FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / Objetivos: A hipovolemia aguda reduz o tÃnus e aumenta a complacÃncia gÃstrica em animais. A complacÃncia do estÃmago proximal à o principal determinante da saciedade no teste de saciedade (drinking test). No entanto, nÃo hà relatos de eventuais alteraÃÃes de complacÃncia, tÃnus, saciedade e de plenitude gÃstricas frente a uma reduÃÃo aguda do volume sangÃÃneo em humanos. MÃtodo: ApÃs aprovaÃÃo pelo Comità de Ãtica, e seguido de jejum noturno de 8 horas, estudou-se 23 voluntÃrios sadios. TÃnus e complacÃncia: ApÃs obtenÃÃo de um acesso venoso, uma sonda-balÃo (12F, saco de PVC de 1600ml) foi afixada no estÃmago proximal dos voluntÃrios (n=17). O volume gÃstrico foi medido continuamente por um sistema computadorizado de barostato (SynecticsÂ), com a pressÃo intragÃstrica fixada em 12mmHg. ApÃs um perÃodo basal de 30min os voluntÃrios foram submetidos aleatoriamente a sangria (doaÃÃo padrÃo de sangue, 450 ml) ou apenas a punÃÃo venosa. Foram realizados tambÃm pequenos aumentos da pressÃo intra-balÃo atà o relato de leve desconforto, antes do perÃodo basal e ao final do estudo. Em sete voluntÃrios foi realizada infusÃo de salina 15min apÃs a sangria. Saciedade e plenitude: Avaliou-se seis voluntÃrios sadios (homens, 28,5Â3,5 anos) em duas ocasiÃes (intervalo de 1 a 2 semanas). ApÃs jejum noturno de 8h, os voluntÃrios ingeriram refeiÃÃo padronizada. Decorridas 2h, foram submetidos à punÃÃo venosa seguida (condiÃÃo experimental) ou nÃo (controle) por doaÃÃo padrÃo de sangue. Logo apÃs, avaliou-se a saciedade e a plenitude gÃstricas pelo drinking test modificado mediante a ingestÃo de refeiÃÃo lÃquida, achocolatada sem lactose, num ritmo fixo de 15 ml/min. A cada 5min da refeiÃÃo teste, avaliou-se a plenitude utilizando escala de 0 a 5 (0-nÃo sinto nada, 5-nÃo agÃento mais) e a saciedade com escala de descritores. Resultados: A sangria causou um aumento no volume gÃstrico (incremento sobre o perÃodo basal: 154  62ml aos 5min e 152  66ml aos 30min, p < 0,05). A inclinaÃÃo da curva volume vs pressÃo aumentou apÃs doaÃÃo de sangue (53,7  4,2 vs 45,1  4,2ml.mmHg-1 basal, p = 0,01). A infusÃo de salina trouxe os valores de volta ao nÃvel basal (0 ml basal vs -14  6 ml aos 30min, p > 0,05). A doaÃÃo padrÃo de sangue aumentou o volume mÃximo ingerido em relaÃÃo à condiÃÃo controle (790Â56,7 vs 1327Â127ml, p<0,05). O tempo para chegar ao valor 5 (plenitude mÃxima) foi maior apÃs doaÃÃo de sangue (52,8Â4 vs 95,8Â8min, p<0,05). O tempo para a primeira sensaÃÃo (âcomeÃando a encherâ) e o tempo para a terceira sensaÃÃo (âcheioâ) foram maiores apÃs a doaÃÃo de sangue (19,2Â1,3 vs 41,6 Â4,2min e 37,8Â3,5 vs 67,5  6,6min, respectivamente, p<0,05). A doaÃÃo de sangue nÃo alterou significativamente a pressÃo arterial e a freqÃÃncia cardÃaca. ConclusÃo: A doaÃÃo de sangue diminuiu o tÃnus e aumentou a complacÃncia gÃstrica. A infusÃo de salina reverteu esse fenÃmeno. A reduÃÃo da volemia aumentou o limiar para a percepÃÃo da plenitude gÃstrica. Isto pode corresponder a um novo fator determinante de sintomas relacionados à plenitude gÃstrica. / Introduction: We have shown that blood shedding reduces tonus and increases gastric compliance in animals. Since satiety to a drinking test is affected by gastric tonus and compliance, we investigated the effect of blood donation (BD) and saline infusion in gastric tonus, compliance and sensitivity in healthy volunteers. Method: After approval of local ethics committee, 23 healthy male volunteers were studied. After an overnight fast (8-10h), followed by a light meal, and a 2h interval, one of the following procedures was performed. Tonus and compliance study. A PVC bag (1.6L) attached to a catheter was placed into the proximal stomach. Gastric volume (GV, ml) was continuously measured by an electronic barostat (SynecticsÂ), with the intrabag pressure fixed at 12mmHg. After 30-min basal recording, the subjects (n=18) were randomly submitted to either BD (450 ml) or venous puncture site manipulation only, and GV was recorded for further 30-min. Small IP increments (until mild pain report) were also performed; before the basal period and at the end of the study. In 5 volunteers, saline infusion (1.3L) was performed 15-min after BD. Satiety. Volunteers were studied in two different occasions, 1 to 2 weeks apart. They were submitted to a blood donation or venous puncture only, before a modified satiety drinking test with a caloric meal was performed. Results: BD caused a rapid increase in GV (values above basal levels: 154  62 ml at 5 minutes after shedding start and 152  66 ml at the end of study, p<0.05). Volume x pressure slope increased (53.7  4.2 vs. 45.1  4.2ml.mmHg-1 basal, P=0.01) after BD. Saline infusion brought GV back to basal levels (0Â1 ml basal vs -14  6 ml at 30 min). BD increased the maximum volume ingested by the volunteers (790Â56,7 vs. 1327Â127ml, p<0.05). The time to reach the maximum score was also increased. (52.8Â4 vs. 95.8Â8min, p<0.05). The time to elicit the first (beginning to feel full) and third (full) sensations was also increased after BD (19.2Â1.3 vs. 41.6 Â4.2min e 37.8Â3.5 vs. 67.5 Â6.6min, respectively, p<0.05). BD did not change blood pressure and cardiac rate. Conclusions: BD decreases gastric tonus and increases gastric compliance. Saline infusion reverted such phenomena. Furthermore BD increases the time and volume sensitivity threshold in a satiety drinking test. This might explain dyspeptic complains in individuals under acute volemic imbalance.

Background: Irritable bowel syndrome (IBS) is an extremely common condition affecting approximately 10-15% of the population. Lower abdominal pain is a common feature and, if the patient also has gynaecological symptoms such as heavy periods, they may be referred to a gynaecologist especially when the bowel symptoms are relatively mild. In this setting a laparoscopy is often undertaken and endometriosis commonly identified as this condition affects up to 10% of women. Consequently pain is frequently attributed to the endometriosis even when it is relatively mild. However it is a common observation amongst gynaecologists that women with mild endometriosis often have severe symptoms which do not seem to respond well to treatment. This raises the possibility that their pain may not actually be due to endometriosis or is being amplified by the visceral hypersensitivity which is a characteristic feature of irritable bowel syndrome.Methods: 20 patients with minimal-mild endometriosis, 20 with moderate-severe endometriosis, 20 healthy volunteers (HV) who have had laparoscopy for sterilisation, 20 IBS patients and 20 patients with pain who were found to have a normal pelvis (on laparoscopy) were studied. Gastrointestinal, gynaecological, and noncolonic symptoms were recorded as well as demography, quality of life and psychological status. Visceral sensitivity was assessed in all patients and abdominal distension was studied in a sub group of 26 endometriosis patients and 20 IBS patients.Results: 20 (100%) of IBS patients, 13 (65%) of minimal-mild endometriosis patients, 11 (55%) of moderate-severe endometriosis patients, 17 (85%) of laparoscopic negative pain patients and no healthy volunteers fulfilled ROME III criteria for IBS. Patients with endometriosis and IBS had similar levels of visceral sensitivity which were significantly lower than that observed in controls (p=0·002, p<0·001).In particular, both minimal-mild and moderate-severe endometriosis patients had significantly lower (mean-95% CI) pain thresholds in mmHg 28.1(24.5, 31.6) and 28.8(24.9, 32.6) respectively compared with controls 39·5 (36·0, 43·0) p=0.001and p=0.002. However, with few exceptions, there were no distinguishing features between patients in terms of demography, symptomatology and distension.Conclusion: Clinically, it is very difficult to distinguish between endometriosis and IBS. However, visceral hypersensitivity appears to be a major component of endometriosis and may explain the problem of excessive pain especially in patients with mild disease offering a potential new target for treatment

La barrière intestinale est la plus grande surface de contact entre le milieu extérieur et le milieu intérieur. Outre ses fonctions d'absorption des nutriments, elle exerce un rôle important de défense contre les agents indésirables (toxines, bactéries) contenus dans la lumière intestinale. Une augmentation de la perméabilité intestinale a été observée chez les patients atteints du syndrome de l'intestin irritable (SII) ou des maladies inflammatoires chroniques de l'intestin (MICI). Cette hyperperméabilité intestinale est contemporaine d'une hypersensibilité viscérale à la distension de la paroi intestinale. Des travaux récents rapportent également une augmentation de l'activité protéolytique du contenu intestinal dans le cadre de ces deux pathologies. Les estrogènes, par leurs propriétés anti-inflammatoires et leur capacité à moduler la perméabilité intestinale par activation de leurs récepteurs (REs) peuvent contribuer à l'amélioration des symptômes associés à ces pathologies digestives. Une variété de traitements médicaux a été utilisée pour la prise en charge thérapeutique du SII et de MICI. Cependant, les patients questionnent les cliniciens sur des conseils diététiques susceptibles d'améliorer leur qualité de vie. Ainsi, l'objectif de ce travail était d'évaluer les effets et les mécanismes d'action impliqués, d'un traitement par du germe de soja fermenté (SG) sur l'hyperalgésie viscérale et l'hyperperméabilité intestinale dans des modèles animaux mimant le SII et les MICI afin de proposer des futures allégations santé à ce produit. Le rationnel de l'évaluation de cet ingrédient était basé sur sa composition intéressante, à savoir, sa teneur en composés à propriétés estrogéniques (isoflavones) et sa capacité à inhiber les protéases (BBI). Dans un premier temps, nous avons montré qu'un traitement oral de 15 jours par le SG diminue de façon significative l'hypersensibilité viscérale, l'hyperperméabilité intestinale ainsi que l'augmentation de l'activité protéolytique induites par un stress de contrainte chez le rat. La diminution de la perméabilité intestinale implique une surexpression de l'occludine, protéine des jonctions serrées. De même, le traitement par du SG réduit la densité des mastocytes au niveau du côlon. Tous les effets préventifs du SG sauf ceux sur l'activité protéolytique sont estrogéno-dépendants car bloqués par l'antagoniste des REs. Dans un second temps, nous avons montré qu'un traitement préventif par le SG pendant 15 jours présente des effets protecteurs vis-à-vis d'une inflammation intestinale induite par du TNBS. Le SG atténue la sévérité de l'inflammation, l'hyperperméabilité, l'hypersensibilité et l'augmentation de l'activité protéolytique induites par la colite. Les effets anti-inflammatoires du SG sont à la fois dépendants des phytoestrogènes et du contenu de l'ingrédient en BBI. En conclusion, ces données sont prometteuses pour une future utilisation du SG dans la gestion thérapeutique du SII et des MICI comme traitement adjuvant / The intestinal barrier is the largest area of contact between the external environment and internal environment. In addition to its function of nutrient absorption, the intestinal barrier plays a key role of defense against noxious agents (toxins, bacteria) contained in the intestinal lumen. An increase in intestinal permeability was observed in patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). This intestinal hyperpermeability was often associated with visceral hypersensitivity to colorectal distension. Recent studies also report an increase in the proteolytic activity in patients with IBS or IBD. Estrogens, through their anti-inflammatory properties and their ability to modulate intestinal permeability by activating estrogen receptors (ERs), can play an important role in these digestive diseases. A variety of medical therapies have been used for treatment of IBS and IBD. However, patients question clinicians about dietary suggestions to improve their symptoms and quality of life. Thus, the aim of this study was to evaluate the effects and mechanisms of action involved of a treatment with fermented soy germ (SG) on visceral hyperalgesia, intestinal hyperpermeability in animal models mimicking the IBS and IBD. The evaluation of this ingredient was based on its interesting composition, i.e its content of isoflavones and a family of serine protease inhibitors known as BBI. Initially, we demonstrated that an oral treatment of 15 days by SG significantly reduces visceral hypersensitivity, intestinal hyperpermeability and increased proteolytic activity induced by acute stress in the rat. Decreased intestinal permeability is due to overexpression of occludin, a transmembrane tight junction protein. Similarly, treatment with SG reduces the density of colonic mast cells. All preventive effects of SG except those on the proteolytic activity are estrogen-dependent because blocked by the antagonist of ERs. In a second step, we demonstrated that a treatment for 15 days with SG induces protective effects against intestinal inflammation induced by TNBS. SG reduces the severity of colitis, decreases TNBS-induced hyperpermeability, hypersensitivity and increased proteolytic activity. The anti-inflammatory effects of SG are estrogen and/or BBI dependent. In conclusion, these data are promising for future use of the SG as adjuvant therapy in IBS and IBD management

En période néonatale, la muqueuse intestinale est immature et particulièrement perméable, notamment aux facteurs environnementaux comme les toxiques, les infections mais aussi les événements stressants. De la bonne maturation de la barrière intestinale va dépendre la mise en place de l'homéostasie intestinale et donc la tolérance vis-à-vis des antigènes luminaux. La survenu d’évènements stressants durant la petite enfance est associée au déclenchement et/ou l’entretien de pathologies gastro-intestinales fonctionnelles comme le Syndrome de l’Intestin Irritable (SII) mais aussi organiques comme les Maladies Inflammatoires Chroniques de l’Intestin (MICI). De plus, ces pathologies malgré leurs différences dans la sévérité et les signes cliniques, partagent un certain nombre de caractéristiques physiopathologiques communes, comme la rupture de l’intégrité de la barrière intestinale associée à une rupture de tolérance vis-à-vis des antigènes luminaux et plus particulièrement contre le microbiote intestinal. L’objectif de ce travail a été d’évaluer les effets d’un Stress de Séparation Maternelle (SSM) sur l’homéostasie intestinale et la réponse immunitaire vis-à-vis du microbiote commensal chez la souris jeune adulte. Nos résultats ont mis en évidence un dimorphisme sexuel dans ce modèle. Chez les souris mâles jeunes adultes, le SSM diminue les fonctions de la barrière intestinale associé à une altération de la réponse humorale et cellulaire au niveau systémique vis-à-vis du microbiote commensal, ainsi qu’à un défaut des cellules présentatrices d’antigènes, conduisant à une inflammation de bas grade malgré un profil proinflammatoire des lymphocytes T. Chez les souris femelles jeunes adultes, le SSM altère la fonctionnalité des cellules de Paneth associée à surpopulation bactérienne intestinale, responsable de la sensibilité viscérale en réponse à une distension colorectale et une réponse humorale systémique dirigée contre le microbiote commensal. Nous avons mis en évidence une empreinte du SSM chez le jeune adulte, capable d'induire des modifications profondes de l’homéostasie intestinale ainsi que de la réponse immunitaire systémique contre le microbiote intestinal. Le SSM altère l'homéostasie intestinale et reproduit des caractéristiques communes aux pathologies digestives à savoir une rupture de barrière associée à une réponse immunitaire contre le microbiote sans symptômes majeurs. Ce travail a permis d'identifier la survenue d'événements stressants pendant la petite enfance comme un facteur environnemental important capable d'altérer l'homéostasie intestinale chez des individus sains et qui pourrait contribuer au déclenchement de pathologies intestinales chez des individus génétiquement prédisposés. / Perinatal period is characterized by an immature intestinal barrier particularly permeable to luminal antigens and as such highly vulnerable to environmental factors like toxins, infections or stressful events. The appropriate maturation of intestinal barrier leads to intestinal homeostasis and tolerance toward luminal contents. Early life stressful events are associated with the development and/or maintenance of functional gastrointestinal disorders like Irritable Bowel Syndrome (IBS) or organic one like Inflammatory Bowel Diseases (IBD). These pathologies are highly different in term of etiology and clinical severity however they share common features like alteration in intestinal barrier associated with an abnormal immune response toward luminal contents especially commensal microbiota. Our aim was to evaluate the consequences of maternal separation (MS) on intestinal homeostasis, host-microbiota relationship and the humoral and cellular response at adulthood. Due to sexual dimorphism in this model, the results are presented separately for male and female. In young adult male mice, MS decreases intestinal barrier functions associated with an alteration of systemic humoral and cellular response toward commensal microbiota. Moreover, a defect of antigen presenting cells in spleen leads to systemic low grade inflammation despite a pro-inflammatory profile of T cell. In young adult female mice, MS alters the functionality of Paneth cells associated with an intestinal bacterial overgrowth, leading to visceral sensitivity and systemic humoral response toward commensal microbiota. We highlighted that MS has long lasting adverse effects on intestinal homeostasis and systemic immune response toward commensal microbiota in young adult. MS impairs intestinal homeostasis in healthy individuals and might contribute to trigger intestinal pathologies in susceptible persons.