relevant pathways in the attraction of cells into inflamed tissues. In addition, CXCR3 is characteristically expressed by Th1 cells. The aim of this work was to investigate the participation of the chemokine CXCL10/CXCR3 axis in CD pathogenesis. A higher concentration of CXCL10 was found in the serum of untreated CD patients. The mRNA levels of CXCL10 and CXCL11 but not CXCL9 were significantly higher in duodenal biopsies from untreated CD patients compared with non-CD controls or treated patients. The results demonstrate that CXCL10 is abundantly produced in untreated CD and reduced in treated patients, and the expression of CXCL10 was found to be correlated with the IFNγ levels in the tissue. Plasma cells and enterocytes were identified as CXCL10-producing cells. Moreover, the CXCL10 expression in intestinal tissues was upregulated by poly I:C and IL-15. IELs, LP T lymphocytes, and plasma cells, which infiltrate the intestinal mucosa in untreated CD, express CXCR3. The CXCR3/CXCL10 signalling axis is overactivated in the small intestinal mucosa in untreated patients, and this finding explains the specific recruitment of the major cell populations that infiltrate the epithelium and the LP in CD.

Broad MICA/B expression in the small bowel mucosa: a link between cellular stress and celiac disease.

The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B(+) T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B(+) B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role.

Evaluación de un suplemento probiótico en la recuperación nutricional de pacientes celíacos sometidos a una dieta SIN TACC / The use of probiotic supplement on the nutritional recovery of celiac patients on gluten-free diet

Se presentan los resultados del progreso de peso de 45 pacientes celíacos de reciente diagnóstico bajo dieta SIN TACC (sin trigo, avena, cebada y centeno), a 23 de los cuales se les agregó un suplemento probiótico, 22 sirvieron de grupo control. Se analizaron también aspectos ambientales y culturales. Si bien el mayor incremento de peso se observó en el grupo que recibió suplemento en la etapa de la recuperación nutricional, este progreso no mostró diferencias estadísticamente significativas. Creemos que el probiótico, la dosis diaria indicada y el tiempo de administración deben ser variables a estudiar en un futuro próximo. Los grupos fueron similares para otras variables potencialmente confundentes.

Celiaquia, una enfermedad paradigmática / Celiac Disease, a paradigmatic disease

Se presentan 10 pacientes recientemente diagnosticados como celíacos, ninguno de los cuales presentaba desnutrición, ni sintomatología sugerente de malabsorción. Seis tenían un pariente celíaco en primer grado, tres diabetes de tipo uno y el restante una tesaurismosis. Todos presentan autoanticuerpos IgA, EMA positivos y ocho IgA tTG2 positiva, los dos restantes tenían valores normales. Las biopsias que facilitaron el diagnóstico de enfermedad celíaca, fueron tomadas previo examen endoscópico minucioso en las áreas proximales y distales del duodeno. La biopsia duodenal (3ra o 4ta porción) de todos estos pacientes se hallaba dentro de límites normales. Los hallazgos resultan particularmente interesantes e ilustrativos para com- paginar o explicar aquellas aparentes discordancias entre la clínica, el laboratorio y la histopatología

La enfermedad celíaca / Celiac disease

La Enfermedad Celíaca (EC) es la intolerancia alimentaría de orden genético mas frecuente de la especie humana. En nuestro servicio de Gastroenterología hemos diagnosticado mas de 1900 casos en los últimos 34 años y 92 y 73 nuevos casos en los años 2004 y 2005, respectivamente.La EC es el resultado de la interacción de factores genéticos (constante absoluta) expresados en la mucosa intestinal y la respuesta inmune (constante relativa) por una parte, y factores ambientales y culturales (variable absoluta), como el consumo de trigo en cantidad impensable para la especie humana como hace no mas de 5000 años. La hipótesis etiopatogénica mas aceptada y extendida de la EC es que resultaría de una respuesta inmune peculiar de la mucosa intestinal al gluten del TACC. En esta revisión analizamos los aspectos históricos de la enfermedad así como información sobre la patogenia y la forma actual de reconocer las características clínicas, de laboratorio, histopatológicas y de tratamiento de la misma. También se analizan la fisiopatología y la experiencia de nuestro grupo, asiendo especial énfasis en el espectro de las enfermedades asociadas.