Intestinal Permeability In Patients Research Articles

An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

A47 A PRELIMINARY ANALYSIS OF THE CROHN'S DISEASE THERAPEUTIC INTERVENTION TRIAL (CD-TDI) IN MILD-TO-MODERATE CROHN'S DISEASE

Abstract Background Studies show a diet-CD remission link, yet a lack of clinical trials exists. The CD Therapeutic Dietary Intervention (CD-TDI) is an evidence-based dietary regimen based on the principles of the Mediterranean diet and incorporates insights from our pilot data as well as the scientific literature about mitigating inflammation through diet in CD. Aims To explore the efficacy of the CD-TDI compared with conventional management (CM) to induce clinical and biochemical remission in patients with active, mild-to-moderate luminal CD. Methods Participants (n=28) were randomly assigned (2:1 ratio) to either CD-TDI (n=16) or conventional management (CM) (n=12) for 13 weeks. Stool and blood samples were collected at the start and end of the 13 weeks, and fecal bacteriome was analyzed by 16S rRNA. Results At baseline, fecal calprotectin (FCP) or C-reactive protein (CRP) levels were not significantly different. By W13, the CD-TDI group's FCP decreased (△ -113±237 µg/g), whereas the CM group experienced an increase (△ 337±1224 µg/g) (p=0.04). CD-TDI significantly reduced CRP (1.0 mg/L, IQR: 0.6-2.4) compared to the CM (4.5 mg/L, IQR: 2.6-13.0, p=0.007). In the CD-TDI group, zonulin decreased (-43 vs. +26, p=0.04) and increased in the CM group (-43 vs. +26, p=0.04), respectively. Lipopolysaccharide-binding protein (LBP) significantly increased in the CM group compared to CD-TDI (CD-TDI = 17 vs. CM = 26; p=0.03). Differential abundance analysis identified a higher abundance of Lachnospiraceae, Selenomonadaceae, Sutterella spp., and Akkermansia muciniphila in the CD-TDI group, whereas Collinsella intestinalis was more prevalent in the CM group. Conclusions The CD-TDI demonstrated a reduction in markers of inflammation and intestinal permeability in patients with mild-to-moderately active CD, along with alterations in the composition of bacterial taxa. These initial findings strongly indicate that CD-TDI holds promise for alleviating the inflammatory burden in CD patients and warrants further exploration as a valuable adjunctive therapy. Funding Agencies Crohn's Colitis Foundation of America; IMAGINE

P1213 The effects of Escherichia coli Nissle 1917 on the gut microbiota composition in ulcerative colitis patients

Abstract Background Escherichia coli Nissle (EcN) 1917 is a Gram-negative bacterium currently used as probiotic in the management of infectious gastroenteritis and ulcerative colitis (UC). We evaluated the effect of administration of EcN on the composition of the gut microbiota and on intestinal permeability in patients affected by UC. Methods Five patients with stable UC were treated with EcN one pill daily for ten days followed by two pills per day for further twenty days. Fecal samples were collected before the treatment (T0), after ten days (T1) and after one month of treatment (T2). Alpha diversity, microbiota composition and taxonomy were analyzed. Results Alpha diversity increased through treatment: Good’s coverage index revealed an increase in the number of operational taxonomic units (OTUs) at T2. At phylum taxonomic level, Firmicutes relative abundance decreased at T1 compared to T0. At family level, Clostridiacae relative abundance at T1 was higher than T0 and T2. The T test on gut microbiota variations at species level reveals the variability at the two timepoints (T0 and T2), with significant increase for Actinomyces, Anaerostipes, Bacteroides, Bulleidia, Corynebacterium, Dialister, Enterobacteriaceae, Erysipelotrichaceae, Finegoldia, Granulicatella, Lactobacillaceae, Peptoniphilus, Phascolarctobacterium, Roseburia, Serratia, Veillonellaceae, Veillonella dispar. Furthermore, the administration of EcN improved intestinal permeability, assessed on a CaCO2 monolayer. Conclusion Treatment with EcN leads to an improvement in the qualitative composition of the gut microbiota in patients affected by UC, in terms of both diversity and taxonomy. These effects are stronger at the end of treatment.

The association between serum heat shock protein 72 and intestinal permeability with intestinal microbiota and clinical severity in patients with cerebral infarction.

We aimed to compare serum heat shock protein 72 (HSP72) and intestinal permeability in patients with cerebral infarction (CI) and healthy individuals to reveal their correlations and link to gut microbiota alterations and clinical severity of CI. Stool samples of 50 patients with CI and 46 healthy volunteers were analyzed through 16S rRNA gene sequencing to characterize intestinal flora profiles. Serum HSP72 and zonulin were assayed using enzyme-linked immunoassay (ELISA). The obtained data were then subjected to comparative and correlative analysis. We found that the levels of zonulin and serum HSP72 were significantly higher in the CI group compared to the healthy group. Serum HSP72 and zonulin levels were positively correlated in the CI group and correlated positively with the clinical severity of CI. β diversity showed significant differences in intestinal microbiota composition between the two groups. In the CI patient group, the abundance of bacteria Eubacterium_fissicatena_group, Eubacterium_eligens_group, and Romboutsia manifested a remarkably positive correlation with serum HSP72. The abundance of bacteria Eubacterium_fissicatena_group and Acetivibrio had a significantly positive correlation with zonulin levels. Our findings indicated that an increase in serum HSP72 and zonulin levels was manifested in patients with CI and was related to specific gut microbiota alterations and the clinical severity of CI.

Запор и мультиморбидная патология: взгляд педиатра

The prevalence of constipation among the Russian child population is extremely high. Chronic constipation is a classic example of a multimorbidity and has significant, including disabling, consequences for the child's health. The syndrome of increased intestinal permeability, which occurs with chronic constipation, forms a whole block of systemic pathology involving almost all human systems and organs. More than half (51.7%) of children with chronic constipation have symptoms of chronic fecal intoxication. The article highlights the etiopathogenetic aspects of the increased intestinal permeability in patients with chronic constipation. The article also discusses the association of intestinal motility disorders with the development of dermatosis, urinary tract pathology, allergic, mental and other diseases. The butyrate role as a key molecule of intestinal metabolism is considered. The importance of lactitol in the constipation treatment and increased intestinal permeability correction is also shown. This drug has a complex effect: during its use, there is an increase in the bowel movement frequency, a decrease in the constipation symptoms, as well as the regulation of the intestinal barrier to protect the body from the constipation effects. KEYWORDS: increased intestinal permeability, constipation, multimorbidity, short-chain fatty acids, butyrate, laxative, lactitol. FOR CITATION: Nizhevich A.A., Valeeva D.S., Loginovskaya V.V. Constipation and multimorbidity: a pediatrician's view. Russian Journal of Woman and Child Health. 2024;7(1):71–78 (in Russ.). DOI: 10.32364/2618-8430-2024-7-1-11.

Assessing the diagnostic value of zonulin as a biomarker for intestinal permeability in patients with metabolic-associated fatty liver disease in combination with type 2 diabetes mellitus

The aim of the study was to assess the diagnostic value of serum zonulin concentrations in patients with metabolic-associated fatty liver disease (МAFLD) in combination with type 2 diabetes mellitus (T2DM). Materials and methods. The study involved 93 patients with MAFLD in combination with T2DM, who were examined and allocated to two groups. Group 1 consisted of 48 patients with non-alcoholic steatohepatitis (NASH) in combination with T2DM without small intestinal bacterial overgrowth (SIBO) syndrome. Group 2 comprised 45 patients with NASH in combination with T2DM and SIBO. The control group consisted of 25 apparently healthy persons. The ELISA method was used for quantitative determination of serum zonulin. Results. When comparing parameters of liver functional activity and ultrasonographic findings of liver steatosis and fibrosis, a significant increase in the activity of ALT and AST was revealed in Group 1 – 67.22 ± 2.25 U/l and 52.97 ± 1.04 U/l (p < 0.001) and in Group 2 – 69.20 ± 1.52 U/l and 54.82 ± 1.10 U/l (p < 0.001) compared to those in the control group – 18.00 ± 1.01 U/l and 18.96 ± 0.82 U/l (p < 0.001) respectively, as well as an increase in the ultrasound attenuation coefficient (UAC) in patients of Groups 1 and 2 amounting to 2.94 ± 0.03 dB/cm and 2.92 ± 0.04 dB/cm, respectively, and also the liver stiffness (LS) in Group 1 – 8.06 ± 0.07 kPa and in Group 2 – 8.00 ± 0.06 kPa compared to those in the control group (p < 0.001). When measuring the level of serum zonulin, a significant increase was revealed in patients of Group 1 – 61.69 ± 1.04 ng/ml and Group 2 – 89.39 ± 1.30 ng/ml compared to that in the control group – 16.76 ± 1.47 ng/ml (p < 0.001). Analyzing correlation coefficients in patients of Groups 1 and 2, a positive linear moderate association was found between the serum zonulin concentration and the activity of ALT, AST and UAC and LS. Conclusions. The study resultsobtained have demonstrated the great diagnostic value of serum zonulin as a biomarker of intestinal permeability in NASH patients in combination with T2DM, and with or without SIBO.

Intestinal permeability in patients undergoing stem cell transplantation correlates with systemic acute phase responses and dysbiosis.

Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day+7 and+30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day+7 but returned to baseline at day+30 in most patients (P= .014). Conditioning regimen intensity did not affect the trajectory of L:R (P= .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2= 0.208; P= .0014). High L:R ratios were associated with lower microbiome diversity (P= .035), loss of anaerobic organisms (P= .020), and higher plasma LBP (P= .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.

Impaired intestinal permeability in patients with multiple sclerosis.

A number of recent studies have shown that the intestinal microbiome, part of the brain-gut axis, is implicated in the pathophysiology of multiple sclerosis. An essential part of this axis, is the intestinal barrier and gastrointestinal disorders with intestinal barrier dysregulation appear to be linked to CNS demyelination, and hence involved in the etiopathogenesis of multiple sclerosis (MS). The aim of this study was to evaluate the integrity of the intestinal barrier in patients with clinically definite multiple sclerosis (CDMS) and clinically isolated syndrome (CIS) using two serum biomarkers, claudin-3 (CLDN3), a component of tight epithelial junctions, and intestinal fatty acid binding protein (I-FABP), a cytosolic protein in enterocytes. Serum levels of CLDN3 in 37 MS patients and 22 controls, and serum levels of I-FABP in 46 MS patients and 51 controls were measured using commercial ELISA kits. Complete laboratory tests excluded the presence of gluten-related disorders in all subjects. Thirty MS patients received either disease-modifying drugs (DMD), immunosuppression (IS) or corticosteroid treatment. CLDN3 levels were only significantly higher in the MS patients treated with DMD or IS compared to the control group (P=0.006). There were no differences in I-FABP serum levels between the groups. Serum CLDN3 levels did not correlate with serum I-FABP levels in CDMS, in CIS patients or controls. In multiple sclerosis patients, the intestinal epithelium may be impaired with increased permeability, but without significant enterocyte damage characterized by intracellular protein leakage. Based on our data, CLDN3 serum levels appear to assess intestinal dysfunction in MS patients but mainly in treated ones.

Association of markers of inflammation and intestinal permeability in suicidal patients with major mood disorders

BackgroundPatients with major mood disorders are at high risk of suicidal behavior compared to the general population. Suicide is a public health concern, accounting for around 1.2% of deaths worldwide. Understanding its underlying mechanisms may help identify predictive biomarkers and design novel targeted treatments. Immune dysfunctions, in particular affecting the gut-brain axis, are of interest given their dual involvement in mood disorders and suicidal behavior. We thus explored the possible relationships between suicide attempt (SA) and circulating biomarkers of intestinal permeability and systemic inflammation in patients with major depressive disorder (MDD) or bipolar disorder (BD) with and without a history of SA. Method137 patients with BD and 168 with MDD were included, and among them, 133 had a history of SA and 172 did not. Among them, 104 were males (34%) and 201 females (66%). Depressive symptoms were evaluated using the Inventory of Depressive Symptomatology clinical scale (IDS-C30). Circulating levels of intestinal fatty acid binding protein (IFABP), calprotectin, apolipoprotein E (ApoE), lipopolysaccharides binding protein (LBP), lipopolysaccharides (LPS), soluble beta-2-microglobulin (B2m), and C-reactive protein (CRP), were determined. Multivariate linear regressions were performed according to the gender status given the proportion of the herein studied male and female individuals and the higher propensity of females to experience SA as compared to males. ResultsAfter adjusting for confounding variables, patients in the SA group had significantly higher CRP, and lower IFABP levels in comparison to the NSA group. LimitationsThe unavailability of confounding variables such as dietary habits, should be noted. In addition, the cross-sectional nature of the study hampers the identification of causative effects. ConclusionAlthough preliminary, our observations revealed associations between markers of inflammation and intestinal permeability in patients with suicidal behavior warranting further confirmation in larger cohorts.

MicroRNA-29b-3p promotes intestinal permeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

Irritable bowel syndrome with predominant diarrhea (IBS-D) is characterized by increased intestinal permeability. Previous studies have shown that the microRNA-29 gene is involved in the regulation of intestinal permeability in patients with IBS-D. NF-κB was proved to play a key role in inflammatory response of intestine and resultant disruption of tight junction integrity, whose activity could be inhibited by TNF Receptor-Associated Factor 3 (TRAF3). However, the exact mechanism that induces increased intestinal permeability in IBS-D patients has not been clarified. In this study, we found that microRNA-29b‑3p (miR-29b-3p) was significantly upregulated, while TRAF3 was decreased and the NF-κB-MLCK pathway was activated within the colonic tissue of IBS-D patients. Subsequently, we confirmed the targeting relationship between miR-29b-3p and TRAF3 through a double-luciferase reporter assay. Lentivirus transfection of NCM460 cells with miR-29b-3p-overexpressing and -silencing vectors demonstrated that the expression of TRAF3 was negatively correlated with the level of miR-29b-3p. The NF-κB/MLCK pathway was activated in the miR-29b-3p-overexpressing group and inhibited to some extent in the miR-29b-3p-silencing group. Results in WT and miR-29 knockout mice showed that miR-29b-3p levels were increased, TRAF3 levels were decreased, and the NF-κB/MLCK signaling was activated in the WT IBS-D group as compared with the WT control group. The protein levels of TRAF3 and TJs in the miR-29b-/- IBS-D group were partially recovered and NF-κB/MLCK pathway indicators were, to a certain extent, decreased as compared with the WT IBS-D group. These results suggested that miR-29b-3p deletion enhances the TRAF3 level in IBS-D mice and alleviates the high intestinal permeability. In brief, through the analysis of intestinal tissue samples from IBS-D patients and miR-29b-/- IBS-D mice, we showed that miR-29b-3p is involved in the pathogenesis of intestinal hyperpermeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

#2511 ASSOCIATION OF CONSTIPATION, MICROBIAL TRANSLOCATION, AND INFLAMMATION IN HD PATIENTS

Abstract Background and Aims Increased gut permeability and intestinal dysbiosis may contribute to chronic inflammation, leading to accelerated atherosclerosis and cardiovascular complications in patients on haemodialysis (HD). Constipation is highly prevalent in HD patients and growing evidence suggested constipation can aggravate gut microbiota dysbiosis and gut inflammation. The aim of this study was to evaluate the association between markers of microbial translocation, intestinal permeability and inflammation in HD patients with and without constipation. Method A cross-sectional, observational study was conducted and 200 stable prevalent HD were enrolled. Serum zonulin, eotaxin-1, amyloid A, intestinal fatty acid-binding protein (iFABP), IL-6, endotoxin core antibodies (EndoCAb) and lipopolysaccharide binding protein (LBP) levels were measured. Functional constipation was defined according to the Rome IV criteria. Results Serum levels of zonulin and eotaxin-1 but not LPS, endo-Cab IgG, amyloid A and IL-6 were significantly higher in HD patients with constipation than in non-constipated HD controls. The multiple logistic regression analysis in constipated HD patients after adjustment for age, and BMI demonstrated that serum zonulin and eotaxin-1 were independently associated with constipation with an odds ratio (OR) of 1.24 (95% CI = 1.09-1.42, p = 0.0016) and 1.02 (95% CI = 1.01-1.03, p = 0.0001), respectively. Conclusion We demonstrate that there was association between serum eotaxin-1 and zonulin levels in constipated HD patients. This may indicates that increased intestinal inflammation or intestinal permeability in these patients but the significance of these findings need further investigation.

FRI-406 - Altered intestinal permeability in patients with drug-induced liver injury and other forms of acute liver injury: a sequential analysis of serum levels of LBP, CD14 and CD163

FRI-406 - Altered intestinal permeability in patients with drug-induced liver injury and other forms of acute liver injury: a sequential analysis of serum levels of LBP, CD14 and CD163

Evaluation of Small Intestinal Permeability in Patients with Overlap Syndrome (Autoimmune Hepatitis/Primary Biliary Cholangitis)

Аim: to evaluate the state of small intestine permeability by the “double sugar test” in patients with overlap syndrome (autoimmune hepatitis / primary biliary cholangitis (AIH / PBC)).Materials and methods. Prospectively, 56 people were included in the study. Of these, 26 were diagnosed with AIH/PBC, 30 were in the control group. The diagnosis was made in accordance with the current recommendations. The average age of patients was 49.7 ± 13.8 years, healthy volunteers — 48.6 ± 9.2 years. The determination of the permeability of the small intestine was carried out by a “double sugar test” (the ratio of lactulose/mannitol in urine), using the method of high-performance liquid chromatography — mass spectrometry.Results. In patients with AIH/PBC, an increase in intestinal permeability was found — 0.20 [0.09; 0.30] (p < 0.001) compared with the control group 0.01 [0.01; 0.02]. We divided patients at the stage of liver damage. An increased small intestinal permeability was revealed: hepatitis stage — 0.19 [0.13; 0.30] (p < 0.001), liver cirrhosis stage — 0.18 [0.09; 0.30] (p < 0.05) compared with the control group. In the early stages of disease (1 month from the onset of the disease) had an increased lactulose/mannitol ratio — 0.13 [0.05; 0.26] (p < 0.001) compared to the control group. In the presence of portal hypertension (PH), small intestinal permeability was increased — 0.18 [0.09; 0.30] (p < 0.001) compared with the control group.Conclusions. An increase in small bowel permeability was found in patients with overlapping syndrome. All patients had increased intestinal permeability (regardless of the presence of extrahepatic manifestations).

Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus.

Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

Latest Findings on the Interaction Mechanism Between Depressive Disorder and Intestinal Permeability

The intestinal barrier, a complex structure consisting of multiple layers of defense barriers, blocks the transfer of intestinal and foreign bacteria and their metabolites into the internal environment of the human body. Intestinal permeability can be used to evaluate the integrity of the intestinal barrier. Increased intestinal permeability has been observed in patients with depressive disorder. Some studies have reported an interaction between depressive disorder and intestinal barrier. Herein, we reviewed reported findings on the mechanisms of how systematic low-grade inflammation, vagal nerve dysfunction, and hypothalamic-pituitary-adrenal axis dysfunction cause changes in intestinal permeability in patients with depressive disorder and the pathogenic mechanism of how bacterial translocation caused by damaged intestinal barrier leads to depressive disorder. In addition, the potential mechanisms of how antidepressants improve intestinal permeability and how probiotics improve depressive disorder have been discussed.

Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU.

Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria resistant to nonsedating H1-antihistamines. We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA derived from Escherichia on mast cells, intestinal permeability of patients with chronic spontaneous urticaria with or without nonsedating H1-antihistamine resistance and healthy controls were determined, and LAD2 cells with knockdown of Syk, Nedd4L, or Sgk1 or with incubation of inhibitors GS9973, GSK650394, and MG132 were posttreated with btDNA. We found that (i) serum intestinal permeability indices and bacterial DNA markedly increased in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance compared with those without (all P < 0.001), and bacterial DNA positively correlated with the degree of inflammation; (ii) IL-6 and TNF-α levels were time- and dose-dependently upregulated in bacterial DNA-stimulated LAD2 cells, which relied on unmethylated CpG in bacterial DNA and Toll-like receptor 9 protein in cells; (iii) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked bacterial DNA-initiated cytokine production; (iv) Nedd4L interacted with Tyr525/526-phosphorylated Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by bacterial DNA-activated Sgk1 was mandatory for bacterial DNA's proinflammatory property; and (v) Sgk1 suppression showed an inhibitory effect on bacterial DNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated Syk. Collectively, we identified previously unknown contributory roles of bacterial translocation and serum bacterial DNA on the inflammation phenotype in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in bacterial DNA-induced inflammation in LAD2 cells.

Intestinal permeability and its role in the pathogenesis and progress of non-alcoholic fatty liver disease. Review

Non‑alcoholic fatty liver disease (NAFLD) is a topical problem for the medicine worldwide, and its association with an «unhealthy» lifestyle and metabolic disorders is well established. The important role of dysbiosis of the intestinal microbiota in the NAFLD pathogenesis and the functioning of the intestine‑liver axis is emphasized. Data on the structure and functioning of the intestinal barrier in physiological conditions are presented. It has been proven that the presence of dysbiotic changes in the microbiota plays an important role in the disruption of the barrier function of the gastrointestinal tract, which in turn increases the level of physiological translocation of both bacteria and their toxins and their life products. Part of these harmful products comes to the liver through the portal vein (endotoxinemia). The antigens’ overload contributes to the development and progression of NAFLD (up to liver cirrhosis). The intestinal barrier is emphasized to be dynamic and sensitive to changes occurring in the intestine. The increased intestinal permeability and bacterial overgrowth syndrome (which is a source of increased endotoxemia) is observed in patients with NAFLD more frequently than in healthy subjects. Number of studies have revealed that the degree of intestinal permeability in NAFLD patients correlated with the steatosis severity. The factors that most significantly affect intestinal permeability in patients with NAFLD include microbial environment, bile acids, levels of fecal short‑chain fatty acids (mainly butyrate), the metabolism of the essential aromatic amino acid tryptophan, as well as the nature of nutrition, alcohol intake, medicinal preparations, stress, and level of physical activity, which act either directly or through the induction of intestinal microbiota dysbacteriosis. The increased intestinal permeability and its consequence — bacterial translocation, are noticed to be involved in the development of such complications as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, hepatocellular carcinoma.&#x0D;

The Effects of Probiotics on Small Intestinal Microbiota Composition, Inflammatory Cytokines and Intestinal Permeability in Patients with Non-Alcoholic Fatty Liver Disease.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the role of GLA. We looked at how multi-strain probiotics (MCP® BCMC® strains) containing six different Lactobacillus and Bifidobacterium species affected the small intestinal gut microbiota, inflammatory cytokines, and permeability in NAFLD patients. After six months of supplementation, biochemical blood analysis did not show any discernible alterations in either group. Five predominant phyla known as Actinobacteria, Proteobacteria, Firmicutes, Bacteroidota and Fusobacteria were found in NAFLD patients. The probiotics group demonstrated a significant cluster formation of microbiota composition through beta-diversity analysis (p < 0.05). This group significantly reduced three unclassifiable species: unclassified_Proteobacteria, unclassified_Streptococcus, and unclassified_Stenotrophomonas. In contrast, the placebo group showed a significant increase in Prevotella_melaninogenica and Rothia_mucilaginosa, which were classified as pathogens. Real-time quantitative PCR analysis of small intestinal mucosal inflammatory cytokines revealed a significant decrease in IFN-γ (-7.9 ± 0.44, p < 0.0001) and TNF-α (-0.96 ± 0.25, p < 0.0033) in the probiotics group but an increase in IL-6 (12.79 ± 2.24, p < 0.0001). In terms of small intestinal permeability analysis, the probiotics group, unfortunately, did not show any positive changes through ELISA analysis. Both probiotics and placebo groups exhibited a significant increase in the level of circulating zonulin (probiotics: 107.6 ng/mL ± 124.7, p = 0.005 vs. placebo: 106.9 ng/mL ± 101.3, p = 0.0002) and a significant decrease in circulating zonula occluden-1 (ZO-1) (probiotics: -34.51 ng/mL ± 18.38, p < 0.0001 vs. placebo: -33.34 ng/mL ± 16.62, p = 0.0001). The consumption of Lactobacillus and Bifidobacterium suggested the presence of a well-balanced gut microbiota composition. Probiotic supplementation improves dysbiosis in NAFLD patients. This eventually stabilised the expression of inflammatory cytokines and mucosal immune function. To summarise, more research on probiotic supplementation as a supplement to a healthy diet and lifestyle is required to address NAFLD and its underlying causes.

Zonulin as a marker of intestinal permeability in patients with acne associated with celiac disease

The intestinal barrier plays an important role in maintaining gut and whole body immune homeostasis. The role of the gastrointestinal microbiota is significant in maintaining intestinal tightness as the latter affects the intestinal barrier. Shifting the balance of the gut microbiota composition towards opportunistic microorganisms is known to lead to increased secretion of the recently discovered protein zonulin. The level of zonulin in patients with various diseases makes it possible to judge the change in intestinal wall permeability during pathological processes or different types of therapy. The present study examined for the first time the effect of a gluten-free diet on the course of acne in patients with and without celiac disease. The given study was the first to investigate the effect of a gluten-free diet on the course of acne in patients with and without celiac disease.

Intestinal permeability evaluation in patients with chronic Chagas heart failure.

We analysed intestinal permeability in patients with chronic Chagas cardiomyopathy (CCC) and evaluated its association with clinical manifestations, haemodynamic parameters measured by echocardiogram, and disease outcome. Intestinal permeability was compared between CCC patients and a group of healthy controls. Intestinal dysfunction may contribute to a more severe disease presentation with worse outcome in patients with CCC and heart failure. Fifty patients with CCC and left ventricular ejection fraction (LVEF) of less than 55% were prospectively selected and followed for a mean period of 18±8months. A group of 27 healthy volunteers were also investigated. One patient was excluded from the analysis since he died before completing the intestinal permeability test. Intestinal permeability was evaluated with the sugar probe drink test. It consists in the urinary recovery of previously ingested sugar probes: mannitol, a monosaccharide, and lactulose, a disaccharide. Patient's mean age was 53.4±10.4years, and 31(63%) were male. Differential urinary excretion of lactulose/mannitol ratio did not differ significantly between healthy controls and CCC patients, regardless of clinical signs of venous congestion, haemodynamic parameters, and severity of presentation and outcome. The present study could not show a disturbance of the intestinal barrier in CCC patients with LVEF <55%, measured by lactulose/mannitol urinary excretion ratio. Further investigations are needed to verify if in patients with LVEF <40% intestinal permeability is increased.