Mucosal Dysfunction Research Articles

Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals.

HIV infection is associated with depletion of intestinal CD4(+) T cells, resulting in mucosal immune dysfunction, microbial translocation, chronic immune activation, and progressive immunodeficiency. In this study, we examined HIV-infected individuals with active virus replication (n = 15), treated with antiretroviral therapy (n = 13), and healthy controls (n = 11) and conducted a comparative analysis of T cells derived from blood and four gastrointestinal (GI) sites (terminal ileum, right colon, left colon, and sigmoid colon). As expected, we found that HIV infection is associated with depletion of total CD4(+) T cells as well as CD4(+)CCR5(+) T cells in all GI sites, with higher levels of these cells found in ART-treated individuals than in those with active virus replication. While the levels of both CD4(+) and CD8(+) T cell proliferation were higher in the blood of untreated HIV-infected individuals, only CD4(+) T cell proliferation was significantly increased in the gut of the same patients. We also noted that the levels of CD4(+) T cells and the percentages of CD4(+)Ki67(+) proliferating T cells are inversely correlated in both blood and intestinal tissues, thus suggesting that CD4(+) T cell homeostasis is similarly affected by HIV infection in these distinct anatomic compartments. Importantly, the level of intestinal CD4(+) T cells (both total and Th17 cells) was inversely correlated with the percentage of circulating CD4(+)Ki67(+) T cells. Collectively, these data confirm that the GI tract is a key player in the immunopathogenesis of HIV infection, and they reveal a strong association between the destruction of intestinal CD4(+) T cell homeostasis in the gut and the level of systemic CD4(+) T cell activation.

Unacceptable side-effects associated with a hyperosmolar vaginal microbicide in a phase 1 trial

We carried out a phase 1 trial of a candidate vaginal microbicide gel against HIV-1 and other sexually transmitted diseases, which contained cellulose acetate 1,2-benzenedicarboxylate (also known as cellulose acetate phthalate) in a glycerol-based vehicle. We had to terminate the study after five women had completed dosing, due to all women experiencing unacceptable vulvo-vaginal side-effects. Further investigations showed that the gel had a very high osmolality, which we believe led to excessive fluid transudation across the vaginal mucosa and acute mucosal dysfunction. We also showed that the rheology of the gel changed dramatically on fluid dilution. The osmolality and rheology of candidate microbicides and other genital mucosal products should therefore be analysed and considered at an early stage of product development.

Salivary Gland Involvement in Chronic Graft-Versus-Host Disease: Prevalence, Clinical Significance, and Recommendations for Evaluation

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Early Gut Barrier Dysfunction in Patients with Severe Acute Pancreatitis: Attenuated by Continuous Blood Purification Treatment

The aim of this study was to investigate the effect of continuous blood purification (CBP) on early gut mucosal dysfunction in patients with severe acute pancreatitis (SAP). Patients with SAP were randomized to receive 24 hours of continuous veno-venous hemofiltration (CVVH; n = 33) or no CVVH (n = 30). Blood samples were taken from the patients at 0, 6, 12, and 24 hours during CVVH therapy. Serum diamine oxidase (DAO) and endotoxin, epithelial permeability, transepithelial electrical resistance (TER) and F-actin rearrangement of the epithelial monolayer were used as the markers for the assessment of gut barrier function and the effect of CBP therapy in patients with SAP. Patients with SAP had increased levels of serum DAO, endotoxin, and epithelial permeability when compared with normal controls, and the increase was more pronounced in patients with organ dysfunction (p<0.01). F-actin rearrangement, loose cell-cell junction, and iNOS mRNA upregulation were found in all patients. After CBP treatment, Acute Physiology and Chronic Health Evaluation II score and SOFA score improved significantly; levels of serum DAO, endotoxin, and epithelial permeability decreased(p<0.05). CBP also significantly attenuated reorganization of actin and downregulated iNOS mRNA expression and NO production (p<0.05). CBP can not only improve the general conditions but also effectively improve gut barrier dysfunction. The beneficial effect of CBP on gut barrier dysfunction is associated with the improvement of cytoskeletal instability, by downregulating iNOS through the removal of excess proinflammatory factors.

Probiotics and human health: Synoptic review.

The development of probiotic, functional foods aims to “kill two birds with one stone,” which is accomplished by providing a microbial stimulus to the host immune system by means of beneficial live microorganism cultures that are characteristic of the healthy, human gut microflora. Several probiotic preparations seem to have promise in prevention or treatment of various conditions. Probiotic bacteria reinforce the different lines of gut defense, which are immune exclusion, immune elimination, and immune regulation. They stimulate non-specific host resistance to microbial pathogens, thereby aiding in pathogen eradication. Best documented clinical application of probiotics is in the treatment of acute diarrhea. In humans, documented effects were reported for the alleviation of intestinal inflammation, normalization of gut mucosal dysfunction, and down-regulation of hypersensitivity reactions. The efficacy of probiotics in acute enteric infections and post-antibiotic syndromes is now established and there is emerging evidence for a role in alleviation of necrotizing enterocolitis, irritable bowel syndrome, and some forms of inflammatory bowel disease. Probiotics are gaining importance because of their innumerable benefits, e.g. treating lactose intolerance, hypercholesterol problem, cardiac diseases and managing cardiac problems like atherosclerosis and arteriosclerosis. However, adequate information by which the consumer and health professional can judge the efficacy andsafety of retailed probiotics is lacking. Probiotic products have not been subjected to large-scale trials of efficacy that are used in the pharmaceutical industry. Without these trials and subsequent approval by fastidious regulatory agencies such as the FDA (USA), probiotics continue to languish in the self-care health market. However, the future is bright; enhanced understanding of the molecular details of host’s microflora flora interactions within the gut promises to yield new therapeutic targets and the potential to move from “bugs to drugs”. With the current focus on disease prevention and the quest for optimal health at all ages, the probiotics market potential is enormous. Health professionals are in an ideal position to help and guide their clients toward appropriate prophylactic and therapeutic uses of probiotics that deliver the desired beneficial health effects.

Importance of neural mechanisms in colonic mucosal and muscular dysfunction in adult rats following neonatal colonic irritation

Previous studies have shown that early life trauma induced by maternal separation or colonic irritation leads to hypersensitivity to colorectal distension in adulthood. We tested the hypothesis that repetitive colorectal distension in neonates leads to abnormalities in colonic permeability and smooth muscle function in the adult rat. In neonatal rats, repetitive colorectal distension was performed on days 8, 10, and 12. As adults, stool consistency was graded from 0 (formed stool) to 3 (liquid stool). Colonic tissue was isolated for histology and myeloperoxidase levels. The colonic mucosa was placed in modified Ussing chambers for measurements of permeability and short-circuit current responses to forskolin, electrical field stimulation, and carbachol. Segments of colonic musculature were placed in organ baths and contractile response to potassium chloride, electrical field stimulation, and carbachol were determined. In adult rats that experienced neonatal colonic irritation, no significant changes in colonic histology or myeloperoxidase activity were observed; however, stool consistency scores were increased. Mucosal permeability, measured as an increase in basal conductance, was significantly increased but no changes in short-circuit current responses were observed. In adulthood, rats that underwent colorectal distension as neonates exhibited an elevated smooth muscle contractile response to potassium chloride, but no changes in response to electrical field stimulation or carbachol. In summary, neonatal colonic irritation, shown previously to produce colonic hypersensitivity, leads to significant alterations in colonic mucosal and smooth muscle function characterized by loose stools, increased mucosal permeability, and increased smooth muscle contractility in the absence of colon inflammation in adulthood.

Autonomic Dysfunction in Fibromyalgia Assessed by the Composite Autonomic Symptoms Scale (COMPASS)

It has been suggested that autonomic nervous system dysfunction may explain all of fibromyalgia (FM) multisystem features. Such proposal is based mostly on the results of diverse heart rate variability analyses. The Composite Autonomic Symptom Scale (COMPASS) is a different validated method to recognize dysautonomia. The main objective of our study was to investigate symptoms of autonomic dysfunction in FM patients by means of COMPASS. A secondary objective was to define whether there is a correlation between COMPASS and Fibromyalgia Impact Questionnaire (FIQ) scores in FM patients. Design, analytical cross-sectional study. Our study population included 3 different groups of women: 30 patients with FM, 30 patients with rheumatoid arthritis, and 30 women who considered themselves healthy. All participants filled out COMPASS and FIQ questionnaires. FM patients had significantly higher values in all COMPASS domains. COMPASS total score (54.6 +/- 20.9; mean +/- standard deviation) clearly differentiated FM patients from the other 2 groups (21.6 +/- 16.5 and 9.5 +/- 10.2, respectively). P < 0.0001. The majority of FM patients gave affirmative answers to questions related to orthostatic, digestive, sleep, sudomotor, or mucosal dysfunction. There was a significant correlation between COMPASS and FIQ scores (Spearman r = 0.5, P < 0.005). Patients with FM have multiple nonpain symptoms related to different expressions of autonomic dysfunction. There is a correlation between a questionnaire that measures FM severity (FIQ) and an autonomic dysfunction questionnaire (COMPASS). Such correlation suggests that autonomic dysfunction is inherent to FM.

Modulation of fecal polyamines by viewing humorous films in patients with atopic dermatitis

Alteration of intestinal flora was involved in the pathogenesis of atopic dermatitis. Patients with atopic dermatitis were less colonized with Lactobacilli or Bifidobacterium, whereas they were more colonized with Staphylococcus aureus or Enterobacteria. Consequently, fecal levels of bacterial metabolite (polyamines) were reduced. In contrast, stress also induced intestinal mucosal dysfunction against bacteria and impaired intestinal barrier function. We studied the effect of relaxation by viewing humorous films on fecal flora and fecal levels of polyamines. Twenty-four healthy individuals and 24 patients with atopic dermatitis either viewed seven control nonhumorous films or seven humorous films sequentially for 7 days. Before and after viewing, feces were obtained, and fecal flora and fecal levels of polyamines were assessed. Neither viewing humorous films nor viewing control nonhumorous films had any effect on healthy individuals. In contrast, viewing humorous films (i) increased colonization with lactobacilli and bifidobacterium, (ii) decreased colonization with S. aureus and Enterobacteria, and (iii) increased fecal levels of polyamines; whereas viewing control nonhumorous films failed to do so in patients with atopic dermatitis. Viewing humorous films may modulate fecal levels of polyamines by restoring intestinal flora in atopic dermatitis.

Tumor necrosis factor-α mediates hyperglycemia-augmented gut barrier dysfunction in endotoxemia*

To examine whether hyperglycemia would augment gut barrier dysfunction and inflammatory responses in endotoxemic rats, and simultaneously to clarify the roles of tumor necrosis factor (TNF)-alpha in alterations of gut mucosal permeability associated with hyperglycemia. Prospective randomized animal study. University research laboratory. : Male Wistar rats treated with lipopolysaccharide (LPS) injection. After LPS injection (4 mg/kg), rats were randomly allocated into group S (n = 6), group G (n = 7), or group GI (n = 8) with continuous infusion of different fluid solutions: normal saline, 40% glucose or 10% glucose mixed with insulin, respectively. Blood glucose, insulin, and proinflammatory cytokines, accompanied by gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran, were measured. Bacterial growth or alterations in mesenteric lymph nodes and cecal contents were also assessed. We further determined the roles of TNF-alpha using an inhibitor of TNF-alpha converting enzyme in gut barrier dysfunction under the same experimental settings. Hyperglycemia over 400 mg/dL was achieved and kept in group G during the study period whereas normoglycemia was preserved in group S and GI, the latter of which showed the similar extent of hyperinsulinemia to group G. Plasma concentrations of fluorescence-labeled dextran and TNF-alpha in group G were significantly higher vs. group S and GI, and the number of bacteria found in mesenteric lymph nodes in group G was greater compared with group S. Intestinal environments including microflora and organic acids were not altered by blood glucose or insulin level. Inhibiting conversion of membrane-bound to soluble type of TNF-alpha restored gut mucosal permeability augmented by hyperglycemia. These findings indicate that hyperglycemia deteriorates LPS-elicited gut barrier dysfunction and bacterial translocation independently of plasma insulin level, and that TNF-alpha mediates such mucosal dysfunction of gut in endotoxemia.

The Impact of Probiotic on Gut Health

The gastrointestinal tract (GIT) microbiota plays an important role in host health due to its involvement in nutritional, immunologic and physiological functions. Microbial imbalances have been associated with enhanced risk of specific diseases. This observation has allowed the introduction of microorganisms as probiotics which are microbes with demonstrated health benefits in humans when ingested in foods. The mechanisms of action include the inhibition of pathogen growth by competition for nutritional sources and adhesion sites, secretion of antimicrobial substances, toxin inactivation. Consequently, the primary clinical interest in the application of probiotics has been in the prevention and treatment of gastrointestinal infections and antibiotic-associated diarrhea diseases. The well-characterized immunomodulatory potential of specific probiotic strains, beyond the effect on the composition of the microbiota, has been be used as innovative tools to alleviate intestinal inflammation, normalize gut mucosal dysfunction, and down-regulate hypersensitivity reactions. Clinical efficacy of specific probiotic strains has been demonstrated in, rotavirus's diarrhea, antibiotic associated diarrhea, irritable bowel syndrome and food allergies. Further, recent clinical and nutritional studies have uncovered the function of specific strains in energy metabolism and thereby have opened up new angles on their exploitation. However, as these processes are highly specific, it is important to characterize the properties of specific probiotic strains an in order to select the best strains or strain combinations for the target in question. Advances have prompted increased the interest of researchers and industry and new applications and targets are being discovered.

Gallbladder emptying in patients with primary sclerosing cholangitis

To assess gallbladder emptying and its association with cholecystitis and abdominal pain in patients with primary sclerosing cholangitis (PSC). Twenty patients with PSC and ten healthy subjects were investigated. Gallbladder fasting volume, ejection fraction and residual volume after ingestion of a test meal were compared in patients with PSC and healthy controls using magnetic resonance imaging. Symptoms, thickness and contrast enhancement of the gallbladder wall and the presence of cystic duct strictures were also assessed. Median fasting gallbladder volume in patients with PSC [67 (19-348) mL] was twice that in healthy controls [32 (16-55) mL] (P < 0.05). The median postprandial gallbladder volume in patients with PSC was significantly larger than that in healthy controls (P < 0.05). There was no difference in ejection fraction, gallbladder emptying volume or mean thickness of the gallbladder wall between PSC patients and controls. Contrast enhancement of the gallbladder wall in PSC patients was higher than that in controls; (69% +/- 32%) and (42% +/- 21%) (P < 0.05). No significant association was found between the gallbladder volumes and occurrence of abdominal pain in patients and controls. Patients with PSC have increased fasting gallbladder volume. Gallbladder Mucosal dysfunction secondary to chronic cholecystitis, may be a possible mechanism for increased gallbladder.

Enteral feeding induces diet-dependent mucosal dysfunction, bacterial proliferation, and necrotizing enterocolitis in preterm pigs on parenteral nutrition

Preterm neonates have an immature gut and metabolism and may benefit from total parenteral nutrition (TPN) before enteral food is introduced. Conversely, delayed enteral feeding may inhibit gut maturation and sensitize to necrotizing enterocolitis (NEC). Intestinal mass and NEC lesions were first recorded in preterm pigs fed enterally (porcine colostrum, bovine colostrum, or formula for 20-40 h), with or without a preceding 2- to 3-day TPN period (n = 435). Mucosal mass increased during TPN and further after enteral feeding to reach an intestinal mass similar to that in enterally fed pigs without TPN (+60-80% relative to birth). NEC developed only after enteral feeding but more often after a preceding TPN period for both sow's colostrum (26 vs. 5%) and formula (62 vs. 39%, both P < 0.001, n = 43-170). Further studies in 3-day-old TPN pigs fed enterally showed that formula feeding decreased villus height and nutrient digestive capacity and increased luminal lactic acid and NEC lesions, compared with colostrum (bovine or porcine, P < 0.05). Mucosal microbial diversity increased with enteral feeding, and Clostridium perfringens density was related to NEC severity. Formula feeding decreased plasma arginine, citrulline, ornithine, and tissue antioxidants, whereas tissue nitric oxide synthetase and gut permeability increased, relative to colostrum (all P < 0.05). In conclusion, enteral feeding is associated with gut dysfunction, microbial imbalance, and NEC in preterm pigs, especially in pigs fed formula after TPN. Conversely, colostrum milk diets improve gut maturation and NEC resistance in preterm pigs subjected to a few days of TPN after birth.

Two Cases of Crohnʼs Disease in the Setting of past Necrotizing Enterocolitis

Purpose: Two 23 year-old women with histories of necrotizing enterocolitis (NEC) subsequently developed Crohn's disease (CD). The first had significant small bowel and colon resection as an infant; she required hyperalimentation until age 4. She was well until age 10, when she presented with abdominal pain and was found to have ileal CD. Her course was complicated by perirectal abscess/fistula treated with incision and drainage and later a fibrin plug. Past medical therapy for CD has included 5-ASAs and antibiotics; 6-mercaptopurine was recently initiated to treat mild active ileal disease and a small rectovaginal fistula. The second patient underwent extensive small bowel resection as an infant and 1 year of enteral tube feeding. She was well until age 19, when she developed diarrhea, nausea and weight loss, and eventually diagnosed with ileal CD: 5-ASA and steroids were not helpful. Adalimumab was initiated with good effect for several months but was stopped after miscommunication with her doctor. One month later, the patient presented with clinical and radiographic small bowel obstruction: surgical exploration revealed ∼ 130 cm of intact small bowel with two distal ileal strictures and an inflammatory mass; ∼ 10 cm was resected and a primary ileocolonic anastomosis performed. Post-operatively, she has been in clinical remission for 7 months; adalimumab was reinstituted given her previous response and the serious potential consequence of short-gut syndrome with a future flare and/or surgery. A colonoscopy 6 months after surgery showed minimal inflammation at the anastomosis. NEC is the most common life-threatening gastrointestinal disorder seen in neonates. The distal small bowel and proximal colon are usually involved, with extensive neutrophilic infiltrate and hemorrhagic necrosis seen on pathology. While the pathogenesis appears multifactorial, 90% of NEC cases occur in premature infants: intestinal ischemia combined with luminal antigen exposure during enteral feeding are key putative events. TNF-α is an important inflammatory mediator and potent vasoconstrictor which has been implicated mechanistically in both NEC and CD. Further, failure of enteric glial cells (EGC) to appropriately respond to ischemic injury has been demonstrated in NEC, and disruption of the EGC network in CD may increase mucosal permeability and vascular dysfunction. These possible links in the pathogenesis of NEC and CD coupled with the above two cases of CD post-NEC are compelling arguments for further study to delineate the commonalities between these two diseases.

Understanding Why Probiotic Therapies Can be Effective in Treating IBD

Probiotics, for the treatment of inflammatory bowel disease, are a group of specific nonpathogenic bacteria that are functionally and genetically defined by their ability to reduce inflammation in the intestine. Although probiotics also seem to have broad beneficial effects in humans, both as a food and as a therapeutic agent, there are specific identified mechanisms in some, but not all, of these bacteria that are important relative to the pathogenesis of inflammatory bowel disease. Recently, studies relative to the mechanism of action of probiotics have identified that these organisms can have a direct effect on epithelial cell function and intestinal health, including enhancing epithelial barrier function, modulating epithelial cytokine secretion into an anti-inflammatory dominant profile, altering mucus production, changing bacterial luminal flora, modifying the innate and systemic immune system, and inducing regulatory T-cell effects. For probiotics to have a therapeutic role in the management of clinical inflammatory bowel disease, their therapeutic mechanism of action must be aligned with the pathogenic mechanism of action of the disease. In this regard, the role of probiotics for the clinical treatment of inflammatory bowel disease is emerging as the mechanisms and pathogenesis are being unraveled. It remains clear that probiotics are able to reduce gastrointestinal inflammation by exerting positive effects on epithelial cell and mucosal immune dysfunction.

Human eosinophil adhesion and degranulation stimulated with eotaxin and RANTES in vitro: Lack of interaction with nitric oxide

BackgroundAirway eosinophilia is considered a central event in the pathogenesis of asthma. The toxic components of eosinophils are thought to be important in inducing bronchial mucosal injury and dysfunction. Previous studies have suggested an interaction between nitric oxide (NO) and chemokines in modulating eosinophil functions, but this is still conflicting. In the present study, we have carried out functional assays (adhesion and degranulation) and flow cytometry analysis of adhesion molecules (VLA-4 and Mac-1 expression) to evaluate the interactions between NO and CC-chemokines (eotaxin and RANTES) in human eosinophils.MethodsEosinophils were purified using a percoll gradient followed by immunomagnetic cell separator. Cell adhesion and degranulation were evaluated by measuring eosinophil peroxidase (EPO) activity, whereas expression of Mac-1 and VLA-4 was detected using flow cytometry.ResultsAt 4 h incubation, both eotaxin (100 ng/ml) and RANTES (1000 ng/ml) increased by 133% and 131% eosinophil adhesion, respectively. L-NAME alone (but not D-NAME) also increased the eosinophil adhesion, but the co-incubation of L-NAME with eotaxin or RANTES did not further affect the increased adhesion seen with chemokines alone. In addition, L-NAME alone (but not D-NAME) caused a significant cell degranulation, but it did not affect the CC-chemokine-induced cell degranulation. Incubation of eosinophils with eotaxin or RANTES, in absence or presence of L-NAME, did not affect the expression of VLA-4 and Mac-1 on eosinophil surface. Eotaxin and RANTES (100 ng/ml each) also failed to elevate the cyclic GMP levels above baseline in human eosinophils.ConclusionEotaxin and RANTES increase the eosinophil adhesion to fibronectin-coated plates and promote cell degranulation by NO-independent mechanisms. The failure of CC-chemokines to affect VLA-4 and Mac-1 expression suggests that changes in integrin function (avidity or affinity) are rather involved in the enhanced adhesion.

Early Administration of Probiotics Alters Bacterial Colonization and Limits Diet-Induced Gut Dysfunction and Severity of Necrotizing Enterocolitis in Preterm Pigs 3

Following preterm birth, bacterial colonization and enteral formula feeding predispose neonates to gut dysfunction and necrotizing enterocolitis (NEC), a serious gastrointestinal inflammatory disease. We hypothesized that administration of probiotics would beneficially influence early bacterial colonization, thereby reducing the susceptibility to formula-induced gut atrophy, dysfunction, and NEC. Caesarean-delivered preterm pigs were provided total parenteral nutrition (1.5 d) followed by enteral feeding (2 d) with porcine colostrum (COLOS; n = 5), formula (FORM; n = 9), or formula with probiotics (FORM-P; Bifidobacterium animalis and Lactobacillus: L. acidophilus,L. casei,L. pentosus,L. plantarum; n = 13). Clinical NEC scores were reduced (P < 0.05) in FORM-P (2.0 ± 0.2) and COLOS groups (1.7 ± 0.5) compared with FORM pigs (3.4 ± 0.6). Lower NEC scores were associated with elevated intestinal weight, mucosa proportion, villus height, RNA integrity, and brush border aminopeptidase A and N activities, and lower gastric organic acid concentration in the FORM-P and COLOS groups (P < 0.05). Diversity of the mucosa-associated bacteria in the distal small intestine was similar among formula-fed pigs, yet the abundance of specific bacterial groups differed between FORM-P and FORM pigs. FORM-P pigs had lower colonization density of a potential pathogen, Clostridium perfringens, and had commensal Lactobacillus bacteria more closely associated with enterocytes along the villus-crypt axis relative to FORM pigs. These results suggest that probiotic administration immediately after birth promotes the colonization of a beneficial commensal microbiota capable of limiting the formula-induced mucosal atrophy, dysfunction, and pathogen load in preterm neonates, thereby reducing the incidence and severity of NEC.

Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress

Chronic psychological stress causes intestinal barrier dysfunction and impairs host defense mechanisms mediated by corticotrophin-releasing factor (CRF) and mast cells; however, the exact pathways involved are unclear. Here we investigated the effect of chronic CRF administration on colonic permeability and ion transport functions in rats and the role of mast cells in maintaining the abnormalities. CRF was delivered over 12 days via osmotic minipumps implanted subcutaneously in wild-type (+/+) and mast cell-deficient (Ws/Ws) rats. Colonic segments were excised for ex vivo functional studies in Ussing chambers [short-circuit current (Isc), conductance (G), and macromolecular permeability (horseradish peroxidase flux)], and analysis of morphological changes (mast cell numbers and bacterial host-interactions) was determined by light and electron microscopy. Chronic CRF treatment resulted in colonic mucosal dysfunction with increased Isc, G, and horseradish peroxidase flux in+/+but not in Ws/Ws rats. Furthermore, CRF administration caused mast cell hyperplasia and abnormal bacterial attachment and/or penetration into the mucosa only in+/+rats. Finally, selective CRF agonist/antagonist studies revealed that stimulation of CRF-R1 and CRF-R2 receptors induced the elevated secretory state and permeability dysfunction, respectively. Chronic CRF causes colonic barrier dysfunction in rats, which is mediated, at least in part, via mast cells. This information may be useful in designing novel treatment strategies for stress-related gastrointestinal disorders.

Probiotics: Use in Allergic Disorders

The underlying denominators and treatment targets in allergic disorders may be outlined as aberrant barrier functions of the skin epithelium and gut mucosa and dysregulation of the immune response to ubiquitous environmental antigens. Dietary methods to control symptoms and reduce the risk of allergic disease have hitherto focused on elimination diets, alone or in combination with other environmental measures. The results have not been satisfactory regarding long-term prevention, and new approaches are urgently needed. Realization of this, together with the demonstration that the immunophysiologic regulation in the gut depends on the establishment of the healthy gut microbiota, has led to the introduction of novel modes of therapeutic intervention on the basis of the consumption of monocultures and mixed cultures of beneficial live probiotic microorganisms. The current aims of intervention are to avert deviant microbiota development, strengthen the gut barrier function, and alleviate abnormal immune responsiveness. Specific probiotics, selected from members of the healthy intestinal microbiota most of them belonging to Lactobacillus or Bifidobacterium, aid in degradation/structural modification of enteral antigens, regulation of the secretion of inflammatory mediators, and direction of the development of the immune system during the critical period of life when these functions are immature and inexperienced and the risk of allergic disease is heightened. In humans, documented effects have been reported for alleviation of intestinal inflammation, normalization of gut mucosal dysfunction, and down-regulation of hypersensitivity reactions, thereby preferentially targeting allergic conditions with intestinal involvement. The probiotic performance of strains differs; each probiotic strain is a unique organism itself with specific properties that cannot be extrapolated from other, even closely related, strains. Moreover, it would seem simplistic to assume that a single supplementation would suffice to counter the plethora of allergic disease. First, it needs to be acknowledged that a more profound understanding of the complex nature of allergic disorders is needed, as it is likely that there are distinct etiologic factors and pathogenetic mechanisms underlying the heterogeneous manifestations. Second, host-related factors influence the probiotic effects; the distinction in the antiallergic potential of probiotics can be explained by the age of the host and the habitual diet with other potentially active compounds and their conceivable joint probiotic effects. Therefore, research activities are currently focusing on identification of specific strains with immunomodulatory potential, and on the question how the food matrix and dietary content interact with the most efficacious probiotic strains or specific strain combinations.

807 Repetitive Colorectal Distension in Neonatal Rats Induces Colonic Mucosal and Muscular Dysfunction in Adulthood

807 Repetitive Colorectal Distension in Neonatal Rats Induces Colonic Mucosal and Muscular Dysfunction in Adulthood

Maladaptive Intestinal Epithelial Responses to Life Stress May Predispose Healthy Women to Gut Mucosal Inflammation

Irritable bowel syndrome (IBS), a highly prevalent disorder among women, has been associated with life stress, but the peripheral mechanisms involved remain largely unexplored. A 20-cm jejunal segment perfusion was performed in 2 groups of young healthy women, equilibrated by menstrual phase, experiencing either low (LS; n = 13) or moderate background stress (MS; n = 11). Intestinal effluents were collected every 15 minutes, for 30 minutes under basal conditions, and for 1 hour after cold pain stress. Cardiovascular and psychological response, changes in circulating stress and gonadal hormones, and epithelial function (net water flux, albumin output and luminal release of tryptase and alpha-defensins) to cold stress were determined. Cold pain induced a psychological response stronger in the MS than in the LS group, but similar increases in heart rate, blood pressure, adrenocorticotrophic hormone, and cortisol, whereas estradiol and progesterone remained unaltered. Notably, the jejunal epithelium of MS females showed a chloride-related decrease in peak secretory response (Delta[15-0 minutes]: LS, 97.5 [68.4-135.0]; MS, 48.8 [36.6-65.0] microL/min/cm; P < .001) combined with a marked enhancement of albumin permeability (LS(AUC), 6.35 [0.9-9.6]; MS(AUC), 13.97 [8.3-23.1] mg/60 min; P = .008) after cold stress. Epithelial response in both groups was associated with similar increases in luminal tryptase and alpha-defensins release. Increased exposure to life events determines a defective jejunal epithelial response to incoming stimuli. This abnormal response may represent an initial step in the development of prolonged mucosal dysfunction, a finding that could be linked to enhanced susceptibility for IBS.