Stress has been shown to have both central and peripheral effects, promoting psychological illness (such as anxiety and depression), as well influencing peripheral disease in the intestine. Stress in humans can exacerbate symptoms of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), lowering visceral pain thresholds and decreasing mucosal barrier function. Studies in rodents have revealed that both acute and chronic exposure to stressors can lead to pathophysiology of the small and large intestine, including altered ion secretion and increased epithelial permeability (by both transcellular and paracellular pathways). Prolonged exposure to stress can induce low-grade inflammation, cause ultrastructural epithelial abnormalities, and alter bacterial-host interactions allowing greater microbial translocation. In this review, we discuss the stress response and the effects of both acute and chronic stress to induce pathophysiological damage to the gut. We present the potential pathways involved, and the proposed mechanisms of action mediating the effects. Furthermore, we explore the impact of early life stress on colonic physiology in neonatal rodents and the implications for gut dysfunction in adulthood.

Dendritic cells (DCs) are thought to play an important role in the pathogenesis of autoimmune inflammation, including Crohn's disease (CD). We investigated the distribution and state of maturation of DCs in the colon in relation to the severity of inflammation and therapy. Using archival specimens from colonic resections in 19 pediatric patients with CD and 14 controls, we identified and characterized the DCs within the lamina propria, submucosa, and muscularis compartments using morphologic and quantitative immunohistochemical methods. The distribution of CD11c+CD83+CD68+DC-SIGN+ and immature CD11c+CD83-CD68-DC-SIGN+ DCs within the different compartments varied according to the presence or absence of CD as well as to the severity of inflammation and systemic corticoid treatment. Immature DCs were only found in non-inflamed control colonic tissue. Marked reductions (60% and 30%) in total CD11c and CD83 DC numbers were observed in CD tissue samples compared with controls (P < 0.05). CD samples from patients on corticosteroid therapy were significantly more depleted than in tissue from untreated patients or those on other drugs. Colonic tissue with severe inflammation had reduced numbers of CD11c+ and CD83+ DCs in the lamina propria and submucosal compartments (80% and 76% for CD11c; 75% and 76% for CD83, respectively, P < 0.05), with a concomitant increase (525% for CD11c and 700% for CD83 P < 0.05) of DCs in the muscularis compartment, compared to moderately inflamed and non-inflamed CD tissue. Our data suggest that an imbalance in intestinal DC subpopulations may play a role in the initiation and/or the maintenance of chronic inflammation in CD. Corticosteroid therapy is associated with colonic DC depletion.

A novel approach is described using chitosan–genipin films as a sustainable method for wine preservation.

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Crohn's disease (CD) is a chronic gastrointestinal inflammatory disorder considered to be the result of an inappropriate and exaggerated mucosal immune reaction to yet undefined triggers from the gut flora in genetically predisposed individuals. This inflammatory phenomenon has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. In the gut, mucosal DCs are separated from the luminal milieu by a monolayer of cylindrical epithelial cells that forms an anatomical and physiological barrier that controls the normal traffic of antigens between both compartments. An imbalance of colonic and ileal DC distribution in tissues from CD patients as well as functional differences between DCs isolated from normal and diseased intestinal samples have been demonstrated. Moreover, a gut barrier defect in the para- and transepithelial routes in addition to a significant reduction in the intestinal secretion of epithelial products involved in barrier function has been well documented in CD. Therefore, this may expose the diseased mucosa to overwhelming amounts of antigens, resulting in abnormal DC activation and a subsequent imbalance in their distribution. In conclusion, this review provides a summary of relevant progress in CD, intestinal epithelial permeability, and DCs highlighting a potential relationship between increased epithelial permeability and abnormal DC distribution during the pathogenesis of intestinal inflammation.

The mucosal immune system is overactivated in Crohn disease (CD) and viral infections have been associated with clinical exacerbations. To investigate the potential association between mucosal inflammation and the cytokines involved in the early response to viruses, we analyzed colonic tissue levels of IL-2Ralpha, interferon-alpha, and IL-15 in CD. Patients undergoing diagnostic colonoscopy were classified into controls (n = 22) and three CD groups based on the histologic severity of inflammation and clinical activity: a) severely active CD (n = 3); b) mild to moderately active CD (n = 14); and c) quiescent CD (n = 23). Rectal biopsies (two per patient) were homogenized and cytokine levels determined by ELISA kits. Statistical analysis was performed by ANOVA with Tukey and Scheffé tests. IL-2Ralpha levels were increased in the active CD group compared with the quiescent CD group: a) 405 +/- 87, b) 159 +/- 31, and c) 33 +/- 15 pg/mg DNA (p < 0.001). The latter group was similar to controls (39 +/- 20 pg/mg DNA). Furthermore, a linear correlation (r = 0.98) between IL-2Ralpha and disease activity (Van Hees index) was observed. IL-15 levels were also higher in active compared with quiescent CD and controls: a) 0.69 +/- 0.23 and b) 0.72 +/- 0.31 versus c) 0.28 +/- 0.21 and 0.28 +/- 0.14 pg/mg DNA for controls (p < 0.05). Interferon-alpha levels were undetectable in all samples. Our data suggest that IL-2Ralpha tissue levels correlate with CD activity. IL-15 is also overproduced in inflamed CD tissue. The lack of a parallel elevation of interferon-alpha does not support a role for viral induction of IL-15 in inflamed CD samples.

We examined ileal dendritic cell (DC) subpopulations in a rat model of indomethacin-induced enteritis to determine changes in phenotype and distribution associated with increased mucosal permeability during acute and chronic stages of inflammation. Sprague-Dawley rats were treated with indomethacin (7.5 mg/kg subcutaneously, 2 injections 48 h apart). Animals were killed at day 4 (acute stage) or at day 15 or 30 (chronic stages); control rats were injected with saline. DC distribution was evaluated by immunohistochemistry for CD103, CD11b, CD83, and CD163; inflammation was assessed by light microscopy; and permeability was determined by flux of horseradish peroxidase in Ussing chambers. In controls, both immature DC subpopulations, CD103+CD11b+CD163-CD83- and CD103+CD11b-CD163-CD83-, were observed in the lamina propria, and the CD11b- population also was present in Peyer's patches. In acute inflammation, permeability was increased (P<0.01), and inflamed areas with or without ulcers were observed. CD103+ and CD11b+ (CD83-) DCs were absent from inflamed areas, reduced in noninflamed tissues, but present in Peyer's patches. In the chronic stage at day 15, CD103+ and CD11b+ cells were located in inflamed and noninflamed areas and in Peyer's patches. In addition, CD83+ DCs were detected in inflamed areas. At day 30, when we observed a complete microscopic resolution of inflammation, numbers of CD103+ and CD11b+ DCs were increased, and there were CD83+ DCs beneath the epithelial cell layer. We conclude that antigen uptake in acute inflammation may activate resident immature DCs, inducing their migration to lymphoid tissue where they mature and then return to the intestine to play a role in the local inflammatory response.

Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer death globally, and new immunotherapies developed and under development targeting PD-1/PD-L1 checkpoint inhibition require accurate patient selection to assure good clinical outcome. PD-L1 immunohistochemistry is the current biomarker assay used for patient selection, but still imprecise in predicting therapy response. Exploring this issue, we performed computational tissue analysis of PD-L1 immunostaining in procured NSCLC tissues (n = 50) using the Merck KGaA anti-PD-L1 clone MKP1A07310. Staining patterns and PD-L1 cut-off points were interrogated using relevant cancer immune-surveillance biomarkers. Groups with high PD-L1 expression levels (above 25/50% staining cut-off points) were enriched for a biomarker profile in the tumor-nest and microenvironment indicating escape from host-immunity, as represented by increased numbers of cells positive for CD8 and Granzyme B (immune-effectors), FOXP3 (immune-suppressive), and CD68 (P < 0.05). Manual analysis of PD-L1 staining patterns identified tumors with an immune-induced reactive pattern relevant for immunotherapy that would ordinarily be excluded by the arbitrary 25% staining threshold (P < 0.05). Conversely, some cases with completely or predominantly immune-independent constitutive PD-L1 staining patterns that indicate insensitivity to immunotherapy may have been incorrectly selected using this staining cut-off point criterion. Therefore, we propose differentiation of reactive vs constitutive PD-L1 staining patterns to improve the accuracy of this biomarker assay in selecting NSCLC patients for PD-1/PD-L1 immunotherapy.