Changes of intestinal wall barrier function and its correlation with susceptibility to infection in patients with cirrhotic portal hypertension / 中华肝脏病杂志

Objective: To investigate the changes of intestinal wall barrier function and its correlation with infection occurrence in patients with cirrhotic portal hypertension. Methods: 263 patients with cirrhotic portal hypertension were split into: the clinically evident portal hypertension (CEPH) combined with infection group (n = 74); CEPH group (n = 104); and Non-CEPH group (n = 85). Among them, 20 CEPH patients and 12 non-CEPH patients in non-infection status were subjected to sigmoidoscopy. Immunohistochemical staining was used to detect the expression of trigger receptor-1 (TREM-1), CD68, CD14, the inducible nitric oxide synthase molecule, and Escherichia coli (E.coli) in the medullary cells of the colon mucosa. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of soluble myeloid cell trigger receptor-1 (sTREM-1), soluble leukocyte differentiation antigen-14 subtype (sCD14-ST) and intestinal wall permeability index enteric fatty acid binding protein (I-FABP). Fisher's exact probability method, one-way ANOVA, Kruskal-Wallis-H test, Bonferroni method, and Spearman correlation analysis were used for statistical analysis. Results: The serum sTREM-1 and I-FABP levels were higher in CEPH patients than those of non-CEPH patients in the non-infectious state (P < 0.05), but the difference in blood sCD14-ST levels was not statistically significant (P > 0.05). Serum levels of sTREM-1, sCD14-ST, and I-FABP in infected patients were higher than those in patients without a concurrent infection (P < 0.05). Serum sCD14-ST levels were positively correlated with serum sTREM-1, C-reactive protein (CRP), and procalcitonin (PCT), and sTREM-1 levels were also positively correlated with CRP and PCT (r > 0.5, P < 0.001). The rates of CD68, inducible nitric oxide synthase, CD14-positive cells, and E.coli-positive glands were higher in the intestinal mucosa of the CEPH group than those of the control group (P < 0.05). Spearman's correlation analysis showed that the rate of E.coli-positive glands in CEPH patients was positively correlated with the expression of molecular markers CD68 and CD14 in the lamina propria macrophages. Conclusion: Patients with cirrhotic portal hypertension have increased intestinal permeability and inflammatory cells, accompanied by bacterial translocation. Serum sCD14-ST and sTREM-1 can be used as indicators to predict and evaluate the occurrence of infection in patients with cirrhotic portal hypertension.

Advances in the study of natural small molecules to protect the intestinal epithelial tight junction barrier in inflammatory bowel disease / 中国药理学通报

Inflammatory bowel disease (IBD), as an idiopathic inflammatory disease of the intestinal tract, consisting mainly of Crohns disease and ulcerative colitis, which can involve the rectum, colon and ileum, and whose pathogenesis is still not fully understood. The initiation of intestinal inflammation associated with IBD and its chronieity begins with increased intestinal permeability caused by intestinal epithelial barrier disruption. The anti-permeability of the intestinal epithelial barrier is maintained by tight junction in the apical region of the intestinal epithelial cells, and disruption of the tight junction structure is closely associated with intestinal epithelial barrier damage and the development of IBD. Therefore, it is significant to find drugs for the prevention and treatment of IBD using tight junctions as regulatory targets. In recent years, many small molecules of natural product origin have been reported to improve the effects of IBD. In particular, we review the compounds that have the function of repairing intestinal epithelial barrier and protecting tight junction structure, in order to provide research ideas for the design and development of new drugs for the prevention and treatment of IBD.

ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis / 医学前沿

Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H2S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H2S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H2S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.

Effects of heat stress on intestinal tract and cognitive function / 环境与职业医学

Heat stress refers to a series of stress reactions such as heat balance disturbance and physiological dysfunction when the body is exposed to the thermal environment for a long time. Studies have found that heat stress can damage intestinal morphology, such as length of intestinal villi, number of goblet cells, and depth of the crypt, affecting the digestion and absorption functions. It also can increase the permeability of the intestinal barrier by damaging the tight junction of the intestinal epithelium, which in turn allows endotoxin and bacteria to enter the blood circulation from the intestinal cavity to cause a systemic inflammatory response. At the same time, heat stress can disrupt the homeostasis of intestinal microbiota, increase pathogenic bacteria, and change downstream metabolites such as short-chain fatty acids. In addition, heat stress can inhibit the occurrence of hippocampal neurons and reduce the number of neurons; decrease the density of synapses; damage important organelles of neurons; induce inflammation of the central nervous system, and then lead to cognitive dysfunction. The brain-gut axis is a two-way signal axis between the intestine and the brain. Intestinal microorganisms and the intestinal barrier can participate in central nervous system regulation, and the brain can change the intestinal homeostatic function and affect the quality of the intestinal barrier through the hypothalamic-pituitary-adrenal axis (HPA axis). The interaction plays an essential role in the body's homeostasis. Therefore, this article reviewed current understandings on the impacts of heat stress on the gut and cognitive function, aiming to provide a reference for subsequent research.

Microbiota intestinal en la salud humana / Gut microbiota in human health

Introducción: La microbiota describe a un grupo de microorganismos en una región o período de tiempo que incluye: bacterias, arqueas, protistas, hongos y virus. Objetivos: Explicar la función de la microbiota intestinal en la salud humana. Métodos: Se realizó una búsqueda en diferentes de bases de datos como NHI, Ebsco y PubMed en idioma español e inglés, se revisó un total de 17 artículos de los cuales el mayor por ciento es de menos de 5 años. Resultados: Las microbiota intestinal en su mayoría se compone de Gram negativa, con una pared celular rica en lipopolisacáridos (LPS) que potencia a la inmunidad innata por interacción de receptor Toll-like (TLR) ligando, desencadena la producción de citoquinas proinflamatorias, entre otros. Conclusiones: La microbiota intestinal funciona como un señalizador antiinflamatorio y regulador de la permeabilidad epitelial intestinal(AU)

Introduction: Microbiota describes a group of microorganisms in a region or period of time that includes bacteria, archaea, protists, fungi, and viruses. Objectives: To explain the role of the intestinal microbiota in human health. Methods: A search was carried out in different databases such as NHI, Ebsco and PubMed in Spanish and English, a total of 17 articles were reviewed, most of them are less than 5 years. Results: Intestinal microbiota is mostly composed of Gram negative, with a cell wall rich in lipopolysaccharides (LPS) that enhances innate immunity by Toll-like receptor (TLR) ligand interaction, triggers the production of proinflammatory cytokines, among others. Conclusions: Intestinal microbiota functions as an anti-inflammatory signaling agent and regulator of intestinal epithelial permeability(AU)

Fatores associados com os níveis séricos de zonulina na doença inflamatória intestinal / Factors associated with circulating zonulin in inflammatory bowel disease

ABSTRACT Background: Inflammatory bowel disease (IBD) comprises the spectrum between Crohn's disease (CD) and ulcerative colitis (UC), a condition whose prevalence in countries such as Brazil has increased significantly in recent years. Changes in the intestinal epithelial barrier function and, consequently, an increase in intestinal permeability, have been suggested as important factors in the pathogenesis of different autoimmune conditions, including IBD. Therefore, there is a need for a practical tool to assess gut barrier integrity in these patients. Objective: To study factors associated with serum zonulin levels, a marker of intestinal permeability, in patients with IBD. Methods: This was a cross-sectional observational study that included 117 patients with IBD and 32 healthy controls. Disease activity was assessed by the Simple Clinical Colitis Activity Index (SCCAI) in UC and by the Harvey-Bradshaw Index (HBI) in CD subjects. Zonulin levels were measured by ELISA and inflammatory cytokines by Cytometric Bead Array, using commercially available kits. Results: The mean age of IBD patients was 44.0±15.9 years, 66.7% were female, 57 subjects were diagnosed with CD and 60 with UC. At evaluation, clinical remission was observed in 56.7% of CD patients and in 59.2% of UC subjects. No differences were observed in zonulin levels when comparing IBD patients with the control group (95.28 ng/mL vs 96.61 ng/mL, P=0.573) and when comparing patients with CD to those with UC (79.68 ng/mL vs 106.10 ng/mL, P=0.887). Among IBD group, zonulin concentrations were higher among females, correlated positively with body mass index (BMI) and age; and negatively with hemoglobin and hematocrit. In patients with UC, zonulin correlated negatively with hemoglobin, hematocrit, and albumin; and positively with BMI and SCCAI. Among CD patients, zonulin was positively correlated with age and BMI, but not with HBI. No correlations were observed between zonulin and circulating cytokines in IBD patients. Conclusion: In this cohort mostly comprised of patients in clinical remission, serum zonulin levels were not higher in patients with IBD than healthy controls, and correlated with variables not linked to baseline disease, such as sex, age and BMI. However, zonulin correlated with clinical and laboratory parameters of disease severity and activity among subjects with UC, but not among patients with CD. These findings indicate a potential role for zonulin as a biomarker in IBD, particularly in UC.

RESUMO Contexto: A doença inflamatória intestinal (DII) compreende o espectro entre a doença de Crohn (DC) e a colite ulcerativa, condição esta cuja prevalência em países como o Brasil vem aumentando significativamente nos últimos anos. Alterações na função da barreira epitelial intestinal e, consequentemente, um aumento da permeabilidade intestinal, têm sido sugeridos como fatores importantes envolvidos na patogênese de diferentes condições autoimunes, dentre elas, a DII. Desta forma, existe a necessidade de uma ferramenta prática para avaliar a integridade da barreira epitelial intestinal nestes pacientes. Objetivo: Estudar os fatores associados com os níveis séricos de zonulina, um marcador da permeabilidade intestinal, em pacientes com DII. Métodos: Estudo observacional transversal que incluiu 117 pacientes com DII e 32 indivíduos que compuseram o grupo controle. A atividade da doença foi avaliada pelo Simple Cliniical Colitis Activity Index (SCCAI) na colite ulcerativa e pelo índice de Harvey-Bradshaw (IHB) em pacientes com DC. Os níveis de zonulina foram quantificados por ELISA e os níveis das citocinas inflamatórias pelo Cytometric Bead Array, utilizando kits comercialmente disponíveis. Resultados: A média de idade dos pacientes com DII foi de 44,0±15,9 anos, 66,7% eram do sexo feminino, 57 pacientes eram portadores de DC e 60 pacientes eram portadores de colite ulcerativa. No momento da avaliação clínico-laboratorial, 56,7% dos pacientes com DC encontravam-se em remissão clínica e, dentre os pacientes com colite ulcerativa, 59,2% deles assim se encontravam. Não foram observadas diferenças nos níveis séricos de zonulina entre pacientes com DII e grupo controle (95,28 ng/mL vs 96,61 ng/mL; P=0,573), assim como entre pacientes com DC e pacientes com colite ulcerativa (79,68 ng/mL vs 106,10 ng/mL, P=0,887). Dentre os pacientes com DII, as concentrações de zonulina foram mais elevadas no sexo feminino e correlacionaram-se positivamente com o índice de massa corporal (IMC) e com a idade, correlacionando-se negativamente com os níveis de hemoglobina e hematócrito. Nos pacientes com colite ulcerativa, as concentrações de zonulina correlacionaram-se negativamente com os parâmetros hemoglobina, hematócrito e albumina e, positivamente, com o IMC e com o SCCAI. Dentre os pacientes com DC, a zonulina sérica correlacionou-se positivamente com a idade e com o IMC, mas não com o IHB. Não foram observadas correlações entre os níveis de zonulina e as citocinas circulantes nos pacientes com DII. Conclusão: Nesta coorte constituída majoritariamente por pacientes em remissão clínica, os níveis séricos de zonulina não se mostraram aumentados em pacientes com DII em relação a indivíduos controles e correlacionaram-se com variáveis não relacionadas à doença de base, como com o sexo, com a idade e com o IMC. No entanto, os níveis séricos de zonulina correlacionaram-se com parâmetros clínicos e laboratoriais de gravidade e atividade da doença dentre os pacientes com colite ulcerativa, mas não dentre os pacientes com DC. Estes achados indicam um potencial papel da zonulina sérica como um biomarcador na DII, principalmente na colite ulcerativa.

Effect and mechanism of Rho kinase inhibitor on intestinal injury in septic rats / 中华危重病急救医学

Objective:To explore the effect of Rho kinase inhibitor on intestinal injury in septic rats and its possible mechanism.Methods:Thirty-two male Sprague-Dawley (SD) rats were randomly divided into sham operation group (Sham group), Rho kinase inhibitor Y-27632 control group (Y+Sham group), sepsis model group [cecal ligation and puncture (CLP) group] and Y-27632 pretreatment group (Y+CLP group), with 8 rats in each group. Rat sepsis model was reproduced by CLP. The rats in the Sham group and Y+Sham group were only separated and moved the cecum without ligation and perforation. The rats in the Y+Sham group and Y+CLP group were pretreated with intraperitoneal injection of Y-27632 solution 5 mg/kg 15 minutes before operation; the rats in the Sham group and CLP group were intraperitoneally injected with the same amount of phosphate buffered saline (PBS). Twenty-four hours after operation, the heart blood was collected and the serum diamine oxidase (DAO) content was determined by enzyme-linked immunosorbent assay (ELISA). Then the small intestine tissue was collected, the pathological changes of the intestinal tissue were observed under the light microscope after hematoxylin-eosin (HE) staining, and Chiu's score was performed. The positive expressions of Rho-related coiled-coil kinase 1 (ROCK1) and nuclear factor-κB (NF-κB) in intestinal tissue were detected by immunohistochemistry. ELISA was used to detect the levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in intestinal tissue homogenate.Results:The intestinal tissue structure of the Sham group and Y+Sham group was intact and the mucosa was arranged neatly. Compared with the Sham group, the intestinal mucosa of the CLP group was arranged disorderly, with a large number of inflammatory cells infiltration, and the Chiu's score was significantly increased (3.83±0.27 vs. 0.12±0.11, P < 0.05), indicating that those rats suffered from septic intestinal injury. Compared with the CLP group, the degree of necrosis of intestinal epithelial cells in the Y+CLP group was reduced, a small amount of inflammatory cells infiltration was seen, and the Chiu's score was significantly decreased (2.85±0.21 vs. 3.83±0.27, P < 0.05), indicating that Y-27632 pretreatment could alleviate intestinal injury in septic rats. Compared with the Sham group, the positive expressions of intestinal tissue ROCK1 and NF-κB, the contents of serum DAO and intestinal homogenate TNF-α in the CLP group were significantly increased [ROCK1 expression ( A value): 0.19 (0.18, 0.22) vs. 0.10 (0.09, 0.11), NF-κB expression ( A value): 0.40±0.02 vs. 0.15±0.01, DAO (ng/L): 287.81±23.31 vs. 144.92±17.72, TNF-α (ng/L): 101.08±5.62 vs. 74.81±5.56, all P < 0.05], the level of intestinal homogenate IL-10 was significantly decreased (μg/L: 55.16±5.20 vs. 95.95±7.53, P < 0.05). Compared with the CLP group, the positive expressions of intestinal tissue ROCK1, NF-κB, the contents of serum DAO and intestinal homogenate TNF-α in the Y+CLP group were significantly decreased [ROCK1 expression ( A value): 0.15 (0.13, 0.18) vs. 0.19 (0.18, 0.22), NF-κB expression ( A value): 0.28±0.01 vs. 0.40±0.02, DAO (ng/L): 243.34±19.76 vs. 287.81±23.31, TNF-α (ng/L): 90.41±8.79 vs. 101.08±5.62, all P < 0.05], while the level of intestinal homogenate IL-10 was significantly increased (μg/L: 66.15±5.74 vs. 55.16±5.20, P < 0.05), indicating that the protective effect of Y-27632 pretreatment on sepsis intestinal injury rats might be related to the regulation of RhoA/ROCK1/NF-κB signaling pathway. Conclusion:Rho kinase inhibitors can reduce intestinal injury in septic rats, and the mechanism may be related to inhibiting RhoA/ROCK1/NF-κB signaling pathway and reducing intestinal inflammation in septic rats.

Study on the mechanisms of the intestinal tight-junction destruction caused by Blastocystis hominis infection in rats / 中国血吸虫病防治杂志

Objective To explore the mechanism of the intestinal barrier damage caused by Blastocystis hominis infections in rats. Methods Thirty SD rats were randomly divided into the control group, and the 1-, 3-, 6- and 9-week-infection groups, of 6 rats in each group. Rats in each infection group were orally infected with B. hominis trophozoites at a density of 2 × 108 parasites per rat, and the control group was given an equal volume of phosphate buffered saline solution. The 7-hour urine samples were collected 1, 3, 6 and 9 weeks post-infection for the measurement of the intestinal permeability. Then, rats were sacrificed using the cervical dislocation method, and the cecum specimens were collected for the detection of the intestinal epithelial cell permeability. The expression of tight junction-related Occludin and Claudin - 1 genes and apoptosis-related Bcl - 2 and Bax genes was quantified in cecum epithelial cells using the real-time fluorescent quantitative PCR (qPCR) assay, and cell apoptosis was detected in the rat cecum using the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Results The median urinary lactolose to mannitol ratios were 0.29, 0.72, 0.44, 0.46 and 0.38 in the control group, and the 1-, 3-, 6- and 9-week-infection groups, respectively, and the difference was statistically significant (H = 12.09, P < 0.05). B. hominis invasion and epithelial injury were observed in intestinal epithelial cells of rats infected with B. hominis, and transmission electron microscopy displayed the destruction of tight junctions between intestinal epithelial cells. The relative expression of Occludin, Claudin-1, Bcl-2 and Bax genes was 1.04, 0.62, 0.71, 0.68 and 0.96; 1.03, 0.61, 0.63, 0.76 and 0.86; 1.08, 0.70, 0.75, 0.74 and 1.03; and 1.00, 1.57, 1.33, 1.35 and 1.10 in the control group and the 1-, 3-, 6- and 9-week-infection groups, respectively, and all differences were statistically significant (F = 2.86, 2.85, 3.37 and 4.45, all P values < 0.05). The median number of positive staining cells were 1.00, 13.00, 9.00, 3.50 and 1.00 in rat cecum specimens in the control group, and the 1-, 3-, 6- and 9-week-infection groups, respectively, and the difference was statistically significant (H = 22.95, P < 0.01). Conclusion B. hominis infection may cause an increase in the rat intestinal permeability through triggering the apoptosis of intestinal epithelial cells to destroy the tight junction between intestinal epithelial cells, thereby destroying the intestinal barrier function.

Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats

Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of

Protective effects of Dendrobium officinale superfine powder against LPS-induced intestinal mucosal injury in mice / 中国中药杂志

This study aims to investigate the preventive effect of Dendrobium officinale in LPS-induced intestinal mucosal damage. Forty SPF-grade C57 BL/6 J male mice were randomly divided into normal group(NC), model group(LPS), and two superfine powder groups of Dendrobium officinale(DOF)(DOF-L, 0.30 g·kg~(-1)and DOF-H, 0.60 g·kg~(-1), respectively), with 10 mice in each group. DOF superfine powder suspension was given via oral administration to mice for 7 days, while the mice in NC and LPS groups received the same volume of saline for 7 days. On the eighth day, the mice in LPS group and DOF treatment groups were injected with LPS(5 mg·kg~(-1)) by intraperitoneal injection to establish the intestinal mucosal injury model, while the mice in NC group were injected with the same volume of sterile saline in the same manner. Six hours after injection with LPS or saline, plasma and the intestinal tissue were collected. The diamine oxidase(DAO) and D-lactate levels in plasma were detected with a biochemical method. The levels of proinflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in plasma were detected by ELISA. The histomorphology and ultrastructure of mouse ileum tissues were observed by hematoxylin-eosin(HE) staining in optical microscope and transmission electron microscope(TEM). The expression and distribution of tight junction(TJ) proteins claudin-1, occludin and F4/80 were detected by immunohistochemistry while the protein expression levels of Toll-like receptor 4(TLR-4) and nuclear factor kappa B p65(NF-κB p65) in jejunum were detected by Western blot. The experimental results showed that continuous intragastric administration of D. officinale superfine powder for 7 days obviously alleviated the damage and ultrastructural changes of intestinal mucosa induced by LPS; significantly decreased DAO and D-lactate levels in plasma in model group(P<0.05); up-regulated the protein expression of claudin-1 and occludin in ileum tissues; down-regulated the protein expression of TLR-4 and NF-κB p65 in jejunum tissues(P<0.01); significantly decreased TNF-α and IL-6 levels in plasma(P<0.05); and decreased the infiltration of F4/80~+ macrophage cells. Our results suggested that D. officinale had significant protective effects on LPS-induced intestinal mucosal damage and reduced intestinal permeability. The mechanism might be related to its effects of inhibiting inflammation via TLR-4/NF-κB p65, and up-regulating the expression of tight junction proteins.

Effects of yacon flour associated with an energy restricted diet on intestinal permeability, fecal short chain fatty acids, oxidative stress and inflammation markers levels in adults with obesity or overweight: a randomized, double blind, placebo controlled clinical trial

ABSTRACT Objectives Yacon flour is rich in bioactive compounds (phenolic compounds and fructooligosaccharides (FOS)), and may therefore reduce the risk of diseases associated with excess body weight. However, its effect on fecal short chain fatty acids (SCFA), intestinal permeability, oxidative stress and inflammation markers has not been studied in adult humans with excess body weight. Thus, we evaluated the effect of the consumption of yacon flour on these variables. Materials and methods Twenty-six excess body weight (30.4 ± 2.4 kg/m2) adults (31.3 ± 8.5y) were randomized to one of two groups (yacon flour or control; n = 13) on a double blind clinical trial. Subjects received a breakfast drink containing or not yacon flour (25g) associated with an energy restricted diet, for six weeks. The flour chemical characterization, FOS and total phenolics contents were evaluated. Antioxidant capacity was evaluated in vitro and in vivo (plasma). Intestinal permeability, fecal SCFA, oxidative stress and inflammatory markers also were evaluated in vivo. Results Yacon flour was well tolerated. It presented an in vitro and in vivo antioxidant capacity, increased plasma total antioxidant capacity (ΔYAC: 49.16 (-4.20; 156.63)) and reduced protein carbonyl concentrations (ΔYAC: -0.98 (-1.54; -0.42)). A reduction in SCFAs was observed in both groups (Δacetic: -3.16 (-5.07; -0.95) vs. -1.05 (-2.65; 1.11); Δpropionic: -1.05 (-2.60;-0.38) vs. -0.41 (-2.08; 0.09); Δbutyric: -0.75 (-1.38; -0.04) vs. -0.28 (-0.98; 0.11), for YAC and CON, respectively). Other variables did not change. Conclusion The yacon flour increased the plasma antioxidant capacity, decreased oxidative stress and SCFAs in adults with obesity or overweight.

Alanyl-glutamine protects the intestinal barrier function in trained rats against the impact of acute exhaustive exercise

Strenuous exercise triggers deleterious effects on the intestinal epithelium, but their mechanisms are still uncertain. Here, we investigated whether a prolonged training and an additional exhaustive training protocol alter intestinal permeability and the putative effect of alanyl-glutamine (AG) pretreatment in this condition. Rats were allocated into 5 different groups: 1) sedentary; 2 and 3) trained (50 min per day, 5 days per week for 12 weeks) with or without 6 weeks oral (1.5 g/kg) AG supplementation; 4 and 5) trained and subjected to an additional exhaustive test protocol with or without oral AG supplementation. Venous blood samples were collected to determine gasometrical indices at the end of the 12-week protocol or after exhaustive test. Lactate and glucose levels were determined before, during, and after the exhaustive test. Ileum tissue collected after all experimental procedures was used for gene expression analysis of Zonula occludens 1 (ZO-1), occludin, claudin-2, and oligopeptide transporter 1 (PepT-1). Intestinal permeability was assessed by urinary lactulose/mannitol test collected after the 12-week protocol or the exhaustive test. The exhaustive test decreased pH and base excess and increased pCO2. Training sessions delayed exhaustion time and reduced the changes in blood glucose and lactate levels. Trained rats exhibited upregulation of PEPT-1, ZO-1, and occludin mRNA, which were partially protected by AG. Exhaustive exercise induced intestinal paracellular leakage associated with the upregulation of claudin-2, a phenomenon protected by AG treatment. Thus, AG partially prevented intestinal training adaptations but also blocked paracellular leakage during exhaustive exercise involving claudin-2 and occludin gene expression.

Protective Effect of Salvianolic Acid B on Intestinal Ischemia-reperfusion Injury in Rats / 中国医学科学院学报

To investigate the protective effect of salvianolic acid B(SAB)on the intestinal tract of rats after intestinal ischemia-reperfusion injury(IIRI). Forty-eight healthy male SD rats were equally randomized into IIRI group,SAB+IIRI group,sham control group,and SAB+sham control group. The malonyldialdehyde(MDA)level and superoxide dismutase(SOD)activity in the ileum were measured in each group according to the kit instructions,the transcription levels of inflammatory factors in the ileum of rats were detected by real-time fluorescence quantitative RT-PCR,the secretion level of inflammatory factors was detected by ELISA,and the effects of intestinal ischemia-reperfusion on intestinal permeability and histological lesions were measured by histopathology. The MDA level in IIRI group was significantly higher than those in negative control group(=0.005)and SAB+IIRI group(=0.012). SOD activity of IIRI group was significantly lower than those of negative control group(=0.006)and SAB+IIRI group(=0.017). The optical densities of tumor necrosis factor-α(TNF-α)(=0.003,=0.009),interleukin(IL)-1β(=0.026,=0.005),IL-6(=0.015,=0.003),and nuclear factor kappa-B(NF-κB)(=0.007,=0.015)in IIRI group were significantly higher than those in sham control group and SAB+IIRI group. The TNF-α(=0.002,=0.006),IL-1β(=0.002,=0.006),IL-6(=0.008,=0.002),and NF-κB(=0.026,=0.005)levels in IIRI group were significantly higher than those in sham control group and SAB+IIRI group. The inulin level in IIRI group was significantly lower than that in negative control group(=0.015)and significantly higher than that in SAB+IIRI group(=0.011). The dextran level in IIRI group was significantly lower than those in sham control group(=0.011)and SAB+IIRI group(=0.012). The dextran gel level in IIRI group was significantly higher than those in sham control group(=0.031)and SAB+IIRI group(=0.020). SAB pretreatment remarkably improved the edema,necrosis,and villus stripping of the intestinal mucosa in the ileum of rats. The Chiu score was significantly higher in SAB+sham control group than in sham control group(=0.001)and was significantly lower in SAB+IIRI group than in IIRI group(=0.001). SAB pretreatment can alleviate IIRI in rat models,and this protective effect may be achieved by alleviating oxidative stress and inflammation in the intestinal tract.

Association of endotoxaemia & gut permeability with complications of acute pancreatitis: Secondary analysis of data

Background & objectives: In acute pancreatitis (AP) gut barrier dysfunction is considered as an important predisposing factor leading to increased intestinal permeability (IP). In this study a pooled analysis of data published in our previous four studies on various aspects of gut permeability and endotoxaemia in patients with AP was attempted to find an association between increased IP and severity of disease and associated complications. Methods: This study was a pooled analysis of data of four previously published prospective studies on AP. Gut permeability, assessed by lactulose/mannitol excretion in urine and endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM) were measured on days zero and seven (D0 and D7) of admission. All patients received standard treatment of AP. We studied whether IgG and IgM anti-endotoxin titres and lactulose-mannitol ratio (LMR) at admission and D7 were associated with organ failure, infection and mortality. Results: The titres of anti-endotoxin IgG and IgM were lower in all patients of AP (n=204), both in mild AP (n=24) and severe AP (n=180) in the first week, compared to controls (n=15). There was no significant difference in serum IgG and IgM anti-endotoxin levels and LMR at baseline and at D7 among patients with organ failure, infection and mortality. Interpretation & conclusions: Our findings showed that serum IgG and IgM anti-endotoxin titres and LMR at admission and at day 7 were not associated with organ failure, infection, and death of patients with AP.

Study on biopharmaceutics classification system of Chinese materia medica for Gegen Qinlians Tablets based on anti-inflammatory activity / 中国中药杂志

The research on biopharmaceutics classification system of Chinese materia medica( CMMBCS) should be finally implemented to the holistic research level of traditional Chinese medicine compounds,while the overall biopharmaceutical properties of traditional Chinese medicine compounds are not only the sum of solubility and permeability of each component. In this study,Gegen Qinlian Tablets was used as the research object,and the contents of 12 representative components,i.e. puerarin,daidzin,baicalin,daidzein,wogonoside,baicalein,wogonin,glycyrrhizic acid,coptisine hydrochloride,epiberberine,berberine hydrochloride and palmatine hydrochloride,were simultaneously determined by HPLC to obtain the mass weight of each component. The in vitro lipopolysaccharide( LPS)-induced RAW264. 7 cells inflammation model was established to investigate the anti-inflammatory effects of 12 representative components and obtain the efficacy weight of each component. In order to obtain the number of doses and effective permeability coefficient which can represent the overall biopharmaceutical properties of Gegen Qinlian Tablets,mass weight was combined with efficacy weight to integrate the solubility and permeability data of each component determined by typical shake flask method and in situ single pass intestinal perfusion model respectively. The results indicated that Gegen Qinlian Tablets should be categorized Ⅳ drug of the CMMBCS with low solubility and low permeability.

Effect of Changji'an Prescription on Intestinal Permeability of IBS-D Rats / 中国实验方剂学杂志

Objective:To observe the effect of Changji'an prescription on intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats and explore its mechanism for treatment of IBS-D. Method:Male SD neonatal rats were randomly divided into five groups:normal group, model group, pinaverium bromide group(0.018 g·kg-1), high-dose(33.48 g·kg-1) and low-dose (16.74 g·kg-1)Changji'an prescription groups. Except for the normal group, the IBS-D model was established by the combination of maternal and infant separation+acetic acid stimulation+restraint stress. After drug treatment, the ultrastructure of rat intestinal mucosa was observed by using transmission electron microscopy and the plasma D-lactate level was detected by enzyme-linked immunosorbent assay (ELISA). The expression levels of tight junction proteins Occludin and Claudin-1 were detected by Western blot. The mRNA expression levels of Occludin,Claudin-1 and zonula occluden(ZO)-1 were detected by real time polymerase chain reaction (Real-time PCR). Result:As compared with the normal group, the intestinal mucosal epithelial cells were damaged in IBS-D model group, and the microvilli arrangement was sparse and tight junction was widened, and some were not obvious,and the plasma D-lactate level in IBS-D rats was increased significantly (PPD-lactate level in pinaverium bromide group and high-dose Changji'an prescription group was significantly decreased (PD-lactate level in the low-dose group Changji'an prescription group had a tendency to decrease with no statistical difference. The mRNA and protein expression levels of Occludin and Claudin-1 and the mRNA expression of ZO-1 in the colon of rats in each administration group were higher than those in the model group (PConclusion:The therapeutic effect of Changji'an prescription on IBS-D may be achieved by improving the intestinal permeability.

Research progress on permeability characteristics of Chinese materia medica and evaluation approaches / 中草药

The research methods of serum pharmacology and serum biochemistry of traditional Chinese medicine isolate and identify serum transitional components from the serum of normal and disease model animals in order to find the material basis of pharmacodynamics. There are some limitations in this method for identifying the components of traditional Chinese medicine to play its pharmacological activities. Most active ingredients of traditional Chinese medicine belong to low-solubility and low-permeability drugs in the classification system of biopharmaceutics. Their bioavailability is low, but their overall biological effects are high. The classical pharmacokinetic-pharmacodynamic theory of serum pharmacology can not explain and evaluate the pharmacological effects of their non-serum transitional components. Based on the complexity of the chemical components of traditional Chinese medicine, the osmotic interaction of traditional Chinese medicine components may affect their osmotic behavior and form different oral absorption prescriptions. Therefore, the study on the permeability of traditional Chinese medicine components, especially under the condition of multi-component coexistence, is one of the topics worth to solve the problem of the functional substance basis of traditional Chinese medicine. This paper first outlines the in vitro and in vivo screening experimental models and their respective application value for the evaluation of intestinal permeability and trans-biological barrier permeability of traditional Chinese medicines. Then, the advantages and disadvantages of each model are compared, and the relationship between the structure and osmotic kinetics of common active components of traditional Chinese medicines based on osmotic model is discussed, especially the research progress of quantitative structure-kinetics relationship in permeability study of traditional Chinese medicines. Finally, based on the relationship between permeability experimental model and structure-kinetics, the recent progress in the study of multi-component osmotic dynamics and osmotic mechanism of traditional Chinese medicine is reviewed. It is found that the osmotic absorption of components can be affected by increasing or promoting drug transport or forming ion compatibility among components of traditional Chinese medicine. The prospects of its application are forecasted. In conclusion, this paper is expected to provide some references for searching and predicting the law of permeability of complex chemical constituents of traditional Chinese medicine and the mechanism of interaction between components and its application value.

Study on the experimental mechanism of Warm Purgative and Strengthening Spleen therapy combined with antibiotics in the treatment of sepsis / 中国中西医结合急救杂志

Objective To explore the synergism efficacy and mechanism of Warm Purgative and Strengthening Spleen (WPSS) therapy combined with antibiotics in the treatment of sepsis. Methods Thirty-two SPF Spargue-Dawley (SD) rats were used to replicate the rat sepsis model by cecum ligation perforation (CLP) method and equally divided into model control (MC) group, ceftriaxone group, Chinese herbal medicine (CHM) group and ceftriaxone +CHM group. Eight SD rats underwent sham surgery were used as a sham operation (Sham) group. Rats in Sham and MC groups were administered with 0.9% normal saline (NS) by intraperitoneal injection and gavage. Rats in CHM group were administered with modified Dahuang Fuzi Decoction (DFD, 8 mg/kg) by gavage + 0.9% NS by intraperitoneal injection, Bid. Rats in ceftriaxone group were administered with 0.9% NS by gavage and ceftriaxone (120 mg/kg) by intraperitoneal injection, Bid. Rats in ceftriaxone + CHM group were administered with modified DFD (8 mg/kg) by gavage and ceftriaxone (120 mg/kg) intraperitoneal injection, Bid. The drugs were given for 2 days. The mortality of rats in each group was observed after treatment. The intestinal flora changes and intestinal permeability [intestinal mucosa injury index (IMII), intestinal mucosa secretory immunoglobulin (sIgA), serum D-lactic acid, diamine oxidase (DAO) and sIgA] were detected. Meanwhile, the levels of serum inflammation indexes [lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] were detected. Results ① Mortality: ceftriaxone+CHM group (25.0%) < CHM group (37.5%) and ceftriaxone group (37.5%) < MC group (50.0%), the differences between groups were statistically significant (all P < 0.05). ② 16S rDNA sequencing analysis: the ratio of Bacteroidetesin in MC group was lower than that in the Sham group [(24.36±7.15)% vs. (45.20±6.05)%], and the ratio of Proteobacteria in MC group was higher than that in Sham group [(10.03±7.55)% vs. (0.41±0.21)%]. The diversity of intestinal flora in ceftriaxone group was significantly lower than that in Sham and CHM groups (404.60±17.09 vs. 470.80±16.97, 469.20±14.59), the differences between groups were statistically significant (all P < 0.05). The principal component analysis (PCA) suggested that the composition of CHM group was closer to that of Sham group, which indicated that WPSS therapy could reduce intestinal flora disorders in rats with sepsis. ③The pathological changes of intestinal mucosa: light microscope showed the intestinal mucosa of Sham group was intact; the intestinal mucosa became thinner, and local inflammatory cells had infiltration in MC group. The thickness of intestinal mucosa in CHM, ceftriaxone and CHM+ceftriaxone groups was slightly thicker, and the infiltration of local inflammatory cells was less than that in MC group. The thickness of intestinal mucosa in CHM group and ceftriaxone+CHM group was slightly thicker than that in the ceftriaxone group, and the arrangement was more regular than that in MC group and ceftriaxone group.④Intestinal mucosa permeability and inflammatory state: IMII, D-lactic acid, DAO, LPS, TNF-α and IL-6 of rats in MC group were higher than those of rats in Sham group [IMII: 4.37±0.56 vs. 0.26±0.29, D-lactic acid (mg/L):12.35±0.83 vs. 7.30±1.29, DAO (kU/L): 2.16±0.43 vs. 0.32±0.06, LPS (kU/L): 0.663±0.012 vs. 0.095±0.003, TNF-α (μg/L): 251.03±82.69 vs. 52.15±6.25, IL-6 (μg/L): 160.50±4.77 vs. 54.30±3.36], while sIgA in MC group was lower than that in Sham group (mg/L: 11.57±0.17 vs. 26.76±1.99). IMII, D-lactic acid, DAO, LPS, TNF-α and IL-6 of rats in CHM, ceftriaxone and CHM+ ceftriaxone groups were significantly lower than those of rats in MC group, while sIgA in CHM, ceftriaxone and CHM+ceftriaxone groups were significantly higher than that of rats in MC group. The change of CHM+ceftriaxone group was more significant than those of CHM group and ceftriaxone group [IMII:1.78±0.23 vs. 1.96±0.62, 3.39±0.43, D-lactic acid (mg/L): 8.56±0.37 vs. 9.62±0.57,11.42±0.39, DAO (kU/L):1.14±0.12 vs. 1.72±0.24, 2.01±0.32, sIgA (mg/L): 25.34±1.49 vs. 23.99±7.85, 17.46±1.20, LPS (kU/L):0.302±0.007 vs. 0.387±0.004, 0.715±0.013, TNF-α (μg/L): 57.10±3.98 vs. 101.49±21.49, 141.91±20.20, IL-6 (μg/L): 93.71±2.39 vs. 87.12±7.31, 104.27±1.84]. Conclusion WPSS therapy may improve the efficacy of antibiotics in the treatment of sepsis by regulating the intestinal flora and reducing the intestinal mucosa permeability and inflammation level.

Effects of Endotoxin Affinity Adsorbent SPV on Intestinal Permeability and Bacterial Translocation in Hemorrhagic Shock Model Rats / 中国药房

OBJECTIVE： To observe the effects of endotoxin affinity adsorbent SPV on intestinal permeability and bacterial translocation in hemorrhagic shock model rats.  METHODS： Totally 85 male SD rats were randomly divided into normal group （5 rats）， shock group （each 5 rats at each time point， 20 rats in total）， SPV low-dose， medium-dose and high-dose groups （Montmorillonite powder 0.3 g， Polymyxin B sulfate 0.5 mg， Vitamin B6 5 mg dissolved in normal saline to obtain SPV solution 5 mL， as low dose； medium and high dose were 2 or 3 times as high as low dose. Each 5 rats of each group at each time point， 60 rats in total）. Administration groups were given SPV solution intragastrically 5， 10， 15 mL once， respectively； normal group and shock group were given normal saline 5 mL intragastrically once. Thirty minutes after last medication， other groups received femoral artery catheterization and bleeding to induce hemorrhagic shock model， except for normal group. The activities or contents of diamine oxidase （DAO）， endotoxin and D-lactic acid， positive rates of intestinal bacterial translocation were detected in each group at 1， 4， 8， 16 h after recovery. RESULTS： Compared with normal group， the activities of DAO of rats in shock group were enhanced significantly， and the serum contents of endotoxin and D-lactic acid were increased significantly （P＜0.05）. Compared with shock group， the activities of DAO were decreased significantly in SPV groups （at each time point during 1-16 h）； the serum contents of endotoxin and D-lactic acid （at each time point during 1-16 h）， positive rates of intestinal bacterial translocation （SPV low-dose group at each time point during 4-16 h， SPV medium-dose and high-dose groups at each time point during 1-16 h） were decreased significantly （P＜0.05）. Above indexes in SPV medium-dose and high-dose groups （at each time point during 1-16 h） were significantly lower than those of SPV low-dose group （P＜0.05）. There was no statistical significance in above indexes between SPV medium-dose group and high-dose group （P＞0.05）. CONCLUSIONS： The endotoxin affinity adsorbent SPV can improve the permeability of the intestinal wall and inhibit bacterial translocation in hemorrhagic shock model rats in dose-dependent manner. The effects of which may be associated with reducing the activities or contents of serum DAO， endotoxin， D-lactic acid， and down-regulating the positive rate of bacterial translocation.