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To determine the effect of peripheral CRF on intestinal barrier function in diarrhea-predominant IBS (IBS-D). Irritable bowel syndrome (IBS) pathophysiology has been linked to life stress, epithelial barrier dysfunction, and mast cell activation. Corticotropin-releasing factor (CRF) is a major mediator of stress responses in the gastrointestinal tract, yet its role on IBS mucosal function remains largely unknown. Intestinal response to sequential i.v. 5-mL saline solution (placebo) and CRF (100 μg) was evaluated in 21 IBS-D and 17 healthy subjects (HSs). A 20-cm jejunal segment was perfused with an isosmotic solution and effluents collected at baseline, 30 minutes after placebo, and 60 minutes after CRF. We measured water flux, albumin output, tryptase release, stress hormones, cardiovascular and psychological responses, and abdominal pain. A jejunal biopsy was obtained for CRF receptor expression assessment. Water flux did not change after placebo in IBS-D and HS but significantly increased after CRF in IBS-D (P = 0.007). Basal luminal output of albumin was higher in IBS-D and increased further after CRF in IBS-D (P = 0.042). Basal jejunal tryptase release was higher in IBS-D, and CRF significantly increased it in both groups (P = 0.004), the response being higher in IBS-D than in HS (P = 0.0023). Abdominal pain worsened only in IBS-D after CRF and correlated with jejunal tryptase release, water flux, and albumin output. IBS-D displayed jejunal up-regulation of CRF2 and down-regulation of CRF1 compared with HS. Stress via CRF-driven mast cell activation seems to be relevant in the pathophysiology of IBS-D.

Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h [95% CI −3·05 to −0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. AbbVie.

High ambient temperature has multiple potential effects on the organism such as hyperthermia, endotoxemia, and/or systemic inflammation. However, it is often difficult to discriminate between cause and consequence of phenotypic effects, such as the indirect influence of heat stress via reduced food intake. Lactating dairy cows are a particularly sensitive model to examine the effects of heat stress due to their intensive metabolic heat production and small surface:volume ratio. Results from this model show heat stress directly induced a so-far unknown infiltration of yet uncategorized cells into the mucosa and submucosa of the jejunum. Due to a pair-feeding design, we can exclude this effect being a consequence of the concurrent heat-induced reduction in feed intake. Isolation and characterization of the infiltrating cells using laser capture microdissection and RNA sequencing indicated a myeloic origin and macrophage-like phenotype. Furthermore, targeted transcriptome analyses provided evidence of activated immune- and phagocytosis-related pathways with LPS and cytokines as upstream regulators directly associated with heat stress. Finally, we obtained indication that heat stress may directly alter jejunal tight junction proteins suggesting an impaired intestinal barrier. The penetration of toxic and bacterial compounds during heat stress may have triggered a modulated immune repertoire and induced an antioxidative defense mechanism to maintain homeostasis between commensal bacteria and the jejunal immune system. Our bovine model indicates direct effects of heat stress on the jejunum of mammals already at moderately elevated ambient temperature. These results need to be considered when developing concepts to combat the negative consequences of heat stress.

Although fat is a crucial source of energy in diets, excessive intake leads to obesity. Fat absorption in the gut is prevailingly thought to occur organ-autonomously by diffusion 1 – 3 . Whether the process is controlled by the brain-to-gut axis, however, remains largely unknown. Here we demonstrate that the dorsal motor nucleus of vagus (DMV) plays a key part in this process. Inactivation of DMV neurons reduces intestinal fat absorption and consequently causes weight loss, whereas activation of the DMV increases fat absorption and weight gain. Notably, the inactivation of a subpopulation of DMV neurons that project to the jejunum shortens the length of microvilli, thereby reducing fat absorption. Moreover, we identify a natural compound, puerarin, that mimics the suppression of the DMV–vagus pathway, which in turn leads to reduced fat absorption. Photoaffinity chemical methods and cryogenic electron microscopy of the structure of a GABA A receptor–puerarin complex reveal that puerarin binds to an allosteric modulatory site. Notably, conditional Gabra1 knockout in the DMV largely abolishes puerarin-induced intestinal fat loss. In summary, we discover that suppression of the DMV–vagus–jejunum axis controls intestinal fat absorption by shortening the length of microvilli and illustrate the therapeutic potential of puerarin binding to GABRA1 in fat loss. Neurons in the dorsal motor nucleus of vagus are involved in the absorption of fat in the intestine, and the natural compound puerarin shows utility in modulating this brain–gut axis to reduce fat absorption.

This study aimed to determine the effects of Saccharomyces yeast postbiotics on cell turnover, immune responses, and oxidative stress in the jejunal mucosa of pigs. Thirty-two newly weaned pigs at 6.05 ± 0.24 kg were assigned to two dietary treatments based on a randomized complete block design. The treatments were control group receiving a basal diet and a group supplemented with Saccharomyces yeast postbiotics (175 g/ton diet) in the basal diet. After 35 d of the study, pigs were euthanized and jejunal mucosa were collected to assess immune status, oxidative stress, barrier markers, cell proliferation, and apoptosis. Saccharomyces yeast postbiotics reduced ( P  < 0.05) the fecal score from d 3 to d 7 and tended to increase the gene expression of interferon-γ (IFN-γ) ( P  = 0.071) and mammalian/mechanistic target of rapamycin (mTOR) ( P  = 0.080), decrease the gene expression of B-cell lymphoma 2-associated X protein 1 (BAX1) ( P  < 0.05), tended to decrease the gene expression of serum and glucocorticoid-induced protein kinase 1 (SGK1) ( P  = 0.066), increased ( P  < 0.05) cell proliferation in the crypts, and tended to increase the villus height ( P  = 0.078) and crypt depth ( P  = 0.052) in the jejunum. In conclusion, the supplementation of Saccharomyces yeast postbiotics in nursery diets reduced diarrhea within the first week after weaning and provided protection to the villi in the jejunum by enhancing the immune responses of nursery pigs, promoting crypt cell proliferation, and reducing the expression of genes associated with apoptosis without affecting inflammatory and oxidative stress status in the jejunum of the nursery pigs.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children 1 . The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence 2 . Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy. In a first step toward developing autologous tissue grafts for the treatment of children with intestinal failure, patient-derived jejunal organoids seeded on scaffolds of decellularized human intestinal matrix formed grafts that had jejunal properties and formed luminal structures when transplanted into mice.

ObjectiveMicro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established. Our aims were (1) to identify miRNAs differentially expressed in the small bowel mucosa of patients with IBS-D and (2) to explore putative target genes specifically involved in epithelial barrier function that are controlled by specific dysregulated IBS-D miRNAs.DesignHealthy controls and patients meeting Rome III IBS-D criteria were studied. Intestinal tissue samples were analysed to identify potential candidates by: (a) miRNA-mRNA profiling; (b) miRNA-mRNA pairing analysis to assess the co-expression profile of miRNA-mRNA pairs; (c) pathway analysis and upstream regulator identification; (d) miRNA and target mRNA validation. Candidate miRNA-mRNA pairs were functionally assessed in intestinal epithelial cells.ResultsIBS-D samples showed distinct miRNA and mRNA profiles compared with healthy controls. TJ signalling was associated with the IBS-D transcriptional profile. Further validation of selected genes showed consistent upregulation in 75% of genes involved in epithelial barrier function. Bioinformatic analysis of putative miRNA binding sites identified hsa-miR-125b-5p and hsa-miR-16 as regulating expression of the TJ genes CGN (cingulin) and CLDN2 (claudin-2), respectively. Consistently, protein expression of CGN and CLDN2 was upregulated in IBS-D, while the respective targeting miRNAs were downregulated. In addition, bowel dysfunction, perceived stress and depression and number of mast cells correlated with the expression of hsa-miR-125b-5p and hsa-miR-16 and their respective target proteins.ConclusionsModulation of the intestinal epithelial barrier function in IBS-D involves both transcriptional and post-transcriptional mechanisms. These molecular mechanisms include miRNAs as master regulators in controlling the expression of TJ proteins and are associated with major clinical symptoms.

High ambient temperatures negatively affect the human well-being as well as animal welfare and production. The gastrointestinal tract is predominantly responsive to heat stress. The currently available information about the multifaceted response to heat stress within different parts of the intestine is limited, especially in avian species. Hence, this study aims to evaluate the heat stress-induced sequence of events in the intestines of chickens. Furthermore, the gut health-promoting effect of dietary galacto-oligosaccharides (GOS) was investigated in these heat stress-exposed chickens. Chickens were fed a control diet or diet supplemented with 1% or 2.5% GOS (6 days) prior to and during a temperature challenge for 5 days (38-39°C, 8h per day). The parameters measured in different parts of the intestines included the genes (qPCR) HSF1, HSF3, HSP70, HSP90, E-cadherin, claudin-1, claudin-5, ZO-1, occludin, TLR-2, TLR-4, IL-6, IL-8, HO-1, HIF-1α) and their associated proteins HSP70, HSP90 and pan-cadherin (western blots). In addition, IL-6 and IL-8 plasma concentrations were measured by ELISA. In the jejunum, HSF3, HSP70, HSP90, E-cadherin, claudin-5, ZO-1, TLR-4, IL-6 and IL-8 mRNA expression and HSP70 protein expression were increased after heat stress exposure and a more pronounced increase in gene expression was observed in ileum after heat stress exposure, and in addition HSF1, claudin-1 and HIF-1α mRNA levels were upregulated. Furthermore, the IL-8 plasma levels were decreased in chickens exposed to heat stress. Interestingly, the heat stress-related effects in the jejunum were prevented in chickens fed a GOS diet, while dietary GOS did not alter these effects in ileum. In conclusion, our results demonstrate the differences in susceptibility to heat stress along the intestine, where the most obvious modification in gene expression is observed in ileum, while dietary GOS only prevent the heat stress-related changes in jejunum.

The most widely used cancer therapy is radiation therapy, but radiation damage to healthy tissues, particularly the gastrointestinal (GI) system, frequently reduces its effectiveness. This study investigates whether etoricoxib-loaded nanostructured lipid carriers (Et-NLC) could help shield the rat jejunum from radiation damage. Gamma irradiation (6 Gy) was used to damage the jejunum of Wistar albino rats, and then Et or Et-NLC (10 mg/kg b.w.) was administered orally for 14 days. It was found that the amounts of glutathione S-transferase (GST), superoxide dismutase (SOD), and nitric oxide (NO) decreased after irradiation but increased after Et-NLC therapy. Molecular analysis showed radiation-induced expression of microRNA-34a (miR34a), which may be involved in cellular stress response. Et-NLC treatments modulated the expression of miR34a, suggesting possible regulatory roles. Western blot analysis revealed changes in P53, interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2 (COX-2) levels. Et-NLC treatments decreased TNF-α, IL-6, IL-10, and COX-2 levels, indicating anti-inflammatory actions. DNA fragmentation analysis revealed a decrease in apoptotic activity after Et-NLC treatments. A histopathological examination confirmed that Et-NLC treatments had attenuated radiation damage, which had improved vascularization and reduced inflammation. The findings show that Et-NLC is more effective than Et-alone at reducing damage to the jejunum caused by radiation by controlling inflammation, oxidative stress, and apoptotic activity.

Objective Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. Design Germ-free mice aged 8–10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, 1H NMR metabonomics and microbiota phylogenetic profiling analyses were used. Results The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4–30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. Conclusion This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance.