Translocation Of Antigens Research Articles

Antibiotics damage the colonic mucus barrier in a microbiota-independent manner.

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation, and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to intestinal inflammation by impeding mucus production.

Carrageenan and TLR4 Crosstalk: A Comprehensive Review of Inflammatory Responses in Animal Models

Abstract: Carrageenan, a naturally occurring polysaccharide derived from red seaweed, has been utilized extensively in the food industry as a stabilizer, thickener, and emulsifier due to its unique gel-forming properties. This versatile compound exists in various forms, including kappa, iota, and lambda, each with distinct characteristics suitable for different applications. Its widespread use as a food additive has raised concerns regarding its safety, particularly its potential inflammatory effects on the gastrointestinal tract. While carrageenan has been deemed safe for consumption by regulatory agencies in small amounts, studies have suggested its association with intestinal inflammation and gastrointestinal disturbances, particularly in susceptible individuals. Animal models, including rodents and non-human primates, have been employed to investigate the inflammatory response induced by carrageenan ingestion. These models have provided valuable insights into the molecular mechanisms underlying its pro-inflammatory properties. At the molecular level, carrageenan is believed to trigger inflammation by activating toll-like receptor 4 (TLR4) signaling pathways, leading to the production of pro-inflammatory cytokines and the recruitment of immune cells to the site of exposure. Furthermore, carrageenan-induced inflammation may disrupt the intestinal barrier function, facilitating the translocation of luminal antigens and exacerbating immune responses. This review provides a comprehensive examination of the current understanding of carrageenan's role in inflammation, encompassing its diverse applications in the food industry, safety concerns, experimental findings from animal models, and molecular mechanisms underlying its pro-inflammatory effects.

The gut-liver axis: ways of maintaining the body’s homeostasis. Historical aspects and the current state of the problem. Literature review

There are close evolutionary anatomical and functional connections between the intestine and the liver. Whereas the peculiarities of functioning of these organs as components of the digestive system have long been the object of scientific research, their role in maintaining the body’s homeostasis has been studied relatively recently. This especially applies to the immune aspects of the interaction of these organs. The intestinal mucosa performs not only the function of a mechanical barrier, but also provides an immune response to pathogens while maintaining tolerance to one’s own flora, which together prevents the translocation of antigens into the internal environment of the body. In this aspect, the intestinal microbiocenosis is of particular interest, as it plays an important role in maintaining the integrity of the intestinal barrier and reducing bacterial translocation, forming and modulating the activity of the local immune system, and has a regulatory effect on the body’s metabolic processes. A decrease in the barrier function of the intestines leads to the contact of translocated antigens of bacterial origin and other xenobiotics with the structures of adaptive immunity, and through the portal blood flow with the lymphoid structures of the liver, triggers a cascade of inflammatory reactions, and as a result, to the development of pathological processes in the hepatobiliary zone and metabolic disorders. Understanding these processes contributes to the emergence of promising directions in the prevention and treatment of a wide range of pathological conditions, for example, violations of food tolerance, some allergic diseases. The review summarizes historical aspects and modern views on the role of the «intestine‑liver» axis in ensuring the metabolic and immune homeostasis of the body, as well as data on pathological conditions that develop when this axis is disturbed.

An Overview of the Toxic Effects and Mechanisms of Zearalenone, Aflatoxins, and Deoxynivalenol on Intestinal Integrity Damage in Humans and Animals: A Comprehensive Review

Abstract: Mycotoxins are known to cause contamination in food crops and animal feeds. Their existence in food sources has caused several health disorders. The intestine is the first line of defense against ingested mycotoxins. Numerous studies have reported that mycotoxins impair effective digestion and absorption of nutrients in the intestinal structure, as well as affect the health and integrity of several animal species. However, the direct effect of many specific mycotoxins on the intestinal integrity factors such as the tight junction protein and gut microbiota has not been fully described. The impairment of the barrier function results in increased translocation of luminal antigens and pathogens and excessive activation of the immune system. Therefore, this review aims to provide a summary of the current evidence regarding the direct effects and mechanisms of Zearalenone, Aflatoxins, and Deoxynivalenol on intestinal integrity, focusing on epithelial cells, tight junction proteins and gut microbiota as main contributors to the development of therapeutic strategies to reduce or eliminate the harmful effects caused by mycotoxins in the intestine and targeted organs (such as liver and kidney) in the humans and animals.

Pivotal Role of Intestinal Microbiota and Intraluminal Metabolites for the Maintenance of Gut-Bone Physiology.

Intestinal microbiota, and their mutual interactions with host tissues, are pivotal for the maintenance of organ physiology. Indeed, intraluminal signals influence adjacent and even distal tissues. Consequently, disruptions in the composition or functions of microbiota and subsequent altered host-microbiota interactions disturb the homeostasis of multiple organ systems, including the bone. Thus, gut microbiota can influence bone mass and physiology, as well as postnatal skeletal evolution. Alterations in nutrient or electrolyte absorption, metabolism, or immune functions, due to the translocation of microbial antigens or metabolites across intestinal barriers, affect bone tissues, as well. Intestinal microbiota can directly and indirectly alter bone density and bone remodeling. Intestinal dysbiosis and a subsequently disturbed gut-bone axis are characteristic for patients with inflammatory bowel disease (IBD) who suffer from various intestinal symptoms and multiple bone-related complications, such as arthritis or osteoporosis. Immune cells affecting the joints are presumably even primed in the gut. Furthermore, intestinal dysbiosis impairs hormone metabolism and electrolyte balance. On the other hand, less is known about the impact of bone metabolism on gut physiology. In this review, we summarized current knowledge of gut microbiota, metabolites and microbiota-primed immune cells in IBD and bone-related complications.

Intestinal Fatty Acid-binding Protein in Patients with Psoriasis: A Marker of Impaired Intestinal Permeability Barrier and its Relation to Demographic Data and Clinical Characteristics

Abstract Background: Alterations of intestinal microbiota may play a role in the pathogenesis of psoriasis. Dysbiosis may cause disruption of the intestinal barrier, which contributes to immune activation by translocation of microbial antigens and metabolites. Intestinal fatty acid-binding protein (I-FABP) serves as a biomarker of enterocyte damage. Purpose: The aim of this study was to investigate serum concentration of I-FABP in patients with psoriasis. Methods: A cross-sectional hospital-based study on fifty psoriatic patients and thirty-five age and sex-matched healthy volunteers as a control group were enrolled in the study, serum I-FABP concentration was measured using an enzyme-linked immunosorbent assay. Results: Concentration of serum I-FABP was higher in patients compared to controls (P = 0.04). The serum level of I-FABP was higher in patients with skin phototype IV than in those with skin phototype III (P = 0.040). There were significant positive statistical correlations between I-FABP with age and disease duration. Conclusion: I-FABP, a biomarker for gut permeability, is increased in psoriasis and correlates with disease duration and age. Further investigations are needed to determine whether reinforcing intestinal barrier may be a new therapeutic target in psoriasis.

Inflammation and Impaired Gut Physiology in Post-operative Ileus: Mechanisms and the Treatment Options.

Post-operative ileus (POI) is the transient cessation of coordinated gastrointestinal motility after abdominal surgical intervention. It decreases quality of life, prolongs length of hospital stay, and increases socioeconomic costs. The mechanism of POI is complex and multifactorial, and has been broadly categorized into neurogenic and inflammatory phase. Neurogenic phase mediated release of corticotropin-releasing factor (CRF) plays a central role in neuroinflammation, and affects both central autonomic response as well hypothalamic-pituitary-adrenal (HPA) axis. HPA-stress axis associated cortisol release adversely affects gut microbiota and permeability. Peripheral CRF (pCRF) is a key player in stress induced gastric emptying and colonic transit. It functions as a local effector and interacts with the CRF receptors on the mast cell to release chemical mediators of inflammation. Mast cells proteases disrupt epithelial barrier via protease activated receptor-2 (PAR-2). PAR-2 facilitates cytoskeleton contraction to reorient tight junction proteins such as occludin, claudins, junctional adhesion molecule, and zonula occludens-1 to open epithelial barrier junctions. Barrier opening affects the selectivity, and hence permeation of luminal antigens and solutes in the gastrointestinal tract. Translocation of luminal antigens perturbs mucosal immune system to further exacerbate inflammation. Stress induced dysbiosis and decrease in production of short chain fatty acids add to the inflammatory response and barrier disintegration. This review discusses potential mechanisms and factors involved in the pathophysiology of POI with special reference to inflammation and interlinked events such as epithelial barrier dysfunction and dysbiosis. Based on this review, we recommend CRF, mast cells, macrophages, and microbiota could be targeted concurrently for efficient POI management.

Induction of leaky gut by repeated intramuscular injections of indomethacin to preweaning Holstein calves

This study was designed to develop a protocol for repeated intramuscular indomethacin injections to replicate leaky-gut-like symptoms in male Holstein calves to model and study the detrimental effects of leaky gut on gut tissue function and inflammatory response. A generalized randomized block design was used to evaluate how repeated indomethacin intramuscular injections affected the development of leaky gut in 18 male Holstein calves. Animals were enrolled at 3 ± 1 d of life, and after 21 d of adaptation, they were randomly assigned to 1 of 3 treatments consisting of intramuscular saline or indomethacin injections every 12 h for 48 h: (1) control (CTL), saline injection, (2) low intramuscular indomethacin (INDO-L) dosed at 1.2 mg/kg of body weight (BW), and (3) high intramuscular indomethacin (INDO-H) dosed at 2.4 mg/kg of BW. During the challenge, milk intake, starter intake, fecal scores, and rectal temperature were measured daily, and BW was measured at the beginning and at the end of the challenge. Plasma samples were used to measure the recovery of markers of intestinal permeability before and after the challenge by dosing lactulose, d-mannitol, and chromium-EDTA. In addition, several cytokines were measured in plasma during the challenge. Calves were dissected at the end of the challenge to obtain tissue and digesta samples from the gastrointestinal tract and liver. No treatment differences were observed for starter and milk intakes, fecal scores, BW, and rectal temperature. The difference in marker concentrations between pre and post challenges was higher for INDO calves compared with CTL calves in the case of lactulose and chromium-EDTA. In addition, chemokine ligand 2 and 4 and IL-6 were higher for INDO-H calves compared with CTL. Both doses of indomethacin resulted in reductions in villus length and surface area in the distal jejunum and ileum and reductions in crypt depth and width in the colon. We showed that repeated indomethacin injections over a 48-h period induced leaky-gut-like symptoms in a region-specific manner, affecting mainly the distal section of the intestine. This outcome was characterized by histomorphological changes in the distal jejunum, ileum, and colon and by increased gut permeability. Interestingly, changes in liver morphology and immune function also occurred, possibly due to the increased translocation of foreign antigens breaching the epithelial cell wall. The leaky gut challenge model described here could be used to improve understanding of the pathogenesis of intestinal disorders in cattle and provide a reliable alternative for testing feed additives with intestinal health benefits.

Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.

Beyond Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome: The Relevance of Complement From Pathogenesis to Pregnancy Outcome in Other Systemic Rheumatologic Diseases.

Evidence about the relevance of the complement system, a highly conserved constituent of the innate immunity response that orchestrates the elimination of pathogens and the inflammatory processes, has been recently accumulated in many different rheumatologic conditions. In rheumatoid arthritis, complement, mainly the classical pathway, contributes to tissue damage especially in seropositive subjects, with complement activation occurring in the joint. Data about complement pathways in psoriatic arthritis are dated and poorly consistent; among patients with Sjögren syndrome, hypocomplementemia exerts a prognostic role, identifying patients at risk of extra-glandular manifestations. Hints about complement involvement in systemic sclerosis have been recently raised, following the evidence of complement deposition in affected skin and in renal samples from patients with scleroderma renal crisis. In vasculitides, complement plays a dual role: on one hand, stimulation of neutrophils with anti-neutrophil cytoplasmic antibodies (ANCA) results in the activation of the alternative pathway, on the other, C5a induces translocation of ANCA antigens, favouring the detrimental role of antibodies. Complement deposition in the kidneys identifies patients with more aggressive renal disease; patients with active disease display low serum levels of C3 and C4. Even though in dermatomyositis sC5b-9 deposits are invariably present in affected muscles, data on C3 and C4 fluctuation during disease course are scarce. C3 and C1q serum levels have been explored as potential markers of disease activity in Takayasu arteritis, whereas data in Behçet disease are limited to in vitro observations. Pregnancies in women with rheumatologic conditions are still burdened by a higher rate of pregnancy complications, thus the early identification of women at risk would be invaluable. A fine-tuning of complement activation is required from a physiological progression of pregnancy, from pre-implantation stages, through placentation to labour. Complement deregulation has been implicated in several pregnancy complications, such as recurrent abortion, eclampsia and premature birth; low complement levels have been shown to reliably identify women at risk of complications. Given its physiologic role in orchestrating pregnancy progression and its involvement as pathogenic effector in several rheumatologic conditions, complement system is an attractive candidate biomarker to stratify the obstetric risk among women with rheumatologic conditions.

Contribution of mycobiota to the pathogenesis of spondyloarthritis

This review lists current evidences for a contribution of gut mycobiota to the pathogenesis of SpA and related conditions. Gut mycobiota has a small size as compared to bacterial microbiota, but an even greater inter- and intra-individual variability. Although most fungi (brought by food or air) are only transitory present, a core mycobiota of gut resident fungi exists, and interplays with bacteria in a complex manner. A dysbiosis of this gut mycobiota has been observed in Crohn's disease and sclerosing cholangitis, with decreased proportion of Saccharomyces cerevisiae and outgrowth of more pathogenic gut fungi. Fungal-induced lower number of commensal gut bacteria can promote translocation of some bacterial/fungal antigens through mucosae, and live fungi can also cross the epithelial border in Crohn's disease. This dysbiosis also lower the ability of bacteria to metabolize tryptophan into regulatory metabolites, consequently enhancing tryptophan metabolism within human cells, which might contribute to fatigue. Translocation of mycobiotal antigens like curdlan (beta-glucan), which plays a major role in the pathogenesis of SpA in the SGK mice, has been observed in humans. This translocation of fungal antigens in human SpA might account for the anti-Saccharomyces antibodies found in this setting. Contribution of fungal antigens to psoriasis and hidradenitis suppurativa would fit with the preferential homing of fungi in the skin area most involved in those conditions. Fungal antigens also possess autoimmune uveitis-promoting function. As genes associated with SpA (CARD9 and IL23R) strongly regulate the innate immune response against fungi, further studies on fungi contribution to SpA are needed.

Mechanism of Lactobacillus reuteri Probiotic in Increasing Intestinal Mucosal Immune System

Probiotics are defined as live microorganisms which, when consumed in adequate quantities as food ingredients, provide health benefits to the host. Lactobacillus, Bifidobacterium, and Saccharomyces, are three probiotics that are intensively used as probiotics in humans and animals. Probiotics have beneficial effects on health when given adequate amounts. The concept of probiotics on human health, namely modulating the gut microbiota and its effect on the host. Probiotics play an important role in maintaining intestinal integrity through a number of different interactions, including changes in cytokine expression in the mucosa. Probiotics compete with intestinal pathogens for mucosal receptors, thereby increasing interepithelial resistance. Probiotics such as Lactobacillus casei sp GG strain was used as a prophylaxis that could increase the expression of epithelial mucin, thereby reducing the translocation of pathogenic bacteria. Abnormal local immune response is characterized by decreased secretion of IgA, thus allowing enterocyte attachment and local translocation of bacterial antigens, which are the main stimulation of pathological events. Colonic stasis can promote the growth of pathogenic bacteria which allows malignant porin bacterial strains to thrive. The gut microbiota has a major influence on human health. The microbial population has an important role in the host, such as the metabolic activity of probiotics producing energy and nutrient absorption, developing the host immune system, and preventing colonization and infection of pathogens. Lactobacillus reuteri is a hetero-fermentative bacterium that lives in the digestive tract of humans. L. reuteri has been used to treat infant necrotizing pseudomembrane. In this paper, the mechanism of L reuteri to increase host immunological response will be reviewed.

Antineutrophil cytoplasmic antibody (ANCA) vasculitis: pathophysiology, diagnosis, and the evolving treatment landscape.

The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several closely related, often severe, multisystem autoimmune diseases characterized by antibodies against serine proteinase 3 (PR3) or myeloperoxidase. Loss of tolerance to these antigens triggers a cascade of events, beginning with the priming of neutrophils by proinflammatory cytokines and complement activation, translocation of ANCA-specific antigens to the plasma membrane, neutrophil hyperactivation, and further activation of the alternative complement pathway, leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due to the heterogeneity in presentation of these diseases, diagnosis is often substantially delayed, leading to poor outcomes. The current treatment pathway for most patients involves induction with cyclophosphamide or rituximab in combination with glucocorticoids, followed by a maintenance phase with rituximab, azathioprine, or methotrexate, during which time glucocorticoids are tapered. Current therapies are often effective in inducing and maintaining remission but are associated with a range of toxicities. Several new therapies are in development for ANCA vasculitis. Avacopan, an orally administered inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a phase 3 clinical trial and may play a role in reducing the cumulative glucocorticoid dose. Preliminary data suggest that cluster of differentiation (CD) 80 and CD86 blockade with abatacept may also have a role in the management of ANCA vasculitis. There is an unmet need for additional therapeutic options for patients with these diseases.

115-OR: Microbiome Antigens as a Vaccination Strategy in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disorder that results from T cell-mediated destruction of the insulin-producing β cells of the pancreatic islets. Accumulating evidence from both human and animal studies points to the gut microbiome, the 100 trillion microbes inhabiting our intestinal tract, as a key component driving the inflammatory processes leading to T1D. However, the mechanisms therein are poorly understood. We propose that this inflammatory milieu occurs in the pancreas, where microbes or microbial fragments that translocate from their usual luminal, mucosal sites persist and induce the cytokine and chemokine signals needed for destructive, autoimmune cellular and humoral responses that destroy the insulin producing β cells. By controlling this inflammation via vaccination against a highly conserved microbial surface antigen, poly-N-acetyl glucosamine (PNAG), we can decrease the inflammatory response such that vaccination prevents diabetes. In analyses of human and murine pancreatic islets, we have found that PNAG is readily detectable within diabetic, but not healthy, pancreases and associated with both T cells and polymorphonuclear cells (PMNs). This finding suggests that inducing an effective immune response that can clear PNAG-containing microbes or microbial fragments may be critical in counteracting the microbiota-driven inflammation leading to autoimmunity. We report that NOD female mice vaccinated against PNAG exhibited a drastic reduction in diabetes incidence from in 70% of 21 controls to 17% of 18 PNAG-immune mice. Immunophenotyping on these mice indicates that PNAG vaccination dramatically increases Foxp3+ Tregs as well as CD4+ and CD4- IL-10-producing cells. Taken together, our work provides evidence that the translocation of microbial antigens to the pancreas may drive inflammation leading to T1D, and that vaccination against one particular microbial antigen, PNAG, may lead to protection against this disease. Disclosure A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. Funding American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13 to A.K.)

Heat stress on microbiota composition, barrier integrity, and nutrient transport in gut, production performance, and its amelioration in farm animals.

Livestock species experience several stresses, particularly weaning, transportation, overproduction, crowding, temperature, and diseases in their life. Heat stress (HS) is one of the most stressors, which is encountered in livestock production systems throughout the world, especially in the tropical regions and is likely to be intensified due to global rise in environmental temperature. The gut has emerged as one of the major target organs affected by HS. The alpha- and beta-diversity of gut microbiota composition are altered due to heat exposure to animals with greater colonization of pathogenic microbiota groups. HS also induces several changes in the gut including damages of microstructures of the mucosal epithelia, increased oxidative insults, reduced immunity, and increased permeability of the gut to toxins and pathogens. Vulnerability of the intestinal barrier integrity leads to invasion of pathogenic microbes and translocation of antigens to the blood circulations, which ultimately may cause systematic inflammations and immune responses. Moreover, digestion of nutrients in the guts may be impaired due to reduced enzymatic activity in the digesta, reduced surface areas for absorption and injury to the mucosal structure and altered expressions of the nutrient transport proteins and genes. The systematic hormonal changes due to HS along with alterations in immune and inflammatory responses often cause reduced feed intake and production performance in livestock and poultry. The altered microbiome likely orchestrates to the hosts for various relevant biological phenomena occurring in the body, but the exact mechanisms how functional communications occur between the microbiota and HS responses are yet to be elucidated. This review aims to discuss the effects of HS on microbiota composition, mucosal structure, oxidant-antioxidant balance mechanism, immunity, and barrier integrity in the gut, and production performance of farm animals along with the dietary ameliorations of HS. Also, this review attempts to explain the mechanisms how these biological responses are affected by HS.

S2235 Therapeutic Hyperbaric Oxygen Therapy Saves the Day in a Patient With Severe Refractory Pan-Ulcerative Colitis

INTRODUCTION: Despite current conventional treatments including steroids, immunomodulators, and anti-inflammatory medications, many patients with recurrent flares of ulcerative colitis (UC) often require more intensive therapy including biologics, and even colectomy. A dysregulated immune response to intestinal mucosal hypoxia contributes to the pathogenesis of UC, resulting in a loss of epithelial barrier function, translocation of luminal antigens into mucosa, and subsequent inflammation, making targeting of hypoxia-sensitive pathways a promising therapeutic approach.1 Recent literature supports the therapeutic potential of adjunctive hyperbaric oxygen therapy (HBOT).2 We present a case in which HBOT was used to help induce remission in an inpatient with severe refractory UC. CASE DESCRIPTION/METHODS: A 32-year-old male with a history of severe, chronic pan-UC presented to our clinic with a severe flare. Previously, he had a lack of response on multiple drug regimens to include azathioprine and infliximab. He was actively on vedolizumab therapy with minimal clinical and endoscopic response despite adequate levels and no antibodies detected. After missing an infusion, he developed an acute flare; presenting with >7 bloody bowel movements daily, fatigue, tenesmus, and a 20lb weight loss. Colonoscopy on hospital day (HD) 1 showed Mayo 3 pancolitis with biopsies negative for CMV. He received daily methylprednisolone and repeat induction dosing of vedolizumab with minimal clinical response. He subsequently underwent three 30-minute sessions of HBOT with significant symptomatic improvement. Tenesmus resolved and stools became non-bloody and semi-formed by the day of discharge. At 3-month follow-up, he remained in clinical remission with a normal fecal calprotectin on vedolizumab. DISCUSSION: Twenty-five percent of patients with UC will develop severe, acute exacerbations of disease during their lifetime. Despite advancements in treatment, half of these patients will fail subsequent medical rescue therapy, and an additional half of those will require colectomy within five years.3 Hyperbaric oxygen therapy is safe, well tolerated, and may play a role in inducing remission.4 The ability to increase tissue oxygen delivery to inflamed bowel to ultimately revert inflammatory pathways and promote healing may help avoid colectomy in select patients.5 Further research and ongoing clinical trials are necessary to investigate and better define the role of HBOT in inflammatory bowel disease.Figure 1.: Endoscopic view of the distal colon showing severe inflammation.Figure 2.: Endoscopic view of the sigmoid colon showing severe inflammation.Figure 3.: Endoscopic view of the rectum showing severe inflammation.

T12. THE RELATIONSHIP OF INTESTINAL PERMEABILITY FACTORS WITH SOCIODEMOGRAPHIC AND PHYSICAL HEALTH FACTORS AND PANSS SCORES IN SCHIZOPHRENIA PATIENTS AND HEALTHY CONTROLS

BackgroundRecent studies have pointed to the gut-brain axis as a new venue for treatment of psychiatric disorders, with increased inflammation stemming from increased intestinal permeability to further affect brain functioning in a significant subset of patients. Yet, this line of research is still in its infancy, with multiple studies showing increased intestinal permeability in schizophrenia and bipolar disorders, demonstrated as translocation of food and bacterial antigens, as well as intestinal microbiome disturbances.MethodsTherefore, we measured intestinal permeability markers soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) in schizophrenia patients and healthy controls. Intestinal permeability markers were compared to several sociodemographic, including age, gender and BMI, and physical health variables, including CRP, glucose, cholesterol, triglycerides, HDL, LDL and non-HDL, and Positive and Negative Syndrome Scale (PANSS) scores. Of the control group (n = 43), 76.7% was male, with a mean age of 25.1 years. Of the schizophrenia group (n = 105) 75.2 % was male, with a mean age of 27.4 years and an average PANSS score of 57.2.ResultsLevels of LBP and sCD14 were not significantly different between schizophrenia patients and controls. LBP and sCD14 levels were neither correlated in the control group, nor in the schizophrenia group. In the control group Females had elevated LBP levels compared to males (p < 0.01), but not in the schizophrenia group. Quantitative levels of LBP, but not sCD14, correlated with triglycerides in the schizophrenia group (R2 = 0.049, p < 0.05). Furthermore, quantitative levels of sCD14, but not LBP, correlated with CRP in the schizophrenia group (R2 = 0.078, p < 0.05). Finally, LBP levels in patients correlated with PANSS negative scores (R2 = 0.055, p < 0.05). Neither a correlation of LBP and sCD14 with age, nor with BMI was observed in both the control and the schizophrenia group.DiscussionIn conclusion, these intestinal permeability markers showed few differences between the schizophrenia and the control group. We found weak, yet significant correlations with triglycerides, CRP and severity of negative symptoms, which may be caused by poor eating habits or metabolic syndrome leading to leaky gut in the more severely affected patients. These results are not in line with results of Severance et al. (2013), who performed a similar analysis and found differences in intestinal permeability markers between a control group and a schizophrenia group. Furthermore, they did observe a positive correlation between sCD14 and LBP in both the control and the schizophrenia group. The difference between that study and our current findings may stem from the different patients samples, as we assessed patients in their first five years after diagnosis, when metabolic syndrome was less abundant.

Acute Effects of Butyrate on Induced Hyperpermeability and Tight Junction Protein Expression in Human Colonic Tissues.

Intact intestinal barrier function is essential for maintaining intestinal homeostasis. A dysfunctional intestinal barrier can lead to local and systemic inflammation through translocation of luminal antigens and has been associated with a range of health disorders. Butyrate, a short-chain fatty acid derived from microbial fermentation of dietary fibers in the colon, has been described as an intestinal barrier-strengthening agent, although mainly by using in vitro and animal models. This study aimed to investigate butyrate’s ability to prevent intestinal hyperpermeability, induced by the mast cell degranulator Compound 48/80 (C48/80), in human colonic tissues. Colonic biopsies were collected from 16 healthy subjects and intestinal permeability was assessed by Ussing chamber experiments. Furthermore, the expression levels of tight junction-related proteins were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pre-treatment with 5 mM butyrate or 25 mM butyrate did not protect the colonic tissue against induced paracellular or transcellular hyperpermeability, measured by FITC-dextran and horseradish peroxidase passage, respectively. Biopsies treated with 25 mM butyrate prior to stimulation with C48/80 showed a reduced expression of claudin 1. In conclusion, this translational ex vivo study did not demonstrate an acute protective effect of butyrate against a chemical insult to the intestinal barrier in healthy humans.

Investigating intestinal permeability and gut microbiota roles in acute coronary syndrome patients

BackgroundAcute Coronary Syndrome (ACS) is a leading cause of morbidity and mortality. Perturbed gut-microbiota (dysbiosis) and increased intestinal permeability (leaky-gut) with translocation of bacterial antigens, play critical role in obesity and metabolic syndrome, which are also major ACS risk factors. Additionally, Trimethylamine-N-Oxide (TMAO), a metabolite produced by phylum Proteobacteria in gut is implicated in developing ACS. As Proteobacteria is a major source of translocated antigen lipopolysaccharides (LPS), we hypothesized that ACS patients have leaky-gut condition characterized by dysbiosis with increased Proteobacteria, leading to elevated blood levels of TMAO and LPS. MethodsIn a pilot case-control study, we enrolled 19 ACS patients (within 72-h of cardiac events) and 19 healthy-controls. Gut barrier function was determined using lactulose-to-mannitol urinary excretion ratio (L/M ratio). Stool microbiome composition was examined using16S sequencing and predictive functional analysis for LPS biosynthesis pathway by PICRUSt tool. Serum TMAO and LPS levels were measured. ResultsACS patients had increased Gammaproteobacteria compared to controls:1.8 ± 3.0 vs. 0.2 ± 0.4% (P = 0.04). Though Proteobacteria level was increased but not statistically significant: 4.1 ± 3.8 vs. 2.1 ± 1.7% (P = 0.056). L/M-ratio was three times higher in ACS patients; 0.06 ± 0.07 vs 0.023 ± 0.02, (P = 0.014). Surprisingly, there was no difference in the mean serum LPS or TMAO levels. However, PICRUSt analysis indicated increased Proteobacteria population increasingly contributed to LPS biosynthesis in ACS patients only. ConclusionsACS patients likely to have leaky-gut and perturbed gut microbiota. Further studies are required to precisely define the role of dysbiosis in ACS.

Intestinal Fatty Acid Binding Protein, a Biomarker of Intestinal Barrier, is Associated with Severity of Psoriasis.

Alterations of intestinal microbiota play a significant role in the pathogenesis of psoriasis. Dysbiosis may cause disruption of the intestinal barrier, which contributes to immune activation by translocation of microbial antigens and metabolites. Intestinal fatty acid binding protein (I-FABP) serves as a biomarker of enterocyte damage. The aim of this study was to investigate clinical and metabolic factors affecting plasma concentration of I-FABP in patients with psoriasis. Eighty patients with psoriasis and 40 control subjects were enrolled in the study. Serum I-FABP (243.00 (108.88–787.10) vs. 114.38 (51.60–241.60) pg/ml, p < 0.001) and neutrophil to lymphocyte ratio (NLR; 2.59 (1.96–3.09) vs. 1.72 (1.36–47 2.11), p < 0.01) were significantly increased in patients with psoriasis compared to controls. A significant positive correlation was found between I-FABP and body mass index (BMI) (r = 0.82, p < 0.001), Psoriasis Area Severity Index (PASI) (r = 0.78, p < 0.001) and neutrophil to lymphocyte ratio (NLR) (r = 0.24, p < 0.001). Rising quartiles of I-FABP were associated with increasing values of BMI, PASI and NLR. The results of the logistic regression model confirmed an increased risk of higher disease severity with I-FABP concentration – odds ratio 3.34 per 100 pg/mL I-FABP increase. In conclusion, intestinal integrity in patients with psoriasis is affected by obesity, severity of the disease and systemic inflammation. The modulation of gut barrier may represent a new therapeutic approach for psoriasis.