Increase In Intestinal Permeability Research Articles

Leaky Gut and the Ingredients That Help Treat It: A Review.

The human body is in daily contact with potentially toxic and infectious substances in the gastrointestinal tract (GIT). The GIT has the most significant load of antigens. The GIT can protect the intestinal integrity by allowing the passage of beneficial agents and blocking the path of harmful substances. Under normal conditions, a healthy intestinal barrier prevents toxic elements from entering the blood stream. However, factors such as stress, an unhealthy diet, excessive alcohol, antibiotics, and drug consumption can compromise the composition of the intestinal microbiota and the homeostasis of the intestinal barrier function of the intestine, leading to increased intestinal permeability. Intestinal hyperpermeability can allow the entry of harmful agents through the junctions of the intestinal epithelium, which pass into the bloodstream and affect various organs and systems. Thus, leaky gut syndrome and intestinal barrier dysfunction are associated with intestinal diseases, such as inflammatory bowel disease and irritable bowel syndrome, as well as extra-intestinal diseases, including heart diseases, obesity, type 1 diabetes mellitus, and celiac disease. Given the relationship between intestinal permeability and numerous conditions, it is convenient to seek an excellent strategy to avoid or reduce the increase in intestinal permeability. The impact of dietary nutrients on barrier function can be crucial for designing new strategies for patients with the pathogenesis of leaky gut-related diseases associated with epithelial barrier dysfunctions. In this review article, the role of functional ingredients is suggested as mediators of leaky gut-related disorders.

The Relationship between Zonulin and Metabolic Syndrome in Renal Transplant Patients.

Levels of zonulin, a surrogate marker of intestinal permeability, are elevated in various disorders including insulin resistance, obesity, celiac disease, and inflammatory bowel disease. We aimed to elucidate the association of zonulin levels and metabolic syndrome (MS) in renal transplant recipients. Seventy-nine renal transplant recipients were enrolled. Diagnosis of MS was established employing the Adult Treatment Panel III (ATP III) criteria. Serum zonulin level was determined using the double antibody sandwich ELISA method. MS was encountered in 37 (41.6%) of the 79 patients. Serum zonulin level was significantly higher in patients with MS compared to those without MS (p < 0.001). Serum zonulin level correlated with presence of MS (r: 739, p < 0.001), abdominal obesity (r: 514, p < 0.001), fasting glucose level (r: 361, p: 0.001), presence of fasting glucose/diabetes criterion of MS (r: 316, p: 0.005), presence of low HDL criterion of MS (r: 266, p: 0.018), and BMI (r: 527, p < 0.001). A Zonulin-mediated increase in intestinal permeability may play a role in the pathogenesis of metabolic syndrome. We propose that zonulin may be a suitable surrogate marker of MS in renal transplant recipients.

Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice.

The microbiota-gut-brain axis (MGBA) involves bidirectional communication between intestinal microbiota and the gastrointestinal (GI) tract, central nervous system (CNS), neuroendocrine/neuroimmune systems, hypothalamic-pituitary-adrenal (HPA) axis, and enteric nervous system (ENS). The intestinal microbiota can influence host physiology and pathology. Dysbiosis involves the loss of beneficial microbial input or signal, diversity, and expansion of pathobionts, which can lead to loss of barrier function and increased intestinal permeability (IP). Colostrum, the first milk from mammals after birth, is a natural source of nutrients and is rich in oligosaccharides, immunoglobulins, growth factors, and anti-microbial components. The aim of this study was to investigate if bovine colostrum (BC) administration might modulate intestinal microbiota and, in turn, behavior in two mouse models, wild-type (WT) and Zonulin transgenic (Ztm)-the latter of which is characterized by dysbiotic microbiota, increased intestinal permeability, and mild hyperactivity-and to compare with control mice. Bioinformatics analysis of the microbiome showed that consumption of BC was associated with increased taxonomy abundance (p = 0.001) and diversity (p = 0.004) of potentially beneficial species in WT mice and shifted dysbiotic microbial community towards eubiosis in Ztm mice (p = 0.001). BC induced an anxiolytic effect in WT female mice compared with WT female control mice (p = 0.0003), and it reduced anxiogenic behavior in Ztm female mice compared with WT female control mice (p = 0.001), as well as in Ztm male mice compared with WT BC male mice (p = 0.03). As evidenced in MGBA interactions, BC supplementation may well be applied for prophylactic approaches in the future. Further research is needed to explore human interdependencies between intestinal microbiota, including eubiosis and pathobionts, and neuroinflammation, and the potential value of BC for human use. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

Hypotonicity-Induced Increase in Duodenal Mucosal Permeability Is Regulated by Cholinergic Receptors in Rats

BackgroundThe role of cholinergic receptors in the regulation of duodenal mucosal permeability in vivo is currently not fully described.AimsTo elucidate the impact of nicotinic and muscarinic acetylcholine receptor signaling in response to luminal hypotonicity (50 mM NaCl) in the proximal small intestine of rat.MethodsThe effect on duodenal blood-to-lumen clearance of 51Cr-EDTA (i.e., mucosal permeability) and motility was studied in the absence and presence of nicotinic and muscarinic receptor agonists and antagonists, a sodium channel blocker (tetrodotoxin), and after bilateral cervical vagotomy.ResultsRats with duodenal contractions responded to luminal hypotonicity by substantial increase in intestinal permeability. This response was absent in animals given a non-selective nicotinic receptor antagonist (mecamylamine) or agonist (epibatidine). Pretreatment with tetrodotoxin reduced the increase in mucosal permeability in response to luminal hypotonicity. Further, the non-selective muscarinic receptor antagonist (atropine) and agonist (bethanechol) reduced the hypotonicity-induced increase in mucosal permeability, while vagotomy was without an effect, suggesting that local enteric reflexes dominate. Finally, neither stimulating nor blocking the α7-nicotinic receptor had any significant effects on duodenal permeability in response to luminal hypotonicity, suggesting that this receptor is not involved in regulation of duodenal permeability. The effect of the different drugs on mucosal permeability was similar to the effect observed for duodenal motility.ConclusionsA complex enteric intramural excitatory neural reflex involving both nicotinic and muscarinic receptor subtypes mediates an increase in mucosal permeability induced by luminal hypotonicity.

Lactic Acid Bacteria Strains Used as Starters for Kimchi Fermentation Protect the Disruption of Tight Junctions in the Caco-2 Cell Monolayer Model.

In this study, we investigated the effect of lactic acid bacteria (LAB) strains used as starters for kimchi fermentation, namely Lactococcus lactis WiKim0124, Companilactobacillus allii WiKim39, Leuconostoc mesenteroides WiKim0121 Leuconostoc mesenteroides WiKim33, and Leuconostoc mesenteroides WiKim32, on the intestinal epithelial tight junctions (TJs). These LAB strains were not cytotoxic to Caco-2 cells at 500 μg/ml concentration. In addition, hydrogen peroxide (H2O2) decreased Caco-2 viability, but the LAB strains protected the cells against H2O2-induced cytotoxicity. We also found that lipopolysaccharide (LPS) promoted Caco-2 proliferation; however, no specific changes were observed upon treatment with LAB strains and LPS. Our evaluation of the permeability in the Caco-2 monolayer model confirmed its increase by both LPS and H2O2. The LAB strains inhibited the increase in permeability by protecting TJs, which we evaluated by measuring TJ proteins such as zonula occludens-1 and occludin, and analyzing them by western blotting and immunofluorescence staining. Our findings show that LAB strains used for kimchi fermentation can suppress the increase in intestinal permeability due to LPS and H2O2 by protecting TJs. Therefore, these results suggest the possibility of enhancing the functionality of kimchi through its fermentation using functional LAB strains.

Randomized placebo-controlled trial of feline-origin Enterococcus hirae probiotic effects on preventative health and fecal microbiota composition of fostered shelter kittens.

Diarrhea is the second most common cause of mortality in shelter kittens. Studies examining prevention strategies in this population are lacking. Probiotics are of particular interest but studies in cats are largely limited to healthy adults or those with induced disease. Only one study in domestic cats describes the use of host-derived bacteria as a probiotic. We previously identified Enterococcus hirae as a dominant species colonizing the small intestinal mucosa in healthy shelter kittens. Oral administration of a probiotic formulation of kitten-origin E. hirae (strain 1002-2) mitigated the increase in intestinal permeability and fecal water loss resulting from experimental enteropathogenic E. coli infection in purpose-bred kittens. Based on these findings, we hypothesized that administration of kitten-origin E. hirae to weaned fostered shelter kittens could provide a measurable preventative health benefit. We conducted a randomized, placebo-controlled, blinded clinical trial to determine the impact of a freeze-dried E. hirae probiotic on body weight gain, incidence of diarrhea, carriage of potential diarrheal pathogens, and composition of the intestinal microbiota in weaned fostered shelter kittens. One-hundred thirty kittens completed the study. Fifty-eight kittens received the probiotic and 72 received the placebo. There were no significant differences in age, weight upon initiation of the study, number of days in the study, average daily gain in body weight, or weight at completion of the study. Kittens treated with E. hirae were 3.4 times less likely to develop diarrhea compared to kittens treated with placebo (odds ratio = 0.294, 95% CI 0.109-0.792, p = 0.022). A significant impact of E. hirae was not observed on the presence or abundance of 30 different bacterial, viral, protozoal, fungal, algal, and parasitic agents in feces examined by qPCR. With exception to a decrease in Megamonas, administration of the E. hirae probiotic did not alter the predominant bacterial phyla present in feces based on 16S rRNA gene amplicon sequencing. Decreased incidence of diarrhea associated with preventative administration of E. hirae to foster kittens supports a rationale for use of E. hirae for disease prevention in this young population at high risk for intestinal disease though additional studies are warranted.

Intra-Amniotic Administration-An Emerging Method to Investigate Necrotizing Enterocolitis, In Vivo (Gallus gallus).

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in premature infants and a leading cause of death in neonates (1-7% in the US). NEC is caused by opportunistic bacteria, which cause gut dysbiosis and inflammation and ultimately result in intestinal necrosis. Previous studies have utilized the rodent and pig models to mimic NEC, whereas the current study uses the in vivo (Gallus gallus) intra-amniotic administration approach to investigate NEC. On incubation day 17, broiler chicken (Gallus gallus) viable embryos were injected intra-amniotically with 1 mL dextran sodium sulfate (DSS) in H2O. Four treatment groups (0.1%, 0.25%, 0.5%, and 0.75% DSS) and two controls (H2O/non-injected controls) were administered. We observed a significant increase in intestinal permeability and negative intestinal morphological changes, specifically, decreased villus surface area and goblet cell diameter in the 0.50% and 0.75% DSS groups. Furthermore, there was a significant increase in pathogenic bacterial (E. coli spp. and Klebsiella spp.) abundances in the 0.75% DSS group compared to the control groups, demonstrating cecal microbiota dysbiosis. These results demonstrate significant physiopathology of NEC and negative bacterial-host interactions within a premature gastrointestinal system. Our present study demonstrates a novel model of NEC through intra-amniotic administration to study the effects of NEC on intestinal functionality, morphology, and gut microbiota in vivo.

Evaluation of plasma zonulin level and its relationship with inflammatory cytokines in patients with vitiligo.

It has been proven that there is an increase in intestinal permeability in some autoimmune diseases. In our study, we purposed to assess intestinal permeability in vitiligo disease by looking at zonulin levels. At the same time, we aimed to examine the correlation of inflammatory cytokines and lipopolysaccharide (LPS) levels with zonulin. Forty-one patients and 41 healthy participants were involved in our study. Blood samples were taken from all patients and controls, and the levels of zonulin, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and LPS were examined. The mean of zonulin in the patient group was found to be statistically higher than the control group (p < 0.05). A positive correlation was found between zonulin level and IL-6, TNF-α, and LPS levels (p < 0.05). TNF-α and LPS levels in the vitiligo group were significantly higher than in the control group, but there was no such significance in terms of IL-6 levels. We think that serum zonulin level increases and intestinal permeability increases in vitiligo disease.

Polysaccharide ORP-1 isolated from Oudemansiella raphanipes ameliorates age-associated intestinal epithelial barrier dysfunction in Caco-2 cells monolayer

Age-associated increase in intestinal permeability is known to relate with gut microbiota dysbiosis and loss of epithelial tissue integrity. To improve healthy aging and prevent age-associated chronic disabilities, the protective potential of polysaccharides from Oudemansiella raphanipes (ORP-1) against age-associated intestinal epithelial barrier dysfunction in d-galactose-induced Caco-2 cells monolayer was investigated. In-vitro results demonstrated that ORP-1 can restore a healthy gut microbial population to handle age-related gut microbiota dysbiosis mainly by facilitating the proliferation and adhesion of probiotics Lactobacillus acidophilus (L. acidophilus) and Bifidobacterium bifidum (B. bifidum) to compete with intestinal pathogenic Escherichia coli (E. coli) for ecological niches and nutrition. Meanwhile, ORP-1 strengthened the intestinal structural integrity primarily by abolishing the aggravation of apoptosis and the age-associated alterations of tight junction (TJ) proteins expression in intestine. These findings highlighted that ORP-1 could be a potential functional food component with preventive utility against age-associated intestinal barrier injury.

Defects in the expression of colonic host defense factors associate with barrier dysfunction induced by a high-fat/high-cholesterol diet.

The effect of Western diets in the gastrointestinal system is largely mediated by their ability to promote alterations in the immunity and physiology of the intestinal epithelium, and to affect the composition of the commensal microbiota. To investigate the response of the colonic epithelium to high-fat/high-cholesterol diets (HFHCDs), we evaluated the synthesis of host defense factors involved in the maintenance of the colonic homeostasis. C57BL/6 mice were fed an HFHCD for 3 weeks and their colons were evaluated for histopathology, gene expression, and microbiota composition. In addition, intestinal permeability and susceptibility to Citrobacter rodentium were also studied. HFHCD caused colonic hyperplasia, loss of goblet cells, thinning of the mucus layer, moderate changes in the composition of the intestinal microbiota, and an increase in intestinal permeability. Gene expression analyses revealed significant drops in the transcript levels of Muc1, Muc2, Agr2, Atoh1, Spdef, Ang4, Camp, Tff3, Dmbt1, Fcgbp, Saa3, and Retnlb. The goblet cell granules of HFHCD-fed mice were devoid of Relmβ and Tff3, indicating defective production of those two factors critical for intestinal epithelial defense and homeostasis. In correspondence with these defects, colonic bacteria were in close contact with, and invading the epithelium. Fecal shedding of C. rodentium showed an increased bacterial burden in HFHCD-fed animals accompanied by increased epithelial damage. Collectively, our results show that HFHCD perturbs the synthesis of colonic host defense factors, which associate with alterations in the commensal microbiota, the integrity of the intestinal barrier, and the host's susceptibility to enteric infections.

IL-6, IL-10, sFas, granulysin and indicators of intestinal permeability as early biomarkers for a fatal outcome in COVID-19

The clinical presentation of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranges between mild respiratory symptoms and a severe disease that shares many of the features of sepsis. Sepsis is a deregulated response to infection that causes life-threatening organ failure. During sepsis, the intestinal epithelial cells are affected, causing an increase in intestinal permeability and allowing microbial translocation from the intestine to the circulation, which exacerbates the inflammatory response. Here we studied patients with moderate, severe and critical COVID-19 by measuring a panel of molecules representative of the innate and adaptive immune responses to SARS-CoV-2, which also reflect the presence of systemic inflammation and the state of the intestinal barrier. We found that non-surviving COVID-19 patients had higher levels of low-affinity anti-RBD IgA antibodies than surviving patients, which may be a response to increased microbial translocation. We identified sFas and granulysin, in addition to IL-6 and IL-10, as possible early biomarkers with high sensitivity (>73 %) and specificity (>51 %) to discriminate between surviving and non-surviving COVID-19 patients. Finally, we found that the microbial metabolite d-lactate and the tight junction regulator zonulin were increased in the serum of patients with severe COVID-19 and in COVID-19 patients with secondary infections, suggesting that increased intestinal permeability may be a source of secondary infections in these patients. COVID-19 patients with secondary infections had higher disease severity and mortality than patients without these infections, indicating that intestinal permeability markers could provide complementary information to the serum cytokines for the early identification of COVID-19 patients with a high risk of a fatal outcome.

Hemp seed significantly modulates the endocannabinoidome and produces beneficial metabolic effects with improved intestinal barrier function and decreased inflammation in mice under a high-fat, high-sucrose diet as compared with linseed.

Omega-3 fatty acids support cardiometabolic health and reduce chronic low-grade inflammation. These fatty acids may impart their health benefits partly by modulating the endocannabinoidome and the gut microbiome, both of which are key regulators of metabolism and the inflammatory response. Whole hemp seeds (Cannabis sativa) are of exceptional nutritional value, being rich in omega-3 fatty acids. We assessed the effects of dietary substitution (equivalent to about 2 tablespoons of seeds a day for humans) of whole hemp seeds in comparison with whole linseeds in a diet-induced obesity mouse model and determined their effects on obesity and the gut microbiome-endocannabinoidome axis. We show that whole hemp seed substitution did not affect weigh gain, adiposity, or food intake, whereas linseed substitution did, in association with higher fasting glucose levels, greater insulin release during an oral glucose tolerance test, and higher levels of liver triglycerides than controls. Furthermore, hemp seed substitution mitigated diet-induced obesity-associated increases in intestinal permeability and circulating PAI-1 levels, while having no effects on markers of inflammation in epididymal adipose tissue, which were, however, increased in mice fed linseeds. Both hemp seeds and linseeds were able to modify the expression of several endocannabinoidome genes and markedly increased the levels of several omega-3 fatty acid–derived endocannabinoidome bioactive lipids with previously suggested anti-inflammatory actions in a tissue specific manner, despite the relatively low level of seed substitution. While neither diet markedly modified the gut microbiome, mice on the hemp seed diet had higher abundance of Clostridiaceae 1 and Rikenellaceae than mice fed linseed or control diet, respectively. Thus, hemp seed-containing foods might represent a source of healthy fats that are not likely to exacerbate the metabolic consequences of obesogenic diets while producing intestinal permeability protective effects and some anti-inflammatory actions.

Korean Red Ginseng extract treatment prevents post-antibiotic dysbiosis-induced bone loss in mice

BackgroundThe intestinal microbiota is an important regulator of bone health. In previous studies we have shown that intestinal microbiota dysbiosis, induced by treatment with broad spectrum antibiotics (ABX) followed by natural repopulation, results in gut barrier dysfunction and bone loss. We have also shown that treatment with probiotics or a gut barrier enhancer can inhibit dysbiosis-induced bone loss. The overall goal of this project was to test the effect of Korean Red Ginseng (KRG) extract on bone and gut health using antibiotics (ABX) dysbiosis-induced bone loss model in mice. MethodsAdult male mice (Balb/C, 12-week old) were administered broad spectrum antibiotics (ampicillin and neomycin) for 2 weeks followed by 4 weeks of natural repopulation. During this 4-week period, mice were treated with vehicle (water) or KRG extract. Other controls included mice that did not receive either antibiotics or KRG extract and mice that received only KRG extract. At the end of the experiments, we assessed various parameters to assess bone, microbiota and in vivo intestinal permeability. ResultsConsistent with our previous results, post-ABX- dysbiosis led to significant bone loss. Importantly, this was associated with a decrease in gut microbiota alpha diversity and an increase in intestinal permeability. All these effects including bone loss were prevented by KRG extract treatment. Furthermore, our studies identified multiple genera including Lactobacillus and rc4-4 as well as Alistipes finegoldii to be potentially linked to the effect of KRG extract on gut-bone axis. ConclusionTogether, our results demonstrate that KRG extract regulates the gut-bone axis and is effective at preventing dysbiosis-induced bone loss in mice.

Uptake, distribution, and depuration of emerging per- and polyfluoroalkyl substances in mice: Role of gut microbiota

The bioaccumulation and fate in mammals of hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide dimer acid (HFPO-DA), as major alternatives for perfluorooctanoate (PFOA), have rarely been reported. In addition, the role of gut microbiota was greatly understudied. In this study, the uptake, distribution, and depuration of HFPO-TA, HFPO-DA, and PFOA were investigated by exposure to mice for 14 days, followed by a clearance period of 7 days. The patterns of tissue distribution and depuration kinetics of HFPO-TA and PFOA were similar, but different from HFPO-DA. Liver was the main deposition organ for HFPO-TA and PFOA, making contributions of 58.8 % and 59.1 % to the total mass recovered on day 14. Depuration of HFPO-DA was more rapid than HFPO-TA and PFOA. Approximately 95.3 % of HFPO-DA in liver was eliminated on day 21 compared with day 14. While the clearance rates of HPFO-TA and PFOA were only 6.1 % and 13.9 % on day 21. The comparison between normal and pseudo germ-free mice (GM) was also conducted to investigate the effect of gut microbial on in vivo absorption of the three per- and polyfluoroalkyl substances (PFASs). Significantly higher (p < 0.05) concentrations of all the three PFASs were observed in most organs and tissues of GM compared with NC group. An analysis of gut microbiota showed that the higher absorption of PFASs in GM group may be attributed to the increase of intestinal permeability (as indicated by the decrease of tight junction protein expression), which were induced by the change of lachnospiraceae abundance. The result highlighted the importance of gut microbiota in absorption and health risk evaluation of emerging PFASs.

Probiotics and Gut Microbiota in Obesity: Myths and Realities of a New Health Revolution.

Obesity and its comorbidities are humans’ most prevalent cardio-metabolic diseases worldwide. Recent evidence has shown that chronic low-grade inflammation is a common feature in all highly prevalent chronic degenerative diseases. In this sense, the gut microbiota is a complete ecosystem involved in different processes like vitamin synthesis, metabolism regulation, and both appetite and immune system control. Thus, dysbiosis has been recognised as one of the many factors associated with obesity due to a predominance of Firmicutes, a decrease in Bifidobacterium in the gut, and a consequent short-chain fatty acids (SCFA) synthesis reduction leading to a reduction in incretins action and intestinal permeability increase. In this context, bacteria, bacterial endotoxins, and toxic bacterial by-products are translocated to the bloodstream, leading to systemic inflammation. This review focuses on gut microbiota composition and its role in obesity, as well as probiotics and prebiotics benefits in obesity.

High Sucrose Diet Induces Intestinal Zinc Dyshomeostasis and Permeability

ObjectivesZinc (Zn) is an essential micronutrient that is critical for many physiological processes including glucose metabolism, regulation of inflammation, regulation of intestinal barrier function, and insulin production and secretion. Further, Zn dysregulation is associated with increased risk of chronic inflammatory diseases such as type II diabetes, inflammatory bowel disease, and obesity. However, it remains unclear whether altered Zn status is a symptom or cause of disease onset. Common symptoms of these three inflammatory diseases include the onset of intestinal inflammation and increased intestinal permeability. The specific focus of this work is to investigate how dietary sources of chronic inflammation, such as high sucrose consumption impacts transporter mediated Zn homeostasis and subsequent Zn dependent physiology.MethodsTo study the interactions between high dietary sucrose and Zn homeostasis, we administered 30% sucrose water to mice for 8 weeks. Tissue metal contents were measured by microwave plasma atomic emission spectrometry. Zn transport was measured using radioisotope tracing of 65Zn. Intestine permeability was assessed by FITC-dextran (4 kDa) assay. Protein expression of Zn transporters, inflammatory markers, and tight junction proteins was measured by western blot.ResultsSucrose treatment resulted in systemic changes in steady-state Zn distribution, including a significant increase in plasma Zn and significant decreases in Zn in the liver, pancreas, and white adipose tissue. We observed changes in Zn transport protein expression in the intestine. In agreement with altered transporter expression, Zn transport studies revealed significant dysregulation of Zn transport in both the small intestine and colon. Further, sucrose treatment resulted in induction of both P-STAT3 and P-NF-κB, dysregulation of tight junction proteins ZO-1 and CLDN1, and increased intestine permeability.ConclusionsOur work suggests that chronic high sucrose consumption leads to changes in systemic Zn homeostasis. This links diet-induced changes in Zn homeostasis to the onset of precursors of chronic disease, intestinal inflammation and permeability.Funding SourcesThis work was supported by Cornell University Division of Nutritional Sciences funds to T. B. Aydemir.

FACTORS ASSOCIATED WITH CIRCULATING ZONULIN IN INFLAMMATORY BOWEL DISEASE.

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. To study factors associated with serum zonulin levels, a marker of intestinal permeability, in patients with IBD. 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. 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. 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.

Considering Intestinal Hyperpermeability and Immune-Inflammatory Metabolism in the Treatment of Food Allergy

Food Allergy is a chronic systemic immuno-inflammatory condition that depends on several factors, but, above all, the gastrointestinal epithelial barrier. The rupture of this intestinal barrier results in a deleterious increase in intestinal permeability allowing the paracellular permeation of molecules greater than 150 Da into the bloodstream, producing an equivalent immune response, decreasing the immune tolerance. Intestinal Hyperpermeability has been linked not only to food allergy but also to Metabolic Syndrome and Non-Alcoholic Fat Liver Disease. Here we review the factors that contribute to producing Intestinal Hyperpermeability, as well the factors that contribute to the restoration of the epithelial barrier, improving the clinical outcome of food-allergic patients. The main factors that increase the Intestinal Hyperpermeability are A) Immune-Inflammatory (food allergy itself and autoimmune conditions); B) Iatrogenic (steroids, non-steroidal anti-inflammatories, antacids, antibiotics, and gastric-bypass surgeries); C) Infectious (rotavirus, HIV, SARS-CO2, Helicobacter pylori, Candida albicans, etc.); and D) Lifestyle-related (alcoholic beverages, food addiction, food overconsumption, consumption of industrialized food with high-fructose content and emulsifiers). The main factors that restore the intestinal barrier and immune tolerances are the intestinal microbiota and functional nutrients such as Vitamin A and vegetal fibers. Mucoprotectants agents, such as gelatin tannate and xyloglucan, are in study to become part of the medical arsenal to treat Intestinal Hyperpermeability conditions.

Altered Mucosal Glycosylation Patterns during Giardia spp. Infection are Time‐Dependent and Tissue‐Specific

IntroductionGlycosylation of intestinal mucin proteins is critical for intestinal barrier function and host‐microbe interactions. Altered mucosal glycosylation patterns have been associated with numerous intestinal diseases and may contribute to dysbiosis and an increase in intestinal permeability. Disruption of intestinal mucus has been described during infection with the protozoan parasite Giardia duodenalis, and may contribute to intestinal mucosal barrier dysfunction and dysbiosis during acute and chronic infection. Little is currently known about the role of mucin glycan alteration in the pathogenesis of Giardia or other enteric infections. The aim of this study was to determine if mucosal glycosylation patterns are altered during Giardia infection.Methods3‐4‐week‐old C57BL/6 mice were infected with Giardia muris for 2 or 7 days, or with Giardia duodenalis isolate GSM for 7 days. Jejunum and colon sections were collected and stained with various fluorescein‐coupled lectins, and quantitative PCR was performed for mucin and mucin‐associated glycosyltransferase gene expression.ResultsDuring early infection, at day 2 post‐infection (PI), fucose and sialic acid abundance was increased in the jejunums of G. muris infected mice in comparison to uninfected mice. Expression of the fucosyltransferase Fut2 and the sialyltransferase St6GalNAc1 were similar between controls and infected mice. Expression of the sulfotransferase Chst4 was decreased in both the jejunums and colons upon infection.At day 7 PI, when trophozoite burden was maximal in the small intestine, the abundance of fucose and sialic acid was significantly decreased in the jejunums of both G. muris and G. duodenalis infected mice. The expression of Fut2 and St6GalNAc1 was increased in infected mice compared to controls. Both fucose abundance and Fut2 expression were similar between control and infected mice in the colon, while sialic acid abundance increased and expression of St6GalNAc1 decreased in the colon upon infection. Expression of the sulfotransferase Chst4 was decreased in infected mice in the jejunum, and similar to control levels in the colon.ConclusionsGlycosylation patterns and the expression of mucin‐associated glycosyltransferase genes are altered in the intestines upon Giardia spp. infection. These alterations are time‐dependent as well as tissue‐specific, occurring in the small intestine, where Giardia colonization occurs, and in the large intestine where no active trophozoites are present during infection. These effects are isolate non‐specific and may contribute to disruption of intestinal barrier function and dysbiosis during Giardia infections, as well as during numerous enteric infections in which mucus disruption is implicated in disease pathogenesis.

Loss of Paneth cells alters intestinal innate lymphoid cells and enhances weight gain in mice.

Abstract Paneth cells are a subset of small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines. Gastrointestinal dysbiosis has been linked to many health concerns and is believed to be a contributing factor in obesity. Despite the role of Paneth cells as a major source of antimicrobial products, the contribution of these cells to health or disease conditions has not been fully explored. We examine the impact loss of Paneth cells would have on the gut microbiota and whether the subsequent dysbiosis could affect metabolic functions of the host and fat accumulation in a mouse model of diet induced obesity. For this purpose, were used wild-type and Sox9ΔIEC mice, which lack Paneth cells due to a Sox9 gene deletion within the intestinal epithelium. Compared to control wild-type mice, the small intestine of Sox9ΔIEC exhibited an altered profile of ILCs characterized by increase ILC2 and decrease ILC3 numbers. After exposure to a high-fat diet for 13 weeks, the Sox9ΔIEC mice gained more weight and had higher glucose intolerance. The intestinal homeostasis was also affected, with an increase in intestinal permeability and an increase in ILC1s within the small intestine of Sox9ΔIEC mice. In the abdominal fat Sox9ΔIEC mice showed increased numbers of immune cells including inflammatory macrophages, T cells, and B cells. Finally, fecal material transplantation experiments revealed that fecal material from the Sox9ΔIEC mice transfer the phenotype in recipient germ-free mice as indicated by a trend towards an increase in weight gain and immune cell infiltration of abdominal fat. These results highlight the importance of Paneth cells as regulators of metabolic functions of the host and fat accumulation. Supported by grants from OSU and NIH.