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Hang Viet Dao,1– 3 Long Bao Hoang,3 Binh Phuc Nguyen,3 Hoa Lan Nguyen,4 Robert Goldberg,4 Jeroan Allison,4 Thi Minh An Dao,5,6 Tomoaki Matsumura,7 Long Van Dao1,3 1Internal Medicine Faculty, Hanoi Medical University, Hanoi, Vietnam; 2Endoscopy Center, Hanoi Medical University Hospital, Hanoi, Vietnam; 3Institute of Gastroenterology and Hepatology, Hanoi, Vietnam; 4Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA; 5School of Public Health, University of Queensland, Brisbane, Australia; 6Epidemiology Department, Hanoi Medical University, Hanoi, Vietnam; 7Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, JapanCorrespondence: Hang Viet Dao, Institute of Gastroenterology and Hepatology, Floor 10, VCCI Tower, No. 9, Dao Duy Anh Street, Dong Da District, Hanoi City, 10000, Vietnam, Tel +84987988075, Email daoviethang@hmu.edu.vnPurpose: Esophageal mucosal admittance (MA) is a promising diagnostic method for gastroesophageal reflux disease (GERD). We conducted a study to describe the esophageal MA in patients with reflux symptoms and determine its diagnostic accuracy.Patients and Methods: We recruited 92 patients with ambulatory pH-impedance monitoring, upper gastrointestinal endoscopy, and MA measured by the tissue conductance meter. MA was measured during endoscopy at 5cm (distal esophagus) and 15cm above the Z line (middle esophagus), repeated at least five times at each position, and median MA was obtained. Afterwards, two biopsies were taken 5cm above the Z line for histopathological evaluation using the Esohisto criteria. Patients were classified as GERD or non-GERD according to the 2018 Lyon consensus.Results: The mean age was 43.2 years, and 42 patients were males. The most common symptoms were regurgitation (75.0%), belching (65.2%), and heartburn (46.7%). Twenty-three (32.3%) were diagnosed with GERD using the Lyon consensus, and 24 (26.1%) had esophagitis on histopathology. The median MA at the distal and middle esophagus was moderately correlated. The median MA at both positions was higher in the GERD group but only statistically significant in the middle esophagus. MA was not associated with pH-impedance parameters and esophagitis on histopathology. The diagnostic model developed using the logistic regression did not have good accuracy.Conclusion: MA was not different between GERD and non-GERD patients.Keywords: mucosal permeability, tissue conductance meter, pH-impedance monitoring, Lyon consensus

Cytisine (CYT) has emerged as a promising molecule to treat nicotine addiction, since it acts as a partial agonist of nicotinic acetylcholine receptors. However, its unfavorable pharmacokinetic properties lead to multiple administrations per day, reducing the patient's compliance and increasing the side effects. To overcome these drawbacks, CYT buccal administration is here proposed. Firstly, CYT stability in the buccal environment was assessed and its intrinsic ability to permeate/penetrate the tissue was determined by applying CYT solutions at increasing concentrations. Furthermore, a spray-drying method was selected and optimized as it is an eco-friendly, easily scalable and effective technique to obtain uniform and reproducible CYT-loaded (5% w/w) pharmaceutical powders, which were directly compressed, thus obtaining different buccal delivery systems (BDSs). The obtained BDSs were homogeneous and reproducible and embedded CYT in its amorphous form. The mechanism of CYT release was evaluated in vitro and found to be mainly driven by a Fickian diffusion phenomenon. Predominantly, the ex vivo permeation assays highlighted the ability of the BDSs to enhance CYT permeation, also producing high drug fluxes through the mucosa. Speculative mathematical evaluations based on the already-known CYT pharmacokinetic parameters showed that CYT-loaded BDSs could potentially be sufficient to obtain a therapeutic effect, thus making the reported formulations suitable candidates for further in vivo trials. [ABSTRACT FROM AUTHOR]

This study investigated the efficiency and the related mechanisms of a new absorption enhancer, DL-malic acid (MA), on the oral bioavailability of docetaxel (DTX). Polyethylene glycol polycarbonate (PEG-PCL) modified liposomes (PLip) were prepared for DTX, and incorporated into the pH-sensitive microspheres (MS) with sustained release. MA decreased the transepithelial electrical resistance (TEER) across a Caco-2 cell monolayer by 20% and 57% after 2 and 3 h of co-incubation with DTX-PLip and the cells, respectively, indicating that MA could open tight junctions but not instantaneously. After long enough exposure (4 h) of MA to the small intestine of rats, only the absorption rate constant (ka) of DTX-PLip, but not Duopafei®, was increased, which could be related to the intestinal mucosal permeability of DTX. After co-administration in rats, MA significantly enhanced the oral bioavailability of DTX in DTX-PLip-MS from 44.67% to 81.27%, rather than DTX-PLip and Duopafei®, which could be related to the prolonged intestinal retention time of DTX-PLip via the MS and the promoted drug intercellular transport by MA. The absorption-enhancing effects of MA on DTX-PLip-MS were further confirmed by in vivo imaging. The above findings suggest that MA served as a new and efficient absorption enhancer for DTX-PLip-MS. In this study, malic acid as a new absorption enhancer for DTX in polymer-liposome (PLip) embedded in pH-sensitive microspheres (MS) was found for the first time. The malic acid could significantly enhance oral bioavailability of DTX in DTX-PLip-MS (from 44.67 % to 81.27%) rather than Duopafei® and DTX-PLip after co-administration. The absorption enhancement may be closely related to the intestinal retention time and mucosal permeability. These findings will provide an important reference for the study of absorption enhancers for promoting intercellular insoluble drug transport. [ABSTRACT FROM AUTHOR]

Cytisine (CYT) has emerged as a promising molecule to treat nicotine addiction, since it acts as a partial agonist of nicotinic acetylcholine receptors. However, its unfavorable pharmacokinetic properties lead to multiple administrations per day, reducing the patient’s compliance and increasing the side effects. To overcome these drawbacks, CYT buccal administration is here proposed. Firstly, CYT stability in the buccal environment was assessed and its intrinsic ability to permeate/penetrate the tissue was determined by applying CYT solutions at increasing concentrations. Furthermore, a spray-drying method was selected and optimized as it is an eco-friendly, easily scalable and effective technique to obtain uniform and reproducible CYT-loaded (5% w/w) pharmaceutical powders, which were directly compressed, thus obtaining different buccal delivery systems (BDSs). The obtained BDSs were homogeneous and reproducible and embedded CYT in its amorphous form. The mechanism of CYT release was evaluated in vitro and found to be mainly driven by a Fickian diffusion phenomenon. Predominantly, the ex vivo permeation assays highlighted the ability of the BDSs to enhance CYT permeation, also producing high drug fluxes through the mucosa. Speculative mathematical evaluations based on the already-known CYT pharmacokinetic parameters showed that CYT-loaded BDSs could potentially be sufficient to obtain a therapeutic effect, thus making the reported formulations suitable candidates for further in vivo trials.

Campylobacter jejuni is a bacterial human pathogen causing gastroenteritis and sequelae like irritable bowel syndrome. Epidemiologists count the human campylobacteriosis by C. jejuni as the most common foodborne zoonosis and bacterial diarrheal disease worldwide. Based on bioinformatics predictions for potential protective compounds in campylobacteriosis, the question was raised whether the plant-based polyphenol resveratrol is sufficient to attenuate intestinal epithelial damage induced by C. jejuni. We investigated this by performing experimental infection studies in an epithelial cell culture and the secondary abiotic IL-10−/− mouse model. In C. jejuni-infected human colonic HT-29/B6 cell monolayers, transepithelial electrical resistance (TER) was decreased and the paracellular marker flux of fluorescein (332 Da) increased. Concomitantly, the tight junction (TJ) proteins occludin and claudin-5 were re-distributed off the tight junction domain. This was accompanied by an increased induction of epithelial apoptosis, both changes contributing to compromised barrier function and the opening of the leak pathway induced by C. jejuni. In parallel, the recovery experiments with the application of resveratrol revealed a functional improvement of the disturbed epithelial barrier in both models in vitro and in vivo. During treatment with resveratrol, TJ localization of occludin and claudin-5 was fully restored in the paracellular domain of HT-29/B6 cells. Moreover, resveratrol decreased the rate of epithelial apoptosis. These resveratrol-induced molecular and cellular effects would therefore be expected to improve epithelial barrier function, thereby minimizing the so-called leaky gut phenomenon. In conclusion, the induction of the leak pathway by C. jejuni and the restoration of barrier function by resveratrol demonstrates its effectiveness as a potential preventive or therapeutic method of mitigating the leaky gut associated with campylobacteriosis.

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally. [ABSTRACT FROM AUTHOR]

The duodenal mucosa is regularly exposed to a low osmolality, and recent experiments suggest that hypotonicity increases mucosal permeability in an osmolality-dependent manner. The aim was to examine whether the sympathetic nervous system, via action on α-adrenoceptors, affects the hypotonicity-induced increase in duodenal mucosal permeability. The duodenum of anaesthetised rats was perfused in vivo with a 50 mM NaCl solution in the presence of adrenergic α-adrenoceptor drugs. Studied were the effects on mucosal permeability (blood-to-lumen clearance of 51Cr-EDTA), arterial blood pressure, luminal alkalinisation, transepithelial fluid flux, and motility. Hypotonicity induced a six-fold increase in mucosal permeability, a response that was reversible and repeatable. The α2-adrenoceptor agonist clonidine abolished the hypotonicity-induced increase in mucosal permeability, reduced arterial blood pressure, inhibited duodenal motility, and decreased luminal alkalinisation. The α2-adrenoceptor antagonists, yohimbine and idazoxan, prevented the inhibitory effect of clonidine on the hypotonicity-induced increase in mucosal permeability. The α1-agonist phenylephrine or the α1-antagonist prazosin elicited their predicted effect on blood pressure but did not affect the hypotonicity-induced increase in mucosal permeability. None of the α1- or α2-adrenoceptor drugs changed the hypotonicity-induced net fluid absorption. In conclusion, stimulation of the adrenergic α2-adrenoceptor prevents the hypotonicity-induced increase in mucosal permeability, suggesting that the sympathetic nervous system has the capability to regulate duodenal mucosal permeability.

Background: Prostasin (PRSS8) is a stimulator of epithelial sodium transport. In this study, we evaluated alteration of prostasin expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and investigated the role of prostasin in the gut inflammation.Methods: Prostasin expression was evaluated by immunohistochemical staining. Dextran sodium sulfate (DSS)-colitis was induced in mice lacking prostasin specifically in intestinal epithelial cells (PRSS8ΔIEC mice).Results: In colonic mucosa of healthy individuals, prostasin was strongly expressed at the apical surfaces of epithelial cells, and this was markedly decreased in active mucosa of both ulcerative colitis and Crohn's disease. DSS-colitis was exacerbated in PRSS8ΔIEC mice compared to control PRSS8lox/lox mice. Toll-like receptor4 (TLR4) expression in colonic epithelial cells was stronger in DSS-treated PRSS8ΔIEC mice than in DSS-treated PRSS8 lox/lox mice. NF-κB activation in colonic epithelial cells was more pronounced in DSS-treated PRSS8ΔIEC mice than in DSS-treated PRSS8lox/lox mice, and the mRNA expression of inflammatory cytokines was significantly higher in DSS-treated PRSS8ΔIEC mice. Broad-spectrum antibiotic treatment completely suppressed the exacerbation of DSS-colitis in PRSS8ΔIEC mice. The mRNA expression of tight junction proteins and mucosal permeability assessed using FITC-dextran were comparable between DSS-treated PRSS8lox/lox and DSS-treated PRSS8ΔIEC mice.Conclusion: Prostasin has an anti-inflammatory effect via downregulation of TLR4 expression in colonic epithelial cells. Reduced prostasin expression in IBD mucosa is linked to the deterioration of local anti-inflammatory activity and may contribute to the persistence of mucosal inflammation. [ABSTRACT FROM AUTHOR]

Figure 1.Schematic illustrations of the fabrication of the implantable nanocrystalline-in-nanofiber device (step1-5) and the delivery process (step 6) of these PEGylated polydopamin PTX NCs from nanofiber matrix to tumor tissues and finally to tumor cells. Created with BioRender (https://biorender.com/) [Display omitted] Overcoming the vaginal barrier to achieve sufficient drug penetration and retention is a huge obstacle for drug delivery in chemotherapeutics for cervical cancer. In this study, we investigate the feasibility of a novel composite nanocrystal/nanofiber system for improving the transmucus penetration and, thus, enhancing retention and drug delivery to the lesion of a cervicovaginal tumor. Herein, paclitaxel (PTX) was sequentially formulated in the form of nanocrystals, coated with polydopamine (PDA), and modified with PEG. The nanocrystals (NCs@PDA–PEG) were creatively fabricated to create a composite nanofibrous membrane (NCs@PDA-PEG NFs) by using an electrospinning technique. The morphology, size distribution, drug loading, encapsulation efficiency, X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectra, in vitro release, in vivo vaginal retention, apoptosis index, anti-tumor efficacy in a murine cervicovaginal tumor model, and local irritation were characterized. The NCs@PDA-PEG were formulated in a cube-like shape with an average size of 385.6 ± 35.47 nm; they were dispersed in electrospun nanofibers, and the drug loading was 7.94 %. The XRD curves indicated that the phase state of PTX changed after the creation of the nanocrystals. The FTIR spectra showed that the drug and the excipients were compatible with each other. In vitro delivery showed that the dissolution of PTX in the electrospun nanofibers was significantly faster than that when using bulk PTX. Compared with the PTX NC NFs, the NC@PDA-PEG NFs exhibited prolonged vaginal residence, superior transmucus penetration, minimal mucosal irritation, and significant tumor inhibition efficacy after the intravaginal administration of the NFs in tumor-bearing mice. In conclusion, by acting as novel pharmaceutical repositories, NCs@PDA-PEG NFs can be promising candidates for non-invasive local treatment, leading to efficient tumor inhibition in cervicovaginal cancer. [ABSTRACT FROM AUTHOR]

The effect of flaxseed lignan secoisolariciresinol diglucoside (SDG) on ulcerative colitis was examined. Experimental colitis was induced in mice by administering 5% dextran sulphate sodium (DSS). SDG in doses of 100 and 200 mg/kg/day and 5-aminosalicylic acid (positive control) were given orally for 3 days before and during DSS administration. Oral SDG treatment significantly decreased the disease activity index and increased colon length. Histological examination revealed that the oral administration of SDG suppressed DSS-induced erosion, ulceration, crypt abscesses and oedema. Furthermore, colonic myeloperoxidase activity and TNF-α expression declined remarkably following treatment with SDG. Additionally, oral SDG treatment significantly increased the expression of several mucoprotection markers, to include zona occludens-1, Tollip and trefoil factor 3, and thus restored intestinal permeability. These results suggested that oral SDG treatment can alleviate DSS-induced colitis and might be a promising supplement for the amelioration of inflammatory bowel disease.

Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (p

Metoclopramide (MCP) can effectively alleviate motion sickness-caused nausea and vomiting. Nasal administration offers the greatest patient compliance. It is suitable for self-administration and offers rapid and complete absorption, no first-pass effects and high bioavailability. In the present study, a MCP nasal spray was prepared and evaluatedin vitroandin vivo.Nasal cilia toxicity of Bufo toads was used to screen the preservative types and concentrations. Rabbit nasal mucosa was used to evaluate the mucosa permeability of different MCP nasal sprays with different penetration enhancers and preservative. A three-period crossover trial was then carried out in beagle dogs with three different MCP dosage forms: nasal sprays, oral tablets and intramuscular (IM) solution. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to measure dog plasma MCP, and pharmacokinetic parameters were calculated. The results of ciliatoxicity and permeation study showed that 0.03% methyl paraben lacking penetration enhancers was optimal. Compared to control IM, the bioavailability of oral tablets of MCP was 24.9%, while that of nasal spray was 62.3%. Meanwhile time-to-maximal plasma concentration (Tmax) of nasal spray was significantly shorter than that of oral tablets. In conclusion, MCP nasal spray prepared here is safe with minimal ciliatoxicity, rapid onset and high relative bioavailability. [ABSTRACT FROM PUBLISHER]

Plasma level of microbial translocation is a marker of mucosal permeability. Increased mucosal permeability ignites elevated microbial translocation and as a consequence of systemic inflammation. Pregnant women with depression have higher levels of inflammatory markers relative to pregnant women without depression, however, no studies have reported whether systemic microbial translocation will change in depressed women during pregnancy. In this study, we examined the plasma LPS level of depressed women during pregnancy. The results showed that the plasma LPS level was significantly increased in depressed mothers during their 8–12 weeks gestation compared to healthy controls. Compared to 8–12 weeks gestation, the plasma LPS levels were significantly decreased at 24–28 weeks gestation and 6–8 weeks postpartum in both depressed subjects and healthy controls. Furthermore, the plasma levels of pro-inflammatory cytokines (TNF-α and MCP/CCL2) associated with microbial translocation were significantly increased in depressed subjects during 8–12 weeks gestation compared to healthy controls. These results indicate that the level of microbial translocation is increased in depressed women during early pregnancy. [ABSTRACT FROM AUTHOR]

Activation of large-conductance Ca2+-activated K+ (BKCa) channels evokes cell survival programs that mitigate intestinal ischemia and reperfusion (I/R) inflammation and injury 24 h later. The goal of the present study was to determine the roles of reactive oxygen species (ROS) and heme oxygenase (HO)-1 in delayed acquisition of tolerance to I/R induced by pretreatment with the BKCa channel opener NS-1619. Superior mesentery arteries were occluded for 45 min followed by reperfusion for 70 min in wild-type (WT) or HO-1-null (HO-1-/-) mice that were pretreated with NS-1619 or saline vehicle 24 h earlier. Intravital microscopy was used to quantify the numbers of rolling and adherent leukocytes. Mucosal permeability, tumor necrosis factor-α (TNF-α) levels, and HO-1 activity and expression in jejunum were also determined. I/R induced leukocyte rolling and adhesion, increased intestinal TNF-α levels, and enhanced mucosal permeability in WT mice, effects that were largely abolished by pretreatment with NS-1619. The anti-inflammatory and mucosal permeability-sparing effects of NS-1619 were prevented by coincident treatment with the HO-1 inhibitor tin protoporphyrin-IX or a cell-permeant SOD mimetic, Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), in WT mice. NS-1619 also increased jejunal HO-1 activity in WT animals, an effect that was attenuated by treatment with the BKCa channel antagonist paxilline or MnTBAP. I/R also increased postischemic leukocyte rolling and adhesion and intestinal TNF-α levels in HO-1-/- mice to levels comparable to those noted in WT animals. However, NS-1619 was ineffective in preventing these effects in HO-1-deficient mice. In summary, our data indicate that NS-1619 induces the development of an anti-inflammatory phenotype and mitigates postischemic mucosal barrier disruption in the small intestine by a mechanism that may involve ROS-dependent HO-1 activity. [ABSTRACT FROM AUTHOR]

While irritable bowel syndrome (IBS) is still considered a ‘disorder of gut function’ and is diagnosed on the basis of symptoms, evidence is growing to indicate the existence of biochemical, molecular, immune, and microbiological abnormalities in large subsets of patients. According to the current view, luminal factors (e.g. derived from food, microbiota, and bile acids) permeate into the mucosa through a leaky epithelial barrier. These substances elicit abnormal responses, partly related to the activation of the immune system, which evoke altered neuro-muscular responses and stimulation of pain pathways. This research is providing a new way of thinking about the pathophysiology of IBS and will potentially lead to the development of novel treatments for these common disorders.

Enteric inflammation models can help researchers study methods to improve health and performance plus evaluate various growth promoters and dietary formulations targeted to improve performance in poultry. Oral administration of fluorescein isothiocyanate dextran (FITC-d; 3-5 kDa) and its pericellular mucosal epithelial leakage is an established marker to evaluate enteric inflammation in multiple species. The present study evaluated different methods to induce gut inflammation in poultry based on FITC-d leakage. Four independent experiments were completed with different inflammation treatment groups; serum FITC-d and/or retention of FITC-d in GI tract was/were determined. In experiment 1 (n=10 birds/treatment; broilers; processed at 14d), groups included control (CON), Dextran sodium sulfate (DSS; drinking water at 0.75%) and feed restriction (FRS; 24h before processing). Experiment 2 (n=14birds/treatment; leghorns; processed at 7d) included CON, DSS, FRS, and rye based diet (RBD). In experiments 3 and 4 (n=15 birds/treatment; broilers; processed at 7d), groups were CON, DSS, high fat diet (HFD), FRS, and RBD. In all experiments, FRS and RBD treatments showed significantly higher serum FITC-d levels compared to the respective CON. This indicates that FRS and RBD results in disruption of the intact barrier of the GIT, resulting in increased gut permeability. DSS and HFD groups showed elevation of serum FITC-d levels although the magnitude of difference from respective CON were inconsistent between experiments. FRS was the only treatment which consistently showed elevated retention of FITC-d in GIT in all experiments. The results from present studies showed that FRS and RBD, based on serum FITC-d levels, can be robust models to induce gut leakage in birds in different age and species/strains.

Dextran sodium sulfate (DSS) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, 2 doses of DSS (0.45 g/dose) administered as oral gavage resulted in increased mucosal permeability. The main objective of the present study was to compare serum turbidity in control and DSS treated birds plus with feed restriction (FR), and evaluate the associated serum chemistry. Three independent experiments were conducted with different combinations of treatment groups. In Experiment 1, control full-fed (CON) and DSS full-fed (FFD) with n = 15 birds/group were evaluated, Experiment 2 had groups (n = 15/group) CON, FFD, feed restriction (FRS for 34 h), and DSS with feed restriction (FRD), and Experiment 3 (n = 15/group) had CON, FFD, and FRS (29 h FRS). All DSS treated birds received one or 2 doses of DSS by oral gavage (0.45 g/dose/bird). Results showed that, compared to CON group, there was an increase (P < 0.05) in serum turbidity in FFD birds, even though the difference between FRS and FRD was not apparent (P > 0.05). Administration of DSS did not result in increase of serum enzymes such as alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH), nonetheless, the FFD showed lower (P < 0.05) LDH level compared to CON in Experiment 2. Among the various serum chemistry parameters evaluated triglycerides had the highest positive correlation (r² = 0.85; P < 0.05) with serum turbidity. DSS administration resulted in decreased serum protein levels, especially albumin. These results suggest that oral gavage with DSS in broiler chicks could result in changes to serum chemistry parameters which could be developed as potential marker/s for gut leakage. [ABSTRACT FROM AUTHOR]

The effect of flaxseed lignan secoisolariciresinol diglucoside (SDG) on ulcerative colitis was examined. Experimental colitis was induced in mice by administering 5% dextran sulphate sodium (DSS). SDG in doses of 100 and 200 mg/kg/day and 5-aminosalicylic acid (positive control) were given orally for 3 days before and during DSS administration. Oral SDG treatment significantly decreased the disease activity index and increased colon length. Histological examination revealed that the oral administration of SDG suppressed DSS-induced erosion, ulceration, crypt abscesses and oedema. Furthermore, colonic myeloperoxidase activity and TNF-α expression declined remarkably following treatment with SDG. Additionally, oral SDG treatment significantly increased the expression of several mucoprotection markers, to include zona occludens-1, Tollip and trefoil factor 3, and thus restored intestinal permeability. These results suggested that oral SDG treatment can alleviate DSS-induced colitis and might be a promising supplement for the amelioration of inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world. [ABSTRACT FROM AUTHOR]

The gastric barrier could be considered an active tissue involved in many synthetic and metabolic functions, as the immunological defense, by activating mucosal immune system. Barrier integrity results from a balance between protective and aggressive endogenous factors and from their interaction with exogenous factors (steroidal or nonsteroidal anti-inflammatory drugs, dietary nitrates, nitrites and/or NaCl, stress, Helicobacter pylori infection, food allergens and contaminants, metals, chemicals, radiation, smoking and alcohol intake). Nutrients represent the most important exogenous factors affecting gastric barrier because of the impact on people's everyday life. We report evidence from the literature about nutrients affecting gastric barrier and we investigate the possible effect that nutrients can play to determining or maintaining a gastric barrier dysfunction. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim The mechanism by which the duodenum adjusts the luminal osmolality remains unclear. The aim was to compare the duodenal osmoregulation in response to different hyperosmolar solutions in Sprague- Dawley and Dark Agouti rats and to elucidate whether cyclooxygenase-2 inhibition affects these responses. Methods The duodenum was perfused in situ with a 700-milliosmolar solution ( Na Cl alone, D-glucose ± Na Cl, D-mannitol ± NaCl or orange juice), and the effects on the duodenal motility, mucosal permeability, luminal alkalinization, fluid flux and osmoregulation were assessed in anaesthetized rats. Results The change in net fluid flux and luminal osmolality, in response to a given hyperosmolar solution, was almost identical in control rats of both strains. In control rats, hypertonic D-glucose-NaCl induced fluid secretion only in the presence of phlorizin, an inhibitor of SGLT1. Cyclooxygenase-2 inhibition potentiated the hypertonicity-induced fluid secretion and increased the osmolality-adjusting capability in both strains, but the responses were greater in Dark Agouti rats. While cyclooxygenase-2-inhibited Dark Agouti rats responded to the hyperosmolar solutions with depression of motility and increased mucosal permeability, these effects were absent or smaller in the Sprague-Dawley strain. In contrast, orange juice induced the same duodenal responses in cyclooxygenase-2-inhibited Dark Agouti and Sprague- Dawley rats. Conclusion The duodenum possesses the ability to absorb fluid despite a very high luminal osmolality. Inhibition of cyclooxygenase-2 markedly enhanced the capability of the duodenum to secrete fluid and to decrease luminal osmolality, irrespective of the hyperosmolar solution or the rat strain used, and revealed notable differences between the two strains with regard to their osmolality-adjusting capability. [ABSTRACT FROM AUTHOR]

The pathophysiology of irritable bowel syndrome (IBS) has not yet been fully elucidated. We reviewed articles addressing IBS that have been published in the last 2 years and selected papers related to IBS pathophysiology and treatment. Studies of intestinal bacteria, low-grade mucosal inflammation, and increased mucosal permeability-factors involved in the pathophysiology of IBS-have been conducted. In addition, the involvement of intestinal bacteria in IBS pathology has been clarified; many studies of treatments related to intestinal bacteria have been reported. Moreover, several studies address the effect on IBS of antidepressants and psychotherapy through the brain-gut axis. The contents of these papers are described in this narrative review.

Background. Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development.Methods. Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of 99mtechnetium–diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours.Results. The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8–21.0) and 8.4 times (95% CI, 5.2–13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1–11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4–11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0–2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0–5.8) but was not greater in blood.Conclusions. Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides.Clinical Trials Registration. NCT00389311. [ABSTRACT FROM AUTHOR]

Zinc L-carnosine is a pharmaceutical compound with direct mucosal cytoprotective and anti-inflammatory action through its antioxidative effects, cytokine modulation and membrane-stabilizing properties. Chemically, it is not an anti-secretory, antacid or raft-forming agent; its properties are mainly mediated by its higher affinity for damaged mucosa that permits the release of zinc locally by ligand exchange. Beneficial effects on various types of mucosal damage have been described in vitro and in vivo, in both animals and humans. It has been shown to promote repair of mucosal injury in human studies and has been widely used for the treatment of peptic ulcers, chemoradiotherapy-induced oral mucositis and esophagitis. More recently, the therapeutic applications of Zinc L-carnosine have been extended to the prevention and cure of various types of intestinal damage, including ulcerative colitis, iatrogenic ulcers after operative endoscopy, hemorrhoidal disease and impaired intestinal permeability. This review concentrates mainly on the current and future applications of zinc L-carnosine in gastrointestinal disease, and may be of use to gastroenterologists and endoscopists. It describes the therapeutic principles and benefits of this interesting molecule and discusses the potential future fields of interest for clinical use in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aim: To examine whether the prevention of post-operative duodenal ileus by treatment with parecoxib, a selective cyclooxygenase-2 ( COX-2) inhibitor, affects the ability of the duodenum to respond to luminal hypertonicity. Methods: The proximal duodenums of anaesthetized rats were perfused with hypertonic Na Cl solutions with osmolalities of 400, 500, 600 or 700 mOsm kg−1, and the effects on mucosal permeability, motility, transepithelial net fluid flux and effluent osmolality were assessed in the absence (control) and presence of parecoxib. Results: Parecoxib-treated, but not control animals, exhibited duodenal contractions, which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg−1. All animals responded to luminal hypertonicity with induction of net fluid secretion, which peaked at an osmolality of 500 mOsm kg−1. The hypertonicity-induced increases in fluid secretion were twofold greater in parecoxib-treated than in control rats and attenuated by nicotinic receptor blockade. The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib-treated animals but the osmolality-adjusting capability was markedly better in the latter group. Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats. Perfusion with 700 mOsm kg−1 increased mucosal permeability in parecoxib-treated animals only, an effect abolished by nicotinic receptor blockade. Conclusion: Parecoxib markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of COX-2 and stimulation of nicotinic acetylcholine receptors. [ABSTRACT FROM AUTHOR]

Abstract: The current study investigated the influence of ethanol and ethanol-containing mouthrinses on model chemical permeability in an in vitro oral buccal mucosal construct (EpiOral, ORL-200, MatTek). Innate ethanol transport and metabolism in the tissue construct was also studied. Caffeine flux in buccal tissue was measured after pre-treatment with < 26.9% ethanol or Listerine® products under conditions modeling a typical mouthwash rinsing. Specifically, a 30s exposure to alcohol products followed by a 10h non-treatment phase and then a second 30s exposure prior to addition of caffeine. At 10min specific intervals, media was collected from the basal part of the tissue insert for HPLC analysis of caffeine. The results demonstrated no increase in caffeine flux due to prior exposure to either ethanol or Listerine®, and the flux and permeability constants were derived from the linear phase. No cytotoxicity or histopathological effects were observed in these tissues. We also studied the transepithelial transport and metabolism of ethanol in these tissues. Transport of ethanol was concentration-dependent with rate of diffusion proportional to the concentration gradient across the membrane. The potential metabolism of ethanol in the EpiOral construct was addressed by analyzing the remaining level of ethanol after incubation and de novo accumulation of acetaldehyde or acetic acid in culture media. Incubation for 30min incubation resulted in no change in ethanol level up to 2000mM, the highest concentration tested. No acetaldehyde or acetic acid was detected in culture media. In conclusion, ethanol and ethanol-containing mouthrinse treatment modeled after a typical daily mouthrinse pattern had no apparent effect on the permeability of the standard model chemical, caffeine. This exposure also had no effect on the viability of the tissue construct or histopathology, and uptake of ethanol was rapid into the tissue construct. [Copyright &y& Elsevier]

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of various human diseases. However, these drugs also have serious adverse effects in the gastrointestinal tract. In the duodenum NSAIDs inhibit mucosal alkaline secretion (DMAS), an important protective mechanism against the acid emptied from the stomach in most species, including humans. Surprisingly, NSAIDs have been shown to stimulate DMAS in an anaesthetized rat model. The aim of this review was to summarize the effects of NSAIDs and selective cyclooxygenase-2 (COX-2) inhibition on duodenal function in the rat and provide an explanation for why these drugs stimulate DMAS. Included are new data examining the effect of α-adrenergic drugs on duodenal motility and DMAS. Experiments were performed in anaesthetized rats. The proximal duodenum was perfused luminally with an isotonic NaCl solution. DMAS, motility, fluid flux and epithelial permeability were assessed in the absence and presence of various COX inhibitors. COX inhibition induced duodenal motility, increased DMAS and augmented the sensitivity as well as the maximal response of the duodenal mucosa to lidocaine- or hypotonicity-induced increases in mucosal permeability. Furthermore, the ability of the duodenum to absorb water and to adjust osmolality in response to luminal hypotonicity was improved in COX-inhibited animals. These improvements are mediated predominately via inhibition of COX-2. Inhibition of COX-2 in rats with postoperative duodenal ileus induces muscle contractions, which in turn activate a nicotinic receptor-dependent intramural reflex that stimulates duodenocytes to increase the activity of apical Cl/HCO exchangers, resulting in a rise in DMAS. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Our lab has developed a novel strategy for intestinal preservation involving the intraluminal delivery of a nutrient-rich preservation solution. The aim of this study was to compare the effectiveness of two impermeant agents for use in our solution: Dextran 70 (D70; Mw=70kDa) and Hydroxyethyl starch (HES; Mw=2200kDa). Methods: Rat intestines were procured, including an intravascular flush with University of Wisconsin solution followed by a ‘backtable’ intraluminal flush with: UW solution (group 1, UW), or an amino acid-based nutrient-rich preservation solution (AA solution) containing either 5% D70 (group 2, AA-D70) or HES (group 3, AA-HES). Tissue samples (n =6) were taken at 2, 4, 8, and 12h cold storage; histology, energetic, end-product, and oxidative parameters were assessed. In separate groups (n =4), D70 and HES were fluorescently labeled with fluorescein isothiocyanate (FITC) in order to directly observe mucosal penetration of the starch and dextran. Results: Over the 12h storage time-course, direct visualization of the fluorescently labeled D70 showed penetration of the mucosal layer as early as 2h and progressively continued to do so throughout the 12h period. In contrast, HES did not cross the mucosal barrier and remained captive within the lumen. As time of storage progressed, grade of injury increased in all groups, however, at 4 and 12h the AA-HES treated tissues exhibited significantly less injury compared to UW and AA-D70, P <0.05. AA-HES group showed on moderate villus clefting (median grade 2; P <0.05) while the AA-D70 group exhibited complete villus denudation (grade 4) and the UW group had extensive injury into the regenerative cryptal regions (grade 6). Metabolic parameters revealed a preferential maintenance of ATP and Energy Charge; increases in lactate, alanine and ammonium supported the involvement of aerobic and anaerobic pathways for energy production. Conclusion: The results of this study challenge the idea that oncotic support is not a fundamental requirement of static organ storage. Furthermore, our data suggests that HES is an effective oncotic agent for use in our intraluminal nutrient-rich preservation solution, while Dextran 70 is not. [Copyright &y& Elsevier]

Aim: To investigate whether the motility- and the vasoactive intestinal peptide (VIP)-induced increase in luminal alkalinization in the duodenum is dependent on luminal Cl−. Methods: Experiments were performed in anaesthetized rats in vivo. The proximal duodenum was perfused luminally with an isotonic solution, containing zero or low Cl− and the effects on luminal alkalinization, motility, fluid flux and epithelial permeability were determined. Parecoxib, a COX-2 inhibitor, was used to induce duodenal contractions. Results: Control rats lacked duodenal wall contractions while parecoxib-treated ones exhibited contractions throughout the experiment. Most animals had a net fluid absorption during the perfusion with isotonic NaCl. Luminal alkalinization was about 100% higher in parecoxib-treated rats than in controls. Cl−-free solutions did not affect epithelial permeability or motility but decreased luminal alkalinization by ≥50% and decreased net fluid absorption in both control and parecoxib-treated animals. Reduction in luminal Cl− decreased alkalinization in a concentration-dependent manner. The parecoxib-induced increase in alkalinization was markedly reduced in the absence of luminal Cl−. VIP increased luminal alkalinization and induced fluid secretion. The lack of luminal Cl− did not affect the VIP-induced increase in alkalinization but reduced fluid secretion. Conclusions: The parecoxib-induced increase in luminal alkalinization is highly dependent on luminal Cl− and it is proposed that COX-2 inhibition, via induction of duodenal motility, enhances HCO3− efflux through stimulation of apical Cl−/HCO3− exchange in duodenal epithelial cells. Although the VIP-induced stimulation of fluid secretion is partly dependent on luminal Cl−, the VIP-induced increase in luminal alkalinization is not. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the motility- and the vasoactive intestinal peptide (VIP)-induced increase in luminal alkalinization in the duodenum is dependent on luminal Cl−. Methods: Experiments were performed in anaesthetized rats in vivo. The proximal duodenum was perfused luminally with an isotonic solution, containing zero or low Cl− and the effects on luminal alkalinization, motility, fluid flux and epithelial permeability were determined. Parecoxib, a COX-2 inhibitor, was used to induce duodenal contractions. Results: Control rats lacked duodenal wall contractions while parecoxib-treated ones exhibited contractions throughout the experiment. Most animals had a net fluid absorption during the perfusion with isotonic NaCl. Luminal alkalinization was about 100% higher in parecoxib-treated rats than in controls. Cl−-free solutions did not affect epithelial permeability or motility but decreased luminal alkalinization by ≥50% and decreased net fluid absorption in both control and parecoxib-treated animals. Reduction in luminal Cl− decreased alkalinization in a concentration-dependent manner. The parecoxib-induced increase in alkalinization was markedly reduced in the absence of luminal Cl−. VIP increased luminal alkalinization and induced fluid secretion. The lack of luminal Cl− did not affect the VIP-induced increase in alkalinization but reduced fluid secretion. Conclusions: The parecoxib-induced increase in luminal alkalinization is highly dependent on luminal Cl− and it is proposed that COX-2 inhibition, via induction of duodenal motility, enhances HCO3− efflux through stimulation of apical Cl−/HCO3− exchange in duodenal epithelial cells. Although the VIP-induced stimulation of fluid secretion is partly dependent on luminal Cl−, the VIP-induced increase in luminal alkalinization is not. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Several mechanisms have been proposed for the development of Crohn's disease. Evidence in favour of a unifying 4-component concept to explain the development of Crohn's disease is presented. The four components are a genetic predisposition to an increased intestinal permeability, the key and initial triggering factor being an oral-pharyngeal bacterium that increases the mucosal permeability of the small intestine with only a minimal inflammatory reaction, an adherent-invasive strain of Escherichia coli that penetrates the mucosa and causes an acute inflammatory reaction in the intestinal wall, and finally a secondary invasion of bacteria causing the chronic inflammatory characteristics. Irritable bowel syndrome (IBS) is a functional bowel disorder with intermittent symptoms of varying intensity. Clinically, there is evidence to suggest a link between IBS patients with diarrhoea and patients with Crohn's disease. The common denominator and initial trigger for IBS with diarrhoea and Crohn's disease seems to be an increased small intestinal permeability, probably caused by an oral-pharyngeal bacterial strain. The important missing factor in IBS patients seems to be the adherent-invasive strain of E. coli in the proximal colon, causing the acute inflammatory process in patients with Crohn's disease. IBS with diarrhoea can then be looked upon as an incomplete Crohn's disease. [ABSTRACT FROM AUTHOR]

The objective of the present investigation was to evaluate the effects of acidic pH of the perfusate and presence of lipopolysaccharide (LPS) on permeability of rumen and colon mucosal tissues to mannitol and LPS using the Using chamber system. Rumen and colon tissues (n = 8), obtained from slaughtered feedlot steers, were tested for changes in permeability to ³H-mannitol under pH of 4.5, 5.5, and 6.5 for rumen and at 5.5, 6.5, and 7.4 for colon, with or without LPS from Escherichia coli B:055 at 500 µg/mL. The ³H-Mannitol was added at 10 ILL (525.4 GBq/mmol) on the mucosal side of the Using chamber to detect changes in permeability, and 4 samples were taken at 20, 25, 30, and 35 min from the serosal side. Permeability of rumen and colon mucosa to ³H-mannitol increased 6- and 5-fold, respectively, at acidic pH values of 4.5 and 5.5 and in the presence of 500 µg/mL of LPS. In contrast, LPS did not affect rumen and colon permeability at pH that ranged from 5.5 and 7.4. Translocation of LPS across the rumen and colon mucosa of cattle was not pH dependent. The LPS translocated through these tissues if present at the mucosal side. In conclusion, the permeability of rumen and colon tissues to ³H-mannitol increased in presence of LPS and under acidic pH, whereas LPS permeated through mucosal tissues independently of the pH of the perfusate. Further research is warranted to understand the mechanism(s) by which acidic pH of the rumen digesta and presence of LPS make rumen and colon tissues "leaky". [ABSTRACT FROM AUTHOR]