Altered Barrier Function Research Articles

The Role of Bovine Kappa-Casein Glycomacropeptide in Modulating the Microbiome and Inflammatory Responses of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder marked by chronic abdominal pain, bloating, and irregular bowel habits. Effective treatments are still actively sought. Kappa-casein glycomacropeptide (GMP), a milk-derived peptide, holds promise because it can modulate the gut microbiome, immune responses, gut motility, and barrier functions, as well as binding toxins. These properties align with the recognized pathophysiological aspects of IBS, including gut microbiota imbalances, immune system dysregulation, and altered gut barrier functions. This review delves into GMP's role in regulating the gut microbiome, accentuating its influence on bacterial populations and its potential to promote beneficial bacteria while inhibiting pathogenic varieties. It further investigates the gut microbial shifts observed in IBS patients and contemplates GMP's potential for restoring microbial equilibrium and overall gut health. The anti-inflammatory attributes of GMP, especially its impact on vital inflammatory markers and capacity to temper the low-grade inflammation present in IBS are also discussed. In addition, this review delves into current research on GMP's effects on gut motility and barrier integrity and examines the changes in gut motility and barrier function observed in IBS sufferers. The overarching goal is to assess the potential clinical utility of GMP in IBS management.

The blood-prostate barrier: an obstacle to drug delivery into the prostate.

The blood-prostate barrier (BPB), a non-static physical barrier, stands as an obstacle between the prostate stroma and the lumen of the prostate gland tube. The barrier has the ability to dynamically regulate and strictly control the mass exchange between the blood and the prostate, thereby limiting drug penetration into the prostate. The basement membrane, fibrous stromal layer, capillary endothelial cell, prostatic ductal epithelial cell, lipid layer, etc., have been confirmed to be involved in the composition of the barrier structure and altered membrane permeability mainly by regulating the size of paracellular ion pores. Various studies have been conducted to improve the efficiency of drug therapy for prostate diseases by changing the administration approaches, improving barrier permeability and increasing drug penetration. To gain a full understanding of BPB, the composition of BPB, the methodology for evaluating the permeability of BPB and alterations in barrier function under pathological conditions are summarized in this review. To find a shortcut for drug delivery across BPB, the biodistribution of drugs in the prostate and different methods of improving drug penetration across BPB are outlined. This review offers an applied perspective on recent advances in drug delivery across BPB.

CHRONIC ETHANOL USE WORSENS GUT PERMEABILITY AND ALTERS TIGHT JUNCTION EXPRESSION IN A MURINE SEPSIS MODEL.

Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability after ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak, and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal myosin light chain (MLC) kinase (MLCK) expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK -/- mice in water/CLP; however, permeability was not different between WT and MLCK -/- mice in ethanol/CLP. Similarly, jejunal IL-1β levels were decreased while systemic IL-6 levels were increased in MLCK -/- mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK -/- mice after water/CLP, mortality was significantly worse in MLCK -/- mice after ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Furthermore, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4 + cells expressing TNF and IL-17A and the frequency of CD8 + cells expressing IFN-γ in Peyer's Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function after CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.

A spike in circulating cytokines TNF-α and TGF-β alters barrier function between vascular and musculoskeletal tissues

Molecular transport between the circulatory and musculoskeletal systems regulates articular joint physiology in health and disease. Osteoarthritis (OA) is a degenerative joint disease linked to systemic and local inflammation. Inflammatory events involve cytokines, which are secreted by cells of the immune system and modulate molecular transport across tissue interfaces (referred to as tight junction [TJ] barrier function). In a previous study from our group, OA knee joint tissues were shown to exhibit size separation of different sized molecules delivered as a single bolus to the heart (Ngo et al. in Sci. Rep. 8:10254, 2018). Here, in a follow up study of parallel design, we test the hypothesis that two common cytokines, with multifaceted roles in the etiology of osteoarthritis as well as immune state in general, modulate the barrier function properties of joint tissue interfaces. Specifically, we probe the effect of an acute cytokine increase (spike) on molecular transport within tissues and across tissue interfaces of the circulatory and musculoskeletal systems. A single bolus of fluorescent-tagged 70 kDa dextran, was delivered intracardially, either alone, or with either the pro-inflammatory cytokine TNF-α or the anti-inflammatory cytokine TGF-β, to skeletally mature (11 to 13-month-old) guinea pigs (Dunkin-Hartley, a spontaneous OA animal model). After five minutes' circulation, whole knee joints were serial sectioned and fluorescent block face cryo-imaged at near-single-cell resolution. The 70 kDa fluorescent-tagged tracer is analogous in size to albumin, the most prevalent blood transporter protein, and quantification of tracer fluorescence intensity gave a measure of tracer concentration. Within five minutes, a spike (acute doubling) in circulating cytokines TNF-α or TGF-β significantly disrupted barrier function between the circulatory and musculoskeletal systems, with barrier function essentially abrogated in the TNF-α group. In the entire volume of the joint (including all tissue compartments and the bounding musculature), tracer concentration was significantly decreased in the TGF-β- and TNF-α- compared to the control-group. These studies implicate inflammatory cytokines as gatekeepers for molecular passage within and between tissue compartments of our joints and may open new means to delay the onset and mitigate the progression of degenerative joint diseases such as OA, using pharmaceutical and/or physical measures.

The role of mucin O-glycans in microbiota dysbiosis, intestinal homeostasis, and host-pathogen interactions.

Mucin O-linked glycans are important mediators of host-microbiota-pathogen interactions in the gastrointestinal tract. The major component of intestinal mucus, the MUC2 mucin, is densely glycosylated, with up to 80% of its weight-to-volume ratio represented by O-linked glycans. Glycosylation of secretory gel-forming mucins has an enormous impact on intestinal barrier function, microbial metabolism, and mucus colonization by both pathogenic and commensal microbes. Mucin O-glycans and glycan-derived sugars may be degraded and used as a nutrient source and may regulate microbial gene expression and virulence. Short-chain fatty acids, produced as a by-product of glycan fermentation, can regulate host immunity and goblet cell activity and are important for host-microbe homeostasis. Mucin glycans may also act as microbial binding sites, influencing intestinal colonization and translocation through the mucus gel barrier. Recent findings indicate that alterations to mucin glycosylation impact the susceptibility of mucins to degradation, resulting in altered barrier function and intestinal permeability. Alterations to mucin glycosylation patterns are frequently observed during intestinal infection and inflammation and have been implicated in microbiota dysbiosis and expansion of pathobionts. Recent work has demonstrated that these alterations can play key roles in disease pathogenesis. The precise mechanisms remain obscure. This review highlights the important roles of O-linked glycans in host-microbe interactions and disease pathogenesis in the context of intestinal infections.

Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9–39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.

P899 Analysis of IL-23 receptor genetic variants associations with gut microbiome composition and barrier function in a cohort of healthy first-degree relatives of subjects with Crohn's disease

Abstract Background Single nucleotide polymorphisms (SNPs) in the Interleukin 23 receptor (IL23R) gene have been implicated in CD pathogenesis and shown in animal models to be involved in regulation of intestinal epithelial barrier function via the production of IL17A. Additionally, previous studies suggest that IL23R may impact gut microbial composition potentially via impairment of microbial clearance. Therefore, we hypothesized that IL23R risk alleles might be associated with altered gut barrier function and gut microbial composition in humans. Methods The Genetic Environmental Microbial (GEM) project recruited a cohort of healthy first-degree relatives (FDRs) of patients with CD. Genotypic data (Illumina HumanCoreExome chip, immunochip or Human Global Screen Array) was available for 2,716 subjects after imputation (Michigan sever). A weighted IL23R genetic risk score (IL23R-GRS) was generated based on 18 IL23R SNPs reported to be associated with susceptibility for CD (PMID: 26678098). The score was dichotomized as Quantile 5 (high IL23R-GRS) versus Quantiles 1-4 (low IL23R-GRS). A subset of this cohort was characterized for urinary fractional excretion of lactulose to mannitol ratio (LMR) to assess gut barrier function (N=1,718), and fecal 16s rDNA gene sequencing (MiSeq) for microbiome profiling (N= 2,638). Dichotomized LMR at a threshold of 0.025 was considered as abnormal. Linear and logistic regression models were used to assess associations of GRS with the LMR and microbial taxa. All models were adjusted for age, gender and five genetic principal components. Results The median age of the cohort was 17 [Interquartile range 12-25] years and 53.9% were females. There were no differences in the proportion of baseline abnormal LMR>0.025 among subjects with high vs. low IL23R-GRS (20.7% vs. 21.4%, respectively; p=0.84). High IL23R-GRS was not associated with either LMR (b-coefficient=-0.0012, SE=0.0013, p=0.32) or dichotomized LMR>0.025 (b-coefficient=-0.052, SE=0.15, p=0.73). Additionally, although high IL23R-GRS was not associated with differences in microbial alpha diversity (Shannon index, p=0.08), it showed modest compositional shifts (Bray Curtis index, PERMANOVA: R2=0.001, p=0.002) and a trend with nine genera differential abundances (including a decrease in Faecalibacterium and Lachnospiraceae_NK4A136_group and an increase in Alistipes and Akkermansia; false discovery rate of q<0.1 for all). Conclusion The IL23R-GRS was not associated with abnormal gut barrier function but showed associations with microbial community composition and trends with individual genera. Further studies are required to understand if the effect of IL23R genetic variants on the risk of CD onset is mediated by the gut microbiome or other biological risk factors.

Histones of Neutrophil Extracellular Traps Directly Disrupt the Permeability and Integrity of the Intestinal Epithelial Barrier.

Increased neutrophil extracellular trap (NET) formation and abundant NET-associated proteins are frequently found in the inflamed colon of patients with inflammatory bowel disease. Peptidyl arginine deiminase 4 (PAD4) activation is essential for the generation of NET and NET-mediated pathogenesis. However, the role of PAD4-dependent NET formation in murine inflammatory bowel disease models and the molecular mechanisms responsible for the altered gut barrier function are unknown. Wild-type and Pad4 knockout (Pad4-/-) mice were administrated 3% dextran sulfate sodium (DSS) in their drinking water. Caco-2 monolayers were used to test the effect of NETs on intestinal barrier function and cytotoxicity. Histones were intrarectally administrated to wild-type mice to determine their effects on intestinal barrier function and cytotoxicity in vivo. PAD4 deficiency reduced the severity of DSS-induced colitis with decreased intestinal NET formation and enhanced gut barrier function and integrity in mice. NETs disrupted the barrier function in intestinal epithelial Caco-2 monolayers through their protein, rather than DNA, components. Pretreatment of NETs with histone inhibitors abrogated the effects on epithelial permeability. Consistent with these observations, adding purified histone proteins to Caco-2 monolayers significantly damaged epithelial barrier function, which was associated with the abnormal distribution and integrity of tight junctions as well as with increased cell death. Furthermore, intrarectal administration of histones damaged the intestinal barrier integrity and induced cytotoxicity in the mouse colon epithelium. PAD4-mediated NET formation has a detrimental role in acute colitis. NET-associated histones directly inhibit intestinal barrier function, resulting in cytotoxicity in vitro and in vivo.

141 Focus on triggering factors in sensitive skin: two biomarkers in a new heat-cold stress in vivo model

Sensitive skin syndrome (SSS) is characterized by barrier function alteration and inflammation in response to several stimuli (mechanical, chemical, thermal, pollution…) but no consensus exists on how to assess SSS. In this context, we developed an innovative model with heat-cold stress to evaluate in subjects with SSS the impact of a dermocosmetic product on two biomarkers, IL-1α and S100A8/9. To confirm its efficacy, the product was evaluated on skin barrier function, immediate and long-lasting soothing effect after stripping/chemical irritation (temperature, microcirculation, capsaicin test), and on Asiatic and Caucasian subjects. In an intra-individual comparative study, 30 females with SSS applied the product on one half-face for 28 days twice daily. At day 0 (D0) and D28, heat-cold stress was performed on both half-faces (radiofrequency system and dry air by 3 cycles 45±5°C,15±5°C). Before and after stress, IL-1α and S100A8/9 release, hydration and global clinical scoring of unpleasant sensations were measured. At D28, the product significantly improved skin barrier and presented a soothing effect whatever the triggering factors. In addition, up to 91% of Asiatic and Caucasian sensitive skin subjects judged the product efficient and significantly improving the burden of sensitive skin (BoSS score -14.1%). The product significantly reduced IL-1α after heat-cold stress at D0 (32.6%, p<0.001), and at D28 (27.7%, p<0.01) vs control. At D0 and D28, the S100A8/9 increase with heat-cold stress was prevented by the product. Moreover, the product significantly improved hydration (up to +45%), and the global clinical scoring (down to -50%) before and after heat-cold stress vs control. Thus, the dermocosmetic product protected skin from mechanical, chemical, and heat-cold aggressions, in addition to pollution/UV previously studied. Through this innovative model, IL-1α and S100A8/9 seems to be relevant biomarkers to assess SSS.

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options.

Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.

Gut-Kidney Axis Investigations in Animal Models of Chronic Kidney Disease.

Chronic kidney disease (CKD) is an incurable disease in which renal function gradually declines, resulting in no noticeable symptoms during the early stages and a life-threatening disorder in the latest stage. The changes that accompany renal failure are likely to influence the gut microbiota, or the ecosystem of micro-organisms resident in the intestine. Altered gut microbiota can display metabolic changes and become harmful to the host. To study the gut–kidney axis in vivo, animal models should ideally reproduce the disorders affecting both the host and the gut microbiota. Murine models of CKD, but not dog, manifest slowed gut transit, similarly to patient. Animal models of CKD also reproduce altered intestinal barrier function, as well as the resulting leaky gut syndrome and bacterial translocation. CKD animal models replicate metabolic but not compositional changes in the gut microbiota. Researchers investigating the gut–kidney axis should pay attention to the selection of the animal model (disease induction method, species) and the setting of the experimental design (control group, sterilization method, individually ventilated cages) that have been shown to influence gut microbiota.

Intestinal Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The mechanisms involved in NAFLD onset are complicated and multifactorial. Recent literature has indicated that altered intestinal barrier function is related to the occurrence and progression of liver disease. The intestinal barrier is important for absorbing nutrients and electrolytes and for defending against toxins and antigens in the enteric environment. Major mechanisms by which the intestinal barrier influences the development of NAFLD involve the altered epithelial layer, decreased intracellular junction integrity, and increased intestinal barrier permeability. Increased intestinal permeability leads to luminal dysbiosis and allows the translocation of pathogenic bacteria and metabolites into the liver, inducing inflammation, immune response, and hepatocyte injury in NAFLD. Although research has been directed to NAFLD in recent decades, the pathophysiological changes in NAFLD initiation and progression are still not completely understood, and the therapeutic targets remain limited. A deeper understanding on the correlation between NAFLD pathogenesis and intestinal barrier regulation must be attained. Therefore, in this review, the components of the intestinal barrier and their respective functions and disruptions during the progression of NAFLD are discussed.

N-Palmitoyl-D-Glucosamine Inhibits TLR-4/NLRP3 and Improves DNBS-Induced Colon Inflammation through a PPAR-α-Dependent Mechanism.

Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.

Gardnerella vaginalis alters cervicovaginal epithelial cell function through microbe-specific immune responses

BackgroundThe cervicovaginal (CV) microbiome is highly associated with vaginal health and disease in both pregnant and nonpregnant individuals. An overabundance of Gardnerella vaginalis (G. vaginalis) in the CV space is commonly associated with adverse reproductive outcomes including bacterial vaginosis (BV), sexually transmitted diseases, and preterm birth, while the presence of Lactobacillus spp. is often associated with reproductive health. While host-microbial interactions are hypothesized to contribute to CV health and disease, the mechanisms by which these interactions regulate CV epithelial function remain largely unknown.ResultsUsing an in vitro co-culture model, we assessed the effects of Lactobacillus crispatus (L. crispatus) and G. vaginalis on the CV epithelial barrier, the immune mediators that could be contributing to decreased barrier integrity and the immune signaling pathways regulating the immune response. G. vaginalis, but not L. crispatus, significantly increased epithelial cell death and decreased epithelial barrier integrity in an epithelial cell-specific manner. A G. vaginalis-mediated epithelial immune response including NF-κB activation and proinflammatory cytokine release was initiated partially through TLR2-dependent signaling pathways. Additionally, investigation of the cytokine immune profile in human CV fluid showed distinctive clustering of cytokines by Gardnerella spp. abundance and birth outcome.ConclusionsThe results of this study show microbe-specific effects on CV epithelial function. Altered epithelial barrier function through cell death and immune-mediated mechanisms by G. vaginalis, but not L. crispatus, indicates that host epithelial cells respond to bacteria-associated signals, resulting in altered epithelial function and ultimately CV disease. Additionally, distinct immune signatures associated with Gardnerella spp. or birth outcome provide further evidence that host-microbial interactions may contribute significantly to the biological mechanisms regulating reproductive outcomes.1WGXG_ks-9NHuMd7p1pzcaVideo

Antibiotics and mental health: The good, the bad and the ugly.

Antibiotics are recognised as, on occasion, producing psychiatric side effects, most notably depression and anxiety. Apart from antimicrobial activity, antibiotics have multiple off-target effects. The brain-gut-microbiota axis has multiple sites for off-target activity, which may produce either positive or negative antibiotic effects. Here we review how antibiotics impact mental health by acting through the brain-gut-microbiota axis. Microbes in the gut influence brain function by acting through the vagus nerve or by altering the production of short-chain fatty acids or the amino acid tryptophan, the building block of serotonin. Not all antimicrobial actions of antibiotics have a negative impact. The first antidepressant discovered was actually an antibiotic: isoniazid is an antibacterial drug developed for treating tuberculosis. Minocycline, which enters the brain and mediates its effects through microglia, shows antidepressant activity. Some antibiotics bring about a significant decrease in gut microbial diversity, and this is viewed as a risk factor for depression. Other risk factors induced by antibiotics include altered gut barrier function, activation of the hypothalamic-pituitary-adrenal axis, reducing levels of brain-derived neurotrophic factor or oxytocin and alteration of vagal tone. Although most patients taking antibiotics do not suffer from an iatrogenic psychiatric disorder, some do. As clinicians, we need to keep this in mind. The development of new antibiotics is primarily focused on antibiotic resistance, but efforts should be made to reduce off-target brain-gut-microbiota effects resulting in mental health problems.

Association between preoperative nutritional status, inflammation, and intestinal permeability in elderly patients undergoing gastrectomy: a prospective cohort study.

Malnutrition is relatively common among elderly patients with gastric cancer. This study sought to analyze whether preoperative nutritional status, inflammatory cytokines, and intestinal permeability were correlated in elderly gastric cancer patients undergoing surgery, and their effects on postoperative recovery. This study was a single-center prospective cohort study. Patients aged 65-90 years who underwent gastrectomy were included. Preoperative nutritional status was assessed by the Mini Nutritional Score (MNA), Nutritional Risk Screening-2002 (NRS2002), body mass index (BMI), free fatty acids (FFAs), albumin, and prealbumin concentrations. Intestinal permeability was assessed by D-lactate and intestinal fatty acid-binding protein (i-FABP). The inflammatory factors included interleukin (IL)-6, IL-10, neutrophil, and lymphocyte counts. The time to first defecation, time to first liquid diet, length of hospital stay (LOS), and postoperative complications were recorded. A total of 134 patients were included. According to the MNA, 50.7% and 32.1% of the cohort had mild to moderate malnutrition, and severe malnutrition, respectively. According to the NRS2002, 38.8% of the patients scored >4 points. I-FABP was significantly negatively correlated with albumin (r=-0.409, P<0.001) and prealbumin (r=-0.397, P<0.001), and significantly positively correlated with MNA (r=0.291, P=0.001), the NRS2002 (r=0.284, P=0.001), and LOS (r=0.245, P=0.004). D-lactate was significantly negatively correlated with BMI (r=-0.229, P=0.008), albumin (r=-0.426, P<0.001), and prealbumin (r=-0.358, P<0.001), and significantly positively correlated with the NRS2002 (r=0.187, P=0.030), time to first defecation (r=0.264, P=0.002), and LOS (r=0.409, P<0.001). There were significant differences in BMI, prealbumin, FFAs, i-FABP, time to first defecation, and time to first fluid diet (P<0.05) among groups based on MNA score. The multivariate logistic analysis showed that D-lactate was an independent risk factor of postoperative complications [odds ratio (OR) =1.354, 95% confidence interval (CI): 1.099-1.669, P=0.004]. The preoperative intestinal permeability indicators (i.e., D-lactate and i-FABP) are significantly correlated with some nutritional indicators and postoperative recovery indicators. The preoperative D-lactate level is an independent risk factor of postoperative complications, suggesting that altered gut barrier function before surgery could to some extent influence postoperative recovery in the elderly.

Pathogenetic and clinical significance of the gut-liver microbiota axis

Today, nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) account for more than 50% of chronic liver diseases and cirrhosis in developed countries. The clinical significance of these pathologies lies in the formation of liver fibrosis and, therefore, in the increased risk of liver cirrhosis and hepatocellular carcinoma, which are life-threatening conditions. NAFLD is based on obesity and insulin resistance, whereas alcohol consumption is central to the etiopathogenesis of ALD. Recently, the role of the gut-liver microbiota axis in the genesis of NAFLD and ALD has also received increasing attention. Changes in qualitative and quantitative composition of intestinal microbiota and alterations of barrier function of intestinal mucosa can lead to entry of intraluminal antigens through portal vein system into the liver, inducing damage to hepatocytes and activation of proinflammatory processes. It is shown that in patients with CLD (NAFLD and ALD) there is an increase in the permeability of the intestinal mucosa and dysbiotic changes of the intestinal microbiome. The role of the gut-liver microbiota axis is well described in the genesis of NAFLD and ALD. Chronic alcohol consumption leads to increased colonies of Gram-negative bacteria in the intestinal mucosa and, therefore, to the accumulation of endotoxins (lipopolysaccharide components of bacterial cell membranes). Acetaldehyde produced by ADH of the intestinal epithelium stimulates tyrosine phosphorylation of tight cell contacts, increasing intestinal mucosal permeability, which leads to translocation of endotoxins into the portal bloodstream. Obesity is a major risk factor for NAFLD, which is also associated with dysbiotic changes in the intestinal microbiome. Obese individuals have increased Firmicutes, decreased Bacteroidetes, mediated reduction of short-chain fatty acid synthesis and increased intestinal wall permeability due to disruption of intercellular dense contacts, which leads to increased translocation of bacteria and endotoxins into the systemic bloodstream.

Altered epithelial barrier functions in the colon of patients with spina bifida

Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 [34.1–47.2]) were compared with those of 16 HVs (age: 39.0 [31.0–46.5]). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = − 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFβ1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches.Clinical Trials: NCT02440984 and NCT03054415.

Variations in the Composition of Human Milk Oligosaccharides Correlates with Effects on Both the Intestinal Epithelial Barrier and Host Inflammation: A Pilot Study.

Background: Human milk oligosaccharides are complex, non-digestible carbohydrates that directly interact with intestinal epithelial cells to alter barrier function and host inflammation. Oligosaccharide composition varies widely between individual mothers, but it is unclear if this inter-individual variation has any impact on intestinal epithelial barrier function and gut inflammation. Methods: Human milk oligosaccharides were extracted from the mature human milk of four individual donors. Using an in vitro model of intestinal injury, the effects of the oligosaccharides on the intestinal epithelial barrier and select innate and adaptive immune functions were assessed. Results: Individual oligosaccharide compositions shared comparable effects on increasing transepithelial electrical resistance and reducing the macromolecular permeability of polarized (Caco-2Bbe1) monolayers but exerted distinct effects on the localization of the intercellular tight junction protein zona occludins-1 in response to injury induced by a human enteric bacterial pathogen Escherichia coli, serotype O157:H7. Immunoblots showed the differential effects of oligosaccharide compositions in reducing host chemokine interleukin 8 expression and inhibiting of p38 MAP kinase activation. Conclusions: These results provide evidence of both shared and distinct effects on the host intestinal epithelial function that are attributable to inter-individual differences in the composition of human milk oligosaccharides.

A54 DIETARY COMPONENTS ARE ASSOCIATED WITH FECAL CALPROTECTIN IN ULCERATIVE COLITIS

BackgroundUlcerative colitis (UC) is thought to arise from dysregulated immune responses due to intestinal dysbiosis and altered epithelial barrier function. Dietary components may affect the gut microbiome and contribute to either inflammation or its resolution. The relationship between diet and disease activity in UC warrants further investigation.AimsThis prospective cohort study explored the relationship between dietary components, and markers of disease activity: fecal calprotectin (FCP) and partial Mayo score (PMS) in patients with UC.Methods40 participants were recruited from University of Calgary IBD clinics. Study staff obtained two 24-hour diet recalls using the validated automated self administered (ASA)-24 and captured PMS at baseline (T1) and follow-up at week 12 (T2). FCP samples were collected at T1 and T2. Diet variables included adjusted macro/micronutrients (n=44), food groups (n=36) and the validated Canadian healthy eating index-2009 (CHEI) where higher scores reflect healthier intake. CHEI captures intake of dark green and orange foods (DGO) and moderation scoring (MOD) of saturated fats (SF), sodium and added sugars. Higher CHEI scores result from increased intake of DGO and lower intake of SF, sodium and added sugars (higher MOD score). Associations with outcome variables were examined at T1 and T2 individually and across both timepoints (BT). Mixed effect logistic regression models identified relationships between dietary variables, FCP and PMS. Models were adjusted for age, sex, BMI, medications, probiotics, and for repeated measures in both timepoint analyses.ResultsA positive association was identified between FCP as a continuous variable and SF (T1:Coef=0.22, p_adj=0.02) and a negative association identified between FCP with citrus/melon/berries (BT:Coef=-1.01, p_adj =0.04), total sugars (BT:Coef=-0.06, p_adj=0.025) and HEI (BT:Coef=-0.13, p_adj =0.06 and T1 coef=-0.18, p_adj =7.0 e-5). FCP increased as SF (-0.30,p_adj=0.01), DGO (-0.60, p_adj=0.02), and MOD (-0.21, p_adj=0.02) scores decreased. The presence of inflammation (as a binary variable, FCP >250) was negatively associated with higher fiber intake (BT: Odds Ratio (OR)= 0.016, CI(0.001,0.40) p_adj=0.08). For PMS as a continuous variable, HEI had a negative association with PMS (T2: -0.05, p_adj=0.06). With PMS as a discrete score (remission=PMS<2) there was no significant association with any diet components.ConclusionsThis study suggests that a healthier diet, both in overall pattern and specific dietary components, was associated with lower FCP and PMS. Our findings related to SF, citrus/melons/berries, and DGO parallel the IOIBD dietary guidelines. Future research should explore through controlled intervention studies whether modifying dietary patterns and components independently reduces disease activity. Funding AgenciesCrohn’s and Colitis Foundation