Increase In Intestinal Permeability Research Articles

Lacticaseibacillus rhamnosus LRa05 alleviated liver injury in mice with alcoholic fatty liver disease by improving intestinal permeability and balancing gut microbiota.

This study investigated the effect of Lacticaseibacillus rhamnosus LRa05 on alcoholic fatty liver disease (ALD) and its mechanism for liver protection. Mice were randomly divided into three groups: a control (CLT) group, an ALD group, and a LRa05 intervention group. The ALD mouse model was established by Lieber-DeCarli chronic alcohol feeding. Tissues staining, enzyme-linked immunosorbent assay (ELISA) was performed to detect changes in histopathology and inflammatory cytokines, respectively. Moreover, intestinal permeability was evaluated by the level of dextran-fluorescein isothiocyanate (Dx-FITC) in serum and tight junction protein in the colon. Changes in the composition of the gut microbiota were assessed by 16S rRNA sequencing. Alcohol consumption induced liver damage in mice with significantly increased levels of triglycerides (TG), aspartate aminotransferase (AST), alanine transaminase (ALT), and inflammatory cytokines. Moreover, alcohol further induced the increase of intestinal permeability and disruption of gut microbiota in mice, with an increase in the relative abundance of potentially pathogenic bacteria Enterococcus, Parabacteroides, and Alistipes. LRa05 intervention significantly attenuated alcohol-induced liver injury by reducing the contents of TG, ALT, and AST, and suppressing the inflammatory responses. Meanwhile, by stimulating the expression of ZO-1, Occludin, and Claudin in the colon tissue, LRa05 additionally strengthened the intestine barrier function. Furthermore, gut microbiota analysis suggested that LRa05 partially ameliorated gut microbiota disorders in ALD mice and up-regulated the abundance of Desulfovibrio and Akkermansia, which were negatively correlated with the indicators of ALD progression. The reconstructive effects of LRa05 on the gut microbiota might be related to the efficacy of LRa05 in improving gut permeability and further protecting against ALD.

The Effect of Dietary Sodium and Potassium Consumption on Intestinal Permeability and its Relation to Blood Pressure, and Endothelial Function: A Pilot Study

High sodium (HS) diets can reduce endothelial function (EF) and increase blood pressure (BP) while high potassium (HK) diets are shown to counter this effect. Furthermore, HS diets have also been shown to lead to gut dysbiosis, which is related to increased intestinal permeability (IP). However, the effect of HS diets on IP and whether the addition of HK can attenuate potential HS-induced changes to IP is unknown. Hypotheses: We hypothesized IP would increase on a HS diet and be mitigated by HK and that a higher IP would be related to elevations in BP and lower EF. Methods: Eleven healthy participants (5W/6M, age 32±8 yrs, BMI 23±1, BP 105±6/66±7 mmHg) consumed three 10-day diets of differing sodium and potassium content in randomized order: low sodium (LS)/low potassium (LK) (50mmol/65mmol), HS/LK (300mmol/65mmol), and HS/HK (300mmol/120mmol). On day 9 of each intervention, they collected their urine and wore an ambulatory BP monitor for 24-hr. On day 10, brachial artery flow-mediated dilation (FMD) was measured. Blood was collected and lipopolysaccharide-binding protein (LBP), a biomarker of IP and bacterial translocation, was measured by ELISA. Mixed design ANOVAs assessed sex differences in LBP, FMD, and BPs between diets. Simple linear regressions assessed relations between variables. Results: Twenty-four-hr urinary sodium excretion was higher on both HS diets compared to LS/LK diet (both p<0.01) and 24-hr urinary potassium excretion was higher on HS/HK compared to LS/LK and HS/LK diets (both p<0.01). LBP was different between diets (p<0.01), and there was a significant diet*sex interaction (p=0.02) where men had increased LBP compared to women on the HS/LK and HS/HK diets (both p<0.01). FMD was not different between diets (p=0.13) although men had a lower FMD compared to women after each diet (sex: p<0.01). Twenty-four-hr mean arterial pressure (MAP) was different between diets (p=0.047) as men demonstrated higher 24-hr MAP on the HS/LK diet compared to LS/LK diet (p=0.03) and lower MAP on the HS/HK diet compared to HS/LK diet (p=0.01). LBP was inversely related to FMD (r=-0.82, p<.01) and positively related to MAP (r=0.72, p<.01), 24-hr systolic BP (r=0.66, p=0.03), and 24-hr diastolic BP (r=0.66, p=0.03) on the HS/LK diet for all participants, but not the LS/LK or HS/HK diets. Conclusions: These pilot data suggest that HS diets may increase IP in men, and, in the context of a HS/LK diet, greater IP is associated with lower FMD and higher BP in all participants. NIH R01 HL145055. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

Altered lactate/pyruvate ratio may be responsible for aging-associated intestinal barrier dysfunction in male rats.

Some evidence points to a link between aging-related increased intestinal permeability and mitochondrial dysfunction in in-vivo models. Several studies have also demonstrated age-related accumulation of the of specific deletion 4834-bp of "common" mitochondrial DNA (mtDNA) in various rat tissues and suggest that this deletion may disrupt mitochondrial metabolism. The present study aimed to investigate possible associations among the mitochondrial DNA (mtDNA) common deletion, mitochondrial function, intestinal permeability, and aging in rats. The study was performed on the intestinal tissue from (24months) and young (4months) rats. mtDNA4834 deletion, mtDNA copy number, mitochondrial membrane potential, and ATP, lactate and pyruvate levels were analyzed in tissue samples. Zonulin and intestinal fatty acid-binding protein (I-FABP) levels were also evaluated in serum. Serum zonulin and I-FABP levels were significantly higher in 24-month-old rats than 4-month-old rats (p = 0.04, p = 0.026, respectively). There is not significant difference in mtDNA4834 copy levels was observed between the old and young intestinal tissues (p > 0.05). The intestinal mitochondrial DNA copy number was similar between the two age groups (p > 0.05). No significant difference was observed in ATP levels in the intestinal tissue lysates between old and young rats (p > 0.05). ATP levels in isolated mitochondria from both groups were also similar. Analysis of MMP using JC-10 in intestinal tissue mitochondria showed that mitochondrial membrane potentials (red/green ratios) were similar between the two age groups (p > 0.05). Pyruvate tended to be higher in the 24-month-old rat group and the L/P ratio was found to be approximately threefold lower in the intestinal tissue of the older rats compared to the younger rats (p < 0.002). The tissue lactate/pyruvate ratio (L/P) was three times lower in old rats than in young rats. Additionally, there were significant negative correlations between intestinal permeability parameters and L/P ratios. The intestinal tissues of aged rats are not prone to accumulate mtDNA common deletion, we suggest that this mutation does not explain the age-related increase in intestinal permeability. It seems to be more likely that altered glycolytic capacity could be a link to increased intestinal permeability with age. This observation strengthens assertions that the balance between glycolysis and mitochondrial metabolism may play a critical role in intestinal barrier functions.

The value of increased intestinal permeability in the pathogenesis of internal diseases

In the process of evolution in the gastrointestinal tract, a system of protection against bacterial and food antigens from getting into the blood was formed. The causes of increased intestinal permeability (IIP) can be microbiota imbalance, use of antibiotics, non-steroidal anti-inflammatory drugs, stress, diet rich in fructose, glucose, sucrose and long-chain fatty acids. The appearance of IIP may be of paramount importance in the pathogenesis of autoimmune diseases. A diet low in fermentable oligodimonosaccharides and polyols, pre- and probiotics, polyphenols, vitamins, short-chain fatty acids, dietary fiber, glutamine contributes to the reduction of IIP. It has been established that the cytoprotector rebamipide strengthens the barrier function throughout the gastrointestinal tract, which is reflected in practical recommendations for its use in diseases accompanied by IIP. The study of this direction will contribute to the emergence of a new strategy for the treatment of internal diseases.

Association of Blast Exposure in Military Breaching with Intestinal Permeability Blood Biomarkers Associated with Leaky Gut.

Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from "breachers" exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP.

Dietary inclusion of a Saccharomyces cerevisiae metabolite improved reproductive performance but did not affect intestinal permeability in two chicken meat breeder lines

Gastrointestinal dysbiosis is a disturbance in mucosal homeostasis, producing low-grade chronic intestinal inflammation and impaired intestinal barrier function. It is induced by several factors, including nutrition and stress, which are both significant factors when considering current broiler breeder practices. A great grandparent (GGP) chicken meat line was identified displaying clinical signs characteristic of potential dysbiosis, including wet droppings and litter, in addition to reduced reproductive performance when compared to a consistently high performing line. This study aimed to determine whether the reduced reproductive performance observed in these hens was a result of dysbiosis and whether dietary supplementation with a Saccharomyces cerevisiae (SC) fermentation product would alleviate clinical signs. Dietary inclusion of SC did not influence intestinal permeability, WBC differentials, or corticosterone concentration in either the wet litter (WL) or high-performing (HP) breeder lines. Compared to hens from the HP line, WL line hens had a significant increase in intestinal permeability at 26 wk (onset of lay). WL hen heterophil counts were increased markedly at week 26 before declining. At weeks 26, 32, and 37 there were also significant increases in monocytes. Higher plasma corticosterone was also observed in WL hens at 37 wk. No significant differences in heterophil to lymphocyte (H:L) ratios or feather corticosterone were observed between lines. Dietary inclusion of SC supplementation to breeder diets had some benefit in regards to reducing hen mortality, improving egg production and hatchability but only in the WL line. Results from this study did not indicate that hens from the wet litter line were experiencing gut dysbiosis. Chronic intestinal inflammation may be a possible reason for the increase in intestinal permeability. These results do indicate that both breeder lines may be exhibiting physiological stress. Future investigation into the physiology and behavior around point of lay is required to find novel strategies to alleviate this stress and in turn, potentially improve welfare and production outcomes.

Polystyrene microplastic-induced oxidative stress triggers intestinal barrier dysfunction via the NF-κB/NLRP3/IL-1β/MCLK pathway

Emerging evidence has demonstrated the association between microplastics (MPs) with a diameter of <5 mm and the risk of intestinal diseases. However, the molecular mechanisms contributing to MP-induced intestinal barrier dysfunction have not been fully appreciated. In this study, C57BL/6 J mice were exposed to polystyrene microplastics (PS-MPs, 0.2, 1 or 5 μm) at 1 mg/kg body weight daily by oral gavage for 28 days. We found that PS-MPs exposure induced oxidative stress and inflammatory cell infiltration in mice colon, leading to an increased expression of pro-inflammatory cytokine. Moreover, there were an increase in intestinal permeability and decrease in mucus secretion, accompanied by downregulation of tight junction (TJ)-related zonula occluden-1 (ZO-1), occluding (OCLN) and claudin-1 (CLDN-1) in mice colon. Especially, 5 μm PS-MPs (PS5)-induced intestinal epithelial TJ barrier damage was more severe than 0.2 μm PS-MPs (PS0.2) and 1 μm PS-MPs (PS1). In vitro experiments indicated that PS5-induced oxidative stress upregulated the expression of nuclear factor kappa B (NF-κB), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, and myosin light chain kinase (MLCK). Meanwhile, pre-treatment with the antioxidant NAC, NLRP3 inhibitor MCC950 and MLCK inhibitor ML-7 considerably reduced PS5-triggered reactive oxygen species (ROS) production and inflammatory response, inhibited the activation of the NF-κB/NLRP3/MLCK pathway, and upregulated ZO-1, OCLN and CLDN-1 expression in Caco-2 cells. Taken together, our study demonstrated that PS-MPs cause intestinal barrier dysfunction through the ROS-dependent NF-κB/NLRP3/IL-1β/MLCK pathway.

Effects of Varying Concentrations of Eimeria Challenge on the Intestinal Integrity of Broiler Chickens

The objective of the current investigation was to evaluate several Eimeria challenges and the resulting alterations in intestinal permeability, intestinal morphology, and intestinal lesion scores in broiler chickens. This study included four groups with ten replicate cages per treatment, in which each group received a different treatment dosage of Eimeria, characterizing high, medium-high, and medium-low challenges. Five days after the challenge, intestinal lesions and permeability were assessed. The results showed that the increase in Eimeria challenge led to a considerable decrease in the height of intestinal villosities, in the ratio between villosity size and crypt depth, and in goblet cells. Moreover, after the challenge, there was a considerable increase in intestinal permeability. In conclusion, the medium-low, medium-high, and high-challenge models can be utilized for experimental infection. In the context of clinical studies, it has been observed that the administration of medium-high and high-challenge doses has proven to be adequate. However, it is advisable to utilize a medium-low challenge level to develop a subclinical challenge model for forthcoming investigations that aim to evaluate nutritional recommendations.

NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.

Gut microbiota facilitate chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) comes with gut dysbiosis, but its relevance remains elusive. Here we use metagenomics sequencing and short-chain fatty acids metabolomics and assess the effects of human CSU fecal microbial transplantation, Klebsiella pneumoniae, Roseburia hominis, and metabolites in vivo. CSU gut microbiota displays low diversity and short-chain fatty acids production, but high gut Klebsiella pneumoniae levels, negatively correlates with blood short-chain fatty acids levels and links to high disease activity. Blood lipopolysaccharide levels are elevated, link to rapid disease relapse, and high gut levels of conditional pathogenic bacteria. CSU microbiome transfer and Klebsiella pneumoniae transplantation facilitate IgE-mediated mast cell(MC)-driven skin inflammatory responses and increase intestinal permeability and blood lipopolysaccharide accumulation in recipient mice. Transplantation of Roseburia hominis and caproate administration protect recipient mice from MC-driven skin inflammation. Here, we show gut microbiome alterations, in CSU, may reduce short-chain fatty acids and increase lipopolysaccharide levels, respectively, and facilitate MC-driven skin inflammation.

High-intensity exercise impairs intestinal barrier function by generating oxidative stress.

The intestine functions as a barrier preventing the entry of extrinsic factors into the body. This barrier function is disrupted by oxidative damage along with an impaired mucosal layer. Excessive exercise can generate oxidative stress in the intestinal tissue; however, the effect of exercise-induced oxidative stress on intestinal permeability is unclear. In this study, we examined the involvement of oxidative stress in barrier function of the ileum of mice following high-intensity exercise. Male ICR mice (12-week-old) were divided into sedentary and exercise groups. Mice in the exercise group underwent a single bout of treadmill running, and the ileum was collected for histological and biochemical analyses. Plasma fluorescence intensity level after oral administration of fluorescein isothiocyanate-dextran gradually increased until 30 min after exercise in response to intensity of exercise. Relatively high levels of oxidative proteins and low level of claudin-1, a tight-junction protein, were observed in the exercise group. Treatment with a xanthine oxidase inhibitor suppressed exercise-induced increases in intestinal permeability. Moreover, excessive exercise training for two weeks led to relatively high intestinal permeability at rest. These results suggest that high-intensity exercise increases intestinal permeability and tight junction damage, which may be mediated by oxidative stress.

The Relationship Between Microbiota and Alzheimer’s Disease

The term microbiota refers to the micro-organisms that interact with the host from birth to death. These interactions can reach the brain via the bloodstream or the gut-brain nervous system. The microbiota performs important beneficial functions, such as contributing to digestive processes, breaking down toxins and creating defense mechanisms against pathogenic bacteria. However, this positive situation only takes place when the microbiota is also positive, i.e. when the probiotics, known as eubiosis, are dominant. Factors such as nutritional habits, age and the use of antibiotics can impair the balance of the microbiota and lead to a situation where harmful microorganisms, known as dysbiosis, are dominant in the gut. In this case, the production of many microbial products that are normally beneficial to the body, such as neurotransmitters and some short-chain fatty acids, reduces and pathogenic metabolites are produced. In the case of dysbiosis, intestinal permeability increases, allowing harmful pathogenic metabolites to enter the bloodstream and even reach the brain via the bloodstream. For these reasons, prolonged dysbiosis is known to pave the way for many diseases such as depression, anxiety, schizophrenia, autism, diabetes, and Alzheimer’s disease. Alzheimer’s disease is characterized by the death of nerve cells in the brain and loss of cognitive abilities. The disease is associated with amyloid plaques and tau protein. It has been argued that disruption of the intestinal microbiota may contribute to the pathology of Alzheimer’s disease and may also have therapeutic potential. Amyloid production may be triggered by the intestinal microbiome, causing a way for the studies on Alzheimer’s disease. This review examines the relationship between the intestinal microbiota and Alzheimer’s disease.

Plasma Interleukin-13 Levels Correlate With the Severity of Symptoms Induced by Functional Dyspepsia.

Functional dyspepsia (FD) is a gastrointestinal functional disorder of the upper gastrointestinal tract that affects the quality of life of patients and poses a significant economic burden. It has been proposed that the local inflammatory immune response at the duodenum is associated with an increase in intestinal permeability, favoring the recruitment of Th2 cells and granulocyte degranulation. Moreover, systemic immune response could also be related to the symptoms of FD. The objective of this study was to evaluate the systemic immune response in Uruguayan patients with FD by analyzing the cytokine levels in plasma and the frequency of circulating T cells associated with duodenal recruitment. An analytic and cross-sectional study in 30 patients with FD and 15 healthy controls (HCs) was carried out. Patients were diagnosed with FD according to the Roma IV Committee definition. Cytokine levels were measured in plasma by a specific assay. Expression of α4β7 and CC chemokine receptor9 in circulating T cells was evaluated by flow cytometry. Higher levels of interleukin (IL)-5, IL-13, and IL-8 and lower levels of IL-10 and IL-12p70 were detected in patients with FD than in HC. Furthermore, a positive linear correlation between IL-13 and the severity of FD symptoms was found. CD4+ T cells from patients with FD expressed higher levels of α4β7 and CC chemokine receptor9 than those from HC. An increase of Th2-like cytokines and a positive correlation between the levels of plasma IL-13 and the severity of symptoms in patients with FD from Uruguay were detected.

Single-particle analysis of circulating bacterial extracellular vesicles reveals their biogenesis, changes in blood and links to intestinal barrier.

Bacterial extracellular vesicles (BEVs) are nano-size particles secreted by bacteria that carry various bioactive components. These vesicles are thought to provide a new window into the mechanisms by which bacteria affect their hosts, but their fundamental proprieties within human remain poorly understood. Here, we developed a single-vesicle analytical platform that enabled BEV detection in complex biological samples of host. Using this platform, we found the presence of BEVs in the host circulation and they were mainly derived from gut microbes. We showed that the levels of circulating BEVs in humans significantly increased with aging due to an age-related increase in intestinal permeability. Significantly different levels of BEVs in blood were also found in patients with colorectal cancer and colitis. Together, our study provides new insights into circulating BEV biology and reveals their potential as a new class of biomarkers.

Western diet components that increase intestinal permeability with implications on health.

Intestinal permeability is a physiological property that allows necessary molecules to enter the organism. This property is regulated by tight junction proteins located between intestinal epithelial cells. However, various factors can increase intestinal permeability (IIP), including diet. Specific components in the Western diet (WD), such as monosaccharides, fat, gluten, salt, alcohol, and additives, can affect the tight junctions between enterocytes, leading to increased permeability. This review explains how these components promote IIP and outlines their potential implications for health. In addition, we describe how a reduction in WD consumption may help improve dietary treatment of diseases associated with IIP. Research has shown that some of these components can cause changes in the gut microbiota, leading to dysbiosis, which can promote greater intestinal permeability and displacement of endotoxins into the bloodstream. These endotoxins include lipopolysaccharides derived from gram-negative bacteria, and their presence has been associated with various diseases, such as autoimmune, neurological, and metabolic diseases like diabetes and cardiovascular disease. Therefore, nutrition professionals should promote the reduction of WD consumption and consider the inclusion of healthy diet components as part of the nutritional treatment for diseases associated with increased intestinal permeability.

Moringa oleifera Leaves Protein Enhances Intestinal Permeability by Activating TLR4 Upstream Signaling and Disrupting Tight Junctions.

Changes in intestinal mucosal barrier permeability lead to antigen sensitization and mast cell-mediated allergic reactions, which are considered to play important roles in the occurrence and development of food allergies. It has been suggested that protein causes increased intestinal permeability via mast cell degranulation, and we investigated the effect of camellia Moringa oleifera leaves protein on intestinal permeability and explored its role in the development of food allergies. The current study investigated the effect of M. oleifera leaves protein on intestinal permeability through assessments of transepithelial electrical resistance (TEER) and transmembrane transport of FITC-dextran by Caco-2 cells. The expression levels of Toll-like receptor 4 (TLR4), IL-8, Occludin, Claudin-1, and perimembrane protein family (ZO-1) were detected by real-time PCR and Western blotting. The effect of M. oleifera leaves protein on intestinal permeability was verified in mice in vivo. The serum fluorescence intensity was measured using the FITC-dextran tracer method, and the expression of tight junction proteins was detected using Western blotting. The results showed that M. oleifera leaves protein widened the gaps between Caco-2 cells, reduced transmembrane resistance, and increased permeability. This protein also reduced the mRNA and protein levels of Occludin, Claudin-1, and ZO-1. Animal experiments showed that intestinal permeability was increased, and that the expression of the tight junction proteins Occludin and Claudin-1 were downregulated in mice. This study shows that M. oleifera leaves protein has components that increase intestinal permeability, decrease tight junction protein expression, promote transmembrane transport in Caco-2 cells, and increase intestinal permeability in experimental animals. The finding that M. oleifera leaves active protein increases intestinal permeability suggests that this protein may be valuable for the prevention, diagnosis, and treatment of M. oleifera leaves allergy.

Changes in Oxidative Stress and Intestinal Permeability during Pregnancy in Women with Gestational Diabetes Mellitus Treated with Metformin or Insulin and Healthy Controls: A Randomized Controlled Trial.

Both oxidative stress and intestinal permeability are increased in hyperglycemic situations and have been shown to be reduced by metformin in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to elucidate the effect of metformin on oxidative stress and intestinal permeability in women with gestational diabetes mellitus (GDM) treated with metformin compared to those treated with insulin and healthy controls. A total of 120 women were included from August 2016 to February 2022: 41 received metformin (MET group), 38 received insulin (INS group), and 41 were healthy controls. Baseline and antenatal visits were carried out at 25.4 ± 4.8 and 36.1 ± 0.8 weeks of pregnancy, respectively. Advanced oxidation protein products (AOPPs), total antioxidant capacity (TAC), and zonulin levels were measured at every visit. Zonulin levels from baseline to prepartum visit increased significantly in both healthy controls (0.6 ± 0.9 to 1.2 ± 1.7 ng/mL, p = 0.004) and the INS group (0.4 ± 0.3 to 0.6 ± 0.5 ng/mL, p = 0.034) but did not significantly change in the MET group (0.4 ± 0.4 to 0.5 ± 0.4 ng/mL, p = 0.202). However, TAC and AOPP levels significantly increased in women with GDM, both in the INS and MET groups but not in the healthy controls. In conclusion, in our population, metformin has been shown to avoid an increase in intestinal permeability but failed to avoid an increase in oxidative stress related to hyperglycemia.

The relationship between zonulin levels and indicators of lipid metabolism in patients with metabolic associated fatty liver disease in combination with type 2 diabetes mellitus

Objective — to determine the relationship between zonulin level and indicators of lipid metabolism in patients with metabolic associated fatty liver disease (MAFLD) in combination with type 2 diabetes mellitus (DM). Materials and methods. The study involved 64 patients with MAFLD in combination with type 2 diabetes, who were examined and divided into 2 groups. The first group included 35 patients with MAFLD in combination with type 2 diabetes without bacterial overgrowth syndrome (SIBO). The second group included 29 patients with MAFLD in combination with type 2 DM and SIBO. The control group consisted of 18 practically healthy individuals. To assess lipid metabolism disorders, the following indicators were studied: total cholesterol (THC), triglycerides (TG), very low density lipoprotein (VLDL) cholesterol, low‑density lipoprotein (LDL) cholesterol, high‑density lipoprotein (HDL) cholesterol, atherogenic index (AI), non‑HDL cholesterol. The content of serum zonulin was determined by ELISA using test systems IDK Zonulin ELISA, KR5601 (Immunodiagnostic AG, Germany). Results. Significant increase of serum zonulin levels was established in patients with MAFLD in combination with type 2 diabetes without SIBO 65.57±3.14 ng/mL and with MAFLD in combination with type 2 diabetes and SIBO 84. 21±2.42 ng/mL compared with the control group 13.62±2.35 ng/mL (p &lt;0.001), respectively. When comparing zonulin levels in patients of the first and second groups, a significant increase was observed in patients of the second group compared with patients of the first group (p &lt;0.001), respectively. When comparing lipid metabolism indicators in the studied groups, a significant increase in the content of THC was found 5.69 (5.41—5.86) mmol/L and 5.73 (5.17—5.98) mmol/L, TG 1.97 (1.88—2.16) mmol/L and 2.0 (1.9—2.11) mmol/L, LDL cholesterol 3.73±0.06 mmol/L and 3.85±0.12 mmol/L, VLDL cholesterol 1.13 (0.91—1.28) mmol/L and 1.18 (0.89—1.32) mmol/L, non‑HDL cholesterol 4.68±0.07 mmol/L and 4.63±0.09 mmol/L, AI 4.32 (4.15—4.79) and 4.47 (4.14—4.76) and a decrease in HDL cholesterol 0.94±0.02 and 0.96±0.05 in patients with MAFLD in combination with type 2 diabetes without SІBO and SIBO compared with the control group (p &lt;0.001). The levels of indicators in patients of the first and second groups did not differ significantly (p &gt;0.05). As a result of correlation studies between the zonulin serum levels and lipid profile indicators in patients of the first and second groups, a direct moderate correlation was established between the levels of zonulin and triglycerides, a weak correlation with total cholesterol and cholesterol of very low density, non‑HDL cholesterol, atherogenic index and inverse moderate correlation with high‑density lipoprotein cholesterol. Conclusions. As a result of the study, the increase of intestinal permeability was revealed in patients with MAFLD in combination with type 2 DM, with or without SIBO. The increased serum levels of zonulin correlated with the indicators of lipid metabolism.

Epigallocatechin Gallate Alleviates Staphylococcal Enterotoxin A-Induced Intestinal Barrier Damage by Regulating Gut Microbiota and Inhibiting the TLR4-NF-κB/MAPKs-NLRP3 Inflammatory Cascade.

Natural phytochemicals have attracted increasing attention because of their promising ability to tackle bacteriotoxin-induced public safety concerns. However, it is unclear how natural phytochemicals regulate the intestinal barrier dysfunction caused by bacteriotoxin, such as staphylococcal enterotoxin A (SEA). This study aims to illustrate the in vitro and in vivo protective mechanism of epigallocatechin gallate (EGCG) on SEA-triggered intestinal barrier damage and inflammation. Results show that EGCG alleviates intestinal barrier damage by effectively inhibiting SEA-induced intestinal permeability increase, tight junction protein and mucin loss, and intestinal cell apoptosis. EGCG also reduces intestinal inflammation by suppressing the TLR4-NF-κB/MAPKs-NLRP3 pathway. Importantly, EGCG reverses gut microbiota dysbiosis and short-chain fatty acid (SCFA) content decrease induced by SEA. It is worth noting that this study also detects the direct interaction between the phytochemical and virulence factors and finds that EGCG effectively not only inhibits the secretion of SEA but also binds with the secreted SEA to attenuate its toxicity. Taken together, EGCG mitigates SEA-induced intestinal barrier dysfunction via gut microbiota SCFA-mediated TLR4-NF-κB/MAPKs-NLRP3 inflammatory cascade inhibition. Overall, this research provides enlightening insight into the application of bacteriotoxin-targeting natural compounds in the field of food safety and human wellness.