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Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation

El estrés psicosocial es uno de los grandes problemas de salud en las sociedades modernas. En condiciones fisiológicas el estrés representa una amenaza para la homeostasis. En respuesta al estrés se genera una respuesta coordinada que implica a los sistemas autonómico, endocrino e inmunitario para mantener la estabilidad del medio. Una sobreexposición al estrés en individuos susceptibles, altera esta respuesta adaptativa pudiendo dar lugar al desarrollo de enfermedades. Uno de los órganos más vulnerables al estrés es el tracto gastrointestinal (GI), ya que las enfermedades más comunes del tracto gastrointestinal, los trastornos funcionales digestivos (FGID), son enfermedades sensibles al estrés, pero los mecanismos subyacentes siguen siendo desconocidos. Tanto el estrés agudo como el crónico han demostrado alterar mecanismos que pueden dar lugar a la disfunción de la barrera intestinal y a la activación de la inmunidad a nivel de la mucosa intestinal, dos factores que se han relacionado con el desarrollo del síndrome del intestino irritable (SII). El objetivo de esta tesis es describir la influencia del estrés en la función GI y describir los componentes moleculares de la respuesta al estrés que pueden predisponer al desarrollo de los FGID. Primero realizamos un estudio retrospectivo para determinar la prevalencia en nuestra comunidad de estrés crónico psicosocial en pacientes con SII con predominio de diarrea (SII-D) y para evaluar el efecto del estrés crónico psicosocial y el sexo en la severidad del SII-D. Evidenciamos que los sujetos con SII-D presentaban una mayor prevalencia de estrés crónico psicosocial que los voluntarios sanos. Asimismo, las mujeres afectas de SII-D presentaban más síntomas dispépticos que los sujetos varones del mismo grupo. El análisis por subgrupos demostró que las comorbilidades condicionaban una mayor severidad clínica del SII-D en aquellos pacientes con depresión. Posteriormente, se realizó un estudio prospectivo para investigar los m, Psychosocial stress is becoming a huge health problem in modern societies in the last years. In physiological conditions, stress represents a threat to the internal homeostasis, and in response to stress a coordinated response involving autonomic, endocrine, and immune systems is generated to maintain stability. However, stress overexposure in susceptible individuals, impairs this adaptive response, and could lead to the development of disease. One of the most vulnerable organs to stress is the gastrointestinal tract (GI), as most common gastrointestinal disorders, functional gastrointestinal disorders (FGID), are considered stress-sensitive disorders although the underlying mechanisms still remain unknown. In the last years, increasing evidence supports the interaction between stress and the GI tract, as both acute and chronic stress have been shown to increase ion and water secretion, impair epithelial permeability, and modify intestinal microbiota leading to intestinal barrier dysfunction and mucosal immune activation that have been related to IBS development. The aim of this thesis is to describe how stress impacts on gastrointestinal function and to describe cellular and molecular components of the stress response that can predispose to the development of FGID. In this study, we first retrospectively determine the prevalence of chronic psychosocial stress in diarrhea-predominant irritable bowel syndrome (IBS-D) in our area and analyze the effect of chronic psychosocial stress and sex in the severity of GI function. The analysis revealed that chronic psychosocial stress is more prevalent in IBS-D subjects than in healthy volunteers. Moreover, females displayed more dyspeptic symptoms than males in the IBS-D group. Subgroup analysis by comorbid factors showed a more severe IBS-D in patients that had concomitant depression. We also performed a prospective study to investigate the molecular mechanisms involved in the intestinal mucosa's response to stress. Two biop

We recently identified mucosal mast cell and eosinophil hyperplasia in association with a duodenal impaired barrier function in functional dyspepsia (FD). We aimed to further describe the implication of these immune cells by assessing their activation state at the ultrastructural level and by evaluating the association between impaired epithelial integrity and immune activation. Duodenal biopsies were obtained from 24 FD patients and 37 healthy controls. The ultrastructure of mast cells and eosinophils was analyzed by transmission electron microscopy. Transepithelial electrical resistance and paracellular permeability were measured to evaluate epithelial barrier function. The type of degranulation in eosinophils and mast cells was piecemeal. Eosinophils displayed higher degree of degranulation in FD patients than in controls (p < 0.0001). Quantification revealed a decreased granular density in eosinophils of FD patients (p < 0.0001). The degree of degranulation in mast cells was similar in both groups. However, a more heterogeneous profile was found in the FD group (p < 0.0001). No association between epithelial integrity and the number and activation state of mucosal eosinophils and mast cells was found. We demonstrated ultrastructural changes in degranulation state of eosinophils and mast cells, suggesting that eosinophil and mast cell activation play a role in the pathophysiology of FD

El Síndrome del Intestino Irritable (SII) es un trastorno funcional con elevada prevalencia en la sociedad que se caracteriza por la presencia de dolor o molestia abdominal asociada a cambios en el hábito deposicional. Su diagnóstico es clínico al carecer de marcadores biológicos, sin embargo, las evidencias científicas aportadas en los últimos años sugieren una etiología multifactorial que origina, en la mucosa intestinal del SII con predominio de diarrea (SII-D), una condición de inflamación crónica de bajo grado y una alteración en la función de la barrera intestinal asociada a la hipersensibilidad visceral y la alteración motora en estos pacientes. El tejido linfoide asociado al intestino forma parte de la función barrera intestinal y es determinante en el mantenimiento de la homeostasis. El exceso de activación del sistema inmunológico se relaciona con alteraciones en las funciones intestinales y, en consecuencia, con el desarrollo de patologías intestinales. Concretamente, la activación del mastocito y su proximidad a terminaciones nerviosas en la mucosa se asocian a la sintomatología característica del SII, por lo que estrategias dirigidas a la modulación de su activación podrían ser beneficiosas para la recuperación de la homeostasis intestinal y la mejoría clínica de estos pacientes. Este trabajo analiza el efecto del tratamiento oral con cromoglicato disódico (CGDS), un agente estabilizador del mastocito, en la evolución de los síntomas propios del SII y los cambios moleculares asociados a la respuesta clínica que acontecen en la mucosa intestinal. Para ello, realizamos un primer estudio exploratorio durante 6 meses que comparó el efecto de la administración oral de CGDS oral (600mg/día) en pacientes de SII-D sobre las principales manifestaciones clínicas frente a otra cohorte que no recibió tratamiento alguno. El CGDS mostró un beneficio clínico al reducir en la mayoría de los pacientes la intensidad del dolor abdominal un 50% y normalizar la consistencia, Irritable Bowel Syndrome (IBS) is a chronic functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habit. Despite its high prevalence in western societies, there is no reliable biological marker and its diagnosis relies on symptom-based criteria. However, in diarrhea-prone IBS (IBS-D), a growing body of evidence suggests a multifactorial etiology including intestinal mucosal low-grade inflammation and intestinal barrier dysfunction. Importantly, these features are associated with visceral hypersensitivity and altered intestinal motility, accepted as features of IBS. The gut associated lymphoid tissue has a key role in maintaining the intestinal barrier and contributing to homeostasis. Over-activation of the intestinal immune system is linked to disturbances in the intestinal functions and to the development of intestinal disorders. Specifically, increased mucosal mast cell (MC) activation and their proximity to nerve endings are associated to IBS symptoms. Therefore, strategies addressed at modulating MC activation might have a clinical benefit in IBS-D patients. This work analyses the effect on clinical symptoms evolution after long-term administration of oral disodium cromoglycate (DSCG) and identifies the underlying molecular mechanisms associated to the clinical improvement. To confirm the hypothesis, we first carried out an exploratory study in which we evaluated the impact of oral administration of DSCG (600 mg/day) on specific symptoms in IBS-D and compared to a cohort of untreated IBS-D patients. DSCG-treated patients showed clinical benefit as the majority of patients reported at least a 50% of improvement on their abdominal pain and bowel movements, and over 75% normalized the consistency of stools. Besides the clinical improvement, our findings corroborate the effectiveness of oral DSCG to promote the stabilization of gut mucosal mast cells by down-regulation of tryptase, as well as innate immunity molecules to comparabl