Increase In Intestinal Permeability Research Articles

Bacterial translocation in acute lymphocytic leukemia.

Bloodstream infection (BSI) is the major cause of mortality in acute lymphocytic leukemia (ALL). Causative pathogens in BSI originate from the gut microbiota due to an increase in intestinal permeability, a process known as bacterial translocation (BT). The gut microbiota in physiological conditions is controlled by a large number of immune cells as part of the gut-associated lymphoid tissue (GALT).The aim of the current study was to investigate the mechanism of bacterial translocation in leukemia by identifying and characterizing alterations in the GALT in leukemic mouse model. Our studies revealed a severe impairment of the GALT characterized by a loss of lymphatic cells in ALL, which eventually led to BSI. We identified differentially expressed genes in the intraepithelium and the lamina propria, which may contribute to BT and to the impairment of lymphocyte migration.

Involvement of gliadin, a component of wheat gluten, in increased intestinal permeability leading to non-steroidal anti-inflammatory drug-induced small-intestinal damage.

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.

Lipopolysaccharide-Induced Increase in Intestinal Permeability Is Mediated by TAK-1 Activation of IKK and MLCK/MYLK Gene

Lipopolysaccharides (LPSs) are a major component of Gram-negative bacterial cell wall and play an important role in promoting intestinal inflammatory responses. Recent studies have shown that physiologically relevant concentrations of LPS (0 to 2000 pg/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability without causing cell death. However, the intracellular pathways and the mechanisms that mediate LPS-induced increase in intestinal TJ permeability remain unclear. The aim was to delineate the intracellular pathways that mediate the LPS-induced increase in intestinal permeability using invitro and invivo intestinal epithelial models. LPS-induced increase in intestinal epithelial TJ permeability was preceded by an activation of transforming growth factor-β-activating kinase-1 (TAK-1) and canonical NF-κB (p50/p65) pathways. The siRNA silencing of TAK-1 inhibited the activation of NF-κB p50/p65. The siRNA silencing of TAK-1 and p65/p50 subunit inhibited the LPS-induced increase in intestinal TJ permeability and the increase in myosin light chain kinase (MLCK) expression, confirming the regulatory role of TAK-1 and NF-κB p65/p50 in up-regulating MLCK expression and the subsequent increase in TJ permeability. The data also showed that toll-like receptor (TLR)-4/myeloid differentiation primary response (MyD)88 pathway was crucial upstream regulator of TAK-1 and NF-κB p50/p65 activation. In conclusion, activation of TAK-1 by the TLR-4/MyD88 signal transduction pathway and MLCK by NF-κB p65/p50 regulates the LPS-induced increase in intestinal epithelial TJ permeability.

P123 LACTOBACILLUS ACIDOPHILUS MODULATION OF MOUSE INTESTINAL TIGHT JUNCTION BARRIER: ROLE OF TOLL-LIKE RECEPTOR-2 (TLR-2)

Lactobacillus acidophilus (LA) is one of the most commonly used probiotics that has been shown to improve the mucosal immune response and protect against pathogens permeation. Few studies suggested that LA may have beneficial effect on intestinal tight junction (TJ) barrier function by direct interaction with intestinal epithelial cells. Although probiotic enhancement of intestinal TJ barrier has been postulated as an important therapeutic mechanism, the effects of LA on intestinal epithelial TJ barrier function and the intracellular mechanisms involved in TJ barrier modulation remain unclear. The major aim of this study was to elucidate the intracellular mechanisms involved in LA modulation of intestinal epithelial TJ barrier function using an in-vivo model consisting of mouse small intestinal perfusion system; in wild type, TLR-2 deficient (TLR -/-) mice and in animal model of DSS-colitis. 1) Oral gavage of LA (1 x 109cfu/ml) caused enhancement of intestinal TJ barrier as measured by the decrease in mouse small intestinal permeability to dextran-10 kDa by day 1 of LA administration, and the LA effect on intestinal barrier continued up to day 5. 2) LA caused an increase in mouse intestinal tissue TLR-2 expression in wild type mice, which correlated with the decrease in mouse intestinal permeability. On the other hand, LA did not cause a decrease in mouse intestinal permeability in TLR-2 deficient mice (TLR-2-/-). 3) We examined the barrier protective effects of LA on the development of DSS-induced colitis. Oral DSS administration caused an increase in mouse intestinal permeability by day 2, prior to the development of colitis which occurs between 5-7 days. 4) LA administration by oral gavage daily starting 2 days prior to DSS treatment and continuing throughout the 7 days of DSS treatment inhibited the DSS-induced increase in colonic permeability. 5) The DSS-induced weight loss and disease activity index were also significantly attenuated in LA-treated mice. 6) Lastly, the involvement of TLR-2 in mediating the LA inhibition of DSS-induced increase in intestinal permeability was examined. LA did not inhibit the DSS-induced increase in mouse colonic permeability or inhibit the DSS-induced colitis in TLR-2-/- mice In conclusion, our data show that LA enhancement of mouse intestinal epithelial TJ barrier function was regulated via upregulation of TLR-2. Our findings also show that administration of probiotic LA is capable to preserve the disruption of tight junctions proteins associated with DSS-induced colitis, an animal model of IBD. Therefore, LA plays an important role as regulator of the integrity of the intestinal barrier in a TLR-2 dependent mechanism, which might have important implications for understanding of probiotic mechanisms in preventing/treating inflammatory conditions of the gut.

Beneficial effects of Saccharomyces boulardii CNCM I-745 on clinical disorders associated with intestinal barrier disruption.

Intestinal barrier defects lead to “leaky gut syndrome”, defined as an increase in intestinal permeability that allows the passage of luminal content into intestinal tissue and the bloodstream. Such a compromised intestinal barrier is the main factor underlying the pathogenesis of inflammatory bowel disease, but also commonly occurs in various systemic diseases such as viral infections and metabolic syndrome. The non-pathogenic yeast Saccharomyces boulardii CNCM I-745 has demonstrated its effectiveness as a probiotic in the prevention and treatment of antibiotic-associated, infectious and functional diarrhea. Via multiple mechanisms of action implicated in intestinal barrier function, S. boulardii has beneficial effects on altered intestinal microbiota and epithelial barrier defects in different pathologies. The well-studied probiotic yeast S. boulardii plays a crucial role in the preservation and/or restoration of intestinal barrier function in multiple disorders. This could be of major interest in diseases characterized by alterations in intestinal barrier function.

Gut derived-endotoxin contributes to inflammation in severe ischemic acute kidney injury

BackgroundRecent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney.MethodsRats were performed sham or renal IR surgery (60 min of bilateral renal ischemia, then 24 h of reperfusion) (n = 5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20 mg/kg/day or saline for 4 weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate.ResultsRenal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity.ConclusionsOur results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.

Association of endotoxaemia & gut permeability with complications of acute pancreatitis: Secondary analysis of data.

Background & objectives:In acute pancreatitis (AP) gut barrier dysfunction is considered as an important predisposing factor leading to increased intestinal permeability (IP). In this study a pooled analysis of data published in our previous four studies on various aspects of gut permeability and endotoxaemia in patients with AP was attempted to find an association between increased IP and severity of disease and associated complications.Methods:This study was a pooled analysis of data of four previously published prospective studies on AP. Gut permeability, assessed by lactulose/mannitol excretion in urine and endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM) were measured on days zero and seven (D0 and D7) of admission. All patients received standard treatment of AP. We studied whether IgG and IgM anti-endotoxin titres and lactulose-mannitol ratio (LMR) at admission and D7 were associated with organ failure, infection and mortality.Results:The titres of anti-endotoxin IgG and IgM were lower in all patients of AP (n=204), both in mild AP (n=24) and severe AP (n=180) in the first week, compared to controls (n=15). There was no significant difference in serum IgG and IgM anti-endotoxin levels and LMR at baseline and at D7 among patients with organ failure, infection and mortality.Interpretation & conclusions:Our findings showed that serum IgG and IgM anti-endotoxin titres and LMR at admission and at day 7 were not associated with organ failure, infection, and death of patients with AP.

MMP-9-induced increase in intestinal epithelial tight permeability is mediated by p38 kinase signaling pathway activation of MLCK gene.

Matrix metalloproteinase-9 (MMP-9) has been implicated as being an important pathogenic factor in inflammatory bowel disease (IBD). MMP-9 is markedly elevated in intestinal tissue of patients with IBD, and IBD patients have a defective intestinal tight-junction (TJ) barrier manifested by an increase in intestinal permeability. The loss of intestinal epithelial barrier function is an important contributing factor in the development and prolongation of intestinal inflammation; however, the role of MMP-9 in intestinal barrier function remains unclear. The purpose of this study was to investigate the effect of MMP-9 on the intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved by using in vitro (filter-grown Caco-2 monolayers) and in vivo (mouse small intestine recycling perfusion) systems. MMP-9 caused a time- and dose-dependent increase in Caco-2 TJ permeability. MMP-9 also caused an increase in myosin light-chain kinase (MLCK) gene activity, protein expression, and enzymatic activity. The pharmacological MLCK inhibition and siRNA-induced knockdown of MLCK inhibited the MMP-9-induced increase in Caco-2 TJ permeability. MMP-9 caused a rapid activation of the p38 kinase signaling pathway and inhibition of p38 kinase activity prevented the MMP-9-induced increase in MLCK gene activity and the increase in Caco-2 TJ permeability. MMP-9 also caused an increase in mouse intestinal permeability in vivo, which was accompanied by an increase in MLCK expression. The MMP-9-induced increase in mouse intestinal permeability was inhibited in MLCK-deficient mice. These data show for the first time that the MMP-9-induced increase in intestinal TJ permeability in vitro and in vivo was mediated by the p38 kinase signal transduction pathway upregulation of MLCK gene activity and that therapeutic targeting of these pathways can prevent the MMP-9-induced increase in intestinal TJ permeability. NEW & NOTEWORTHY MMP-9 is highly elevated in patients with IBD. IBD patients have compromised intestinal TJ barrier function manifested by an increase in intestinal permeability and intestinal inflammation. This study shows that MMP-9, at clinically achievable concentrations, causes an increase in intestinal TJ permeability in vitro and in vivo. In addition, a MMP-9-induced increase in intestinal TJ permeability was mediated by an increase in MLCK gene and protein expression via the p38 kinase pathway.

Exercise-Induced Anaphylaxis: Literature Review and Recent Updates.

This paper will review the pathophysiology, diagnosis, and treatment of exercise-induced anaphylaxis and food-dependent, exercise-induced anaphylaxis with an emphasis on novel studies published in the past several years. Exercise-induced anaphylaxis (EIAn) is a clinical syndrome characterized by anaphylaxis during or shortly after physical exertion. The syndrome is broadly grouped into two categories: exercise-induced anaphylaxis and food-dependent, exercise-induced anaphylaxis (FDEIAn). Recent literature indicates that FDEIAn is a primary IgE-mediated food allergy which is augmented by several cofactors. Cofactors such as exercise, NSAIDs, and alcohol increase intestinal permeability and allow increased antigen uptake, thereby causing symptoms. The pathophysiology of EIAn is still under investigation. EIAn and FDEIAn are rare clinical syndromes characterized by symptoms during or shortly after exercise. Despite recent advances in the understanding of EIAn and FDEIAn, the pathophysiology of both conditions is not fully understood.

The Gut-Brain Axis in Alzheimer's Disease and Omega-3. A Critical Overview of Clinical Trials.

Despite intensive study, neurodegenerative diseases remain insufficiently understood, precluding rational design of therapeutic interventions that can reverse or even arrest the progressive loss of neurological function. In the last decade, several theories investigating the causes of neurodegenerative diseases have been formulated and a condition or risk factor that can contribute is described by the gut-brain axis hypothesis: stress, unbalanced diet, and drugs impact altering microbiota composition which contributes to dysbiosis. An altered gut microbiota may lead to a dysbiotic condition and to a subsequent increase in intestinal permeability, causing the so-called leaky-gut syndrome. Herein, in this review we report recent findings in clinical trials on the risk factor of the gut-brain axis in Alzheimer’s disease and on the effect of omega-3 supplementation, in shifting gut microbiota balance towards an eubiosis status. Despite this promising effect, evidences reported in selected randomized clinical trials on the effect of omega-3 fatty acid on cognitive decline in Alzheimer’s disease are few. Only Mild Cognitive Impairment, a prodromal state that could precede the progress to Alzheimer’s disease could be affected by omega-3 FA supplementation. We report some of the critical issues which emerged from these studies. Randomized controlled trials in well-selected AD patients considering the critical points underlined in this review are warranted.

The co-administration of proanthocyanidins and an obesogenic diet prevents the increase in intestinal permeability and metabolic endotoxemia derived to the diet

The consumption of Westernized diets leads to hyperphagia and obesity, as well as intestinal alterations. In the present study, we evaluated the effect of the administration of a grape seed proanthocyanidin extract (GSPE) at different time points on the modulation of intestinal barrier function (intestinal permeability and metabolic endotoxemia), in rats with high-fat/high-carbohydrate diet-induced obesity. Animals were fed a cafeteria diet (CAF) supplemented with a preventive (PRE-CAF) or simultaneously intermittent (SIT-CAF) GSPE treatment (500 mg/kg bw). Changes in the plasma levels of an orally administered marker of intestinal permeability (ovalbumin, OVA), lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were analyzed after animals were fed the obesogenic diet for 8, 12 and 17 weeks. In addition, ex vivo variations in transepithelial electrical resistance (TEER), the expression of tight junction (TJ) genes and the activity of myeloperoxidase (MPO) in the small and large intestines were monitored at the end of the experiment. The CAF diet increased OVA, LPS, MPO and TNF-α levels, accompanied by decreased TEER values in the small and large intestines. Interestingly, both GSPE treatments prevented these detrimental effects of the CAF diet, being the SIT-CAF group the most effective after 17 weeks of diet intervention. For the first time, this study provides evidence of the ameliorative effect of a proanthocyanidin extract, administered before or together with an obesogenic diet, on barrier dysfunction, as measured by intestinal permeability and metabolic endotoxemia.

Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations.

Chronic (psychosocial) stress changes gut microbiota composition, as well as inducing behavioural and physiological deficits. The microbial metabolites short-chain fatty acids (SCFAs) have been implicated in gastrointestinal functional, (neuro)immune regulation and host metabolism, but their role in stress-induced behavioural and physiological alterations is poorly understood. Administration of SCFAs to mice undergoing psychosocial stress alleviates enduring alterations in anhedonia and heightened stress-responsiveness, as well as stress-induced increases in intestinal permeability. In contrast, chronic stress-induced alterations in body weight gain, faecal SCFAs and the gene expression of the SCFA receptors FFAR2 and FFAR3 remained unaffected by SCFA supplementation. These results present novel insights into mechanisms underpinning the influence of the gut microbiota on brain homeostasis, behaviour and host metabolism, informing the development of microbiota-targeted therapies for stress-related disorders. There is a growing recognition of the involvement of the gastrointestinal microbiota in the regulation of physiology and behaviour. Microbiota-derived metabolites play a central role in the communication between microbes and their host, with short-chain fatty acids (SCFAs) being perhaps the most studied. SCFAs are primarily derived from fermentation of dietary fibres and play a pivotal role in host gut, metabolic and immune function. All these factors have previously been demonstrated to be adversely affected by stress. Therefore, we sought to assess whether SCFA supplementation could counteract the enduring effects of chronic psychosocial stress. C57BL/6J male mice received oral supplementation of a mixture of the three principle SCFAs (acetate, propionate and butyrate). One week later, mice underwent 3weeks of repeated psychosocial stress, followed by a comprehensive behavioural analysis. Finally, plasma corticosterone, faecal SCFAs and caecal microbiota composition were assessed. SCFA treatment alleviated psychosocial stress-induced alterations in reward-seeking behaviour, and increased responsiveness to an acute stressor and in vivo intestinal permeability. In addition, SCFAs exhibited behavioural test-specific antidepressant and anxiolytic effects, which were not present when mice had also undergone psychosocial stress. Stress-induced increases in body weight gain, faecal SCFAs and the colonic gene expression of the SCFA receptors free fatty acid receptors 2 and 3 remained unaffected by SCFA supplementation. Moreover, there were no collateral effects on caecal microbiota composition. Taken together, these data show that SCFA supplementation alleviates selective and enduring alterations induced by repeated psychosocial stress and these data may inform future research into microbiota-targeted therapies for stress-related disorders.

Acid-Hydrolyzed Gliadins Worsen Food Allergies through Early Sensitization.

Food allergies result from a complex immune response involving both innate and adaptive immune cells. Major proteins of wheat flour, gliadins, appear to be important allergens, and their characteristics can influence the allergic response. This study investigates the immune reaction when developing a food allergy to gliadins in native, deamidated, or hydrolyzed forms. The immune response after one or two intraperitoneal sensitizations and after oral challenge with each gliadin form is analyzed. Results demonstrate that deamidated gliadins induce a stronger allergic reaction compared to native gliadins. Moreover, deamidation induces an earlier increase in intestinal permeability associated with more pronounced Th2 and Th17 polarizations together with an influx of antigen-presenting cells, especially cDC2. Altogether, Results indicate that industrial processes such as deamidation or hydrolysis influences food allergenicity through immune modulation and helps us to develop tools to determine how these processes can influence this reaction and encourage or decrease allergic reactions.

Hepatic connexin 32 associates with nonalcoholic fatty liver disease severity.

Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet‐induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786‐797)

Leptin alleviates intestinal mucosal barrier injury and inflammation in obese mice with acute pancreatitis.

Obesity is an independent risk factor for severe acute pancreatitis (AP). Leptin plays an important role in energy homeostasis. It has been reported that leptin might also participate in the regulation of the intestinal mucosal barrier and inflammatory response. This study aimed to evaluate the effects of leptin on the intestinal mucosal barrier and inflammatory injury in obese mice with AP. AP was induced in leptin-deficient (ob/ob) or wild type (WT) mice by peritoneal injection of caerulein. The animals were divided into 4 groups: WT mice with or without exogenous leptin injection and ob/ob mice with or without leptin treatment. The inflammatory scoring of the pancreas and intestine were evaluated. Intestinal permeability, ileal interleukin (IL)-6 and IL-1β, proliferation, apoptosis and intestinal expression levels of claudin-1 and occludin were measured. Pancreatic pathologic scores (8.50 ± 0.96 vs. 3.78 ± 1.35, p < 0.001), pancreatic levels of IL-6 (8.34 ± 3.21 ng/mg vs. 4.99 ± 0.53 ng/mg, p = 0.022), intestinal oedema scores (2.25 ± 0.46 vs. 1.14 ± 0.69, p = 0.001) and intestinal permeability to FD4 (0.78 ± 0.06 μg/ml vs. 0.53 ± 0.11 μg/ml, p < 0.001) were significantly higher in ob/ob mice than those in WT mice. Leptin replacement in ob/ob mice greatly improved the intestinal permeability (FD4 0.66 ± 0.03 μg/ml, vs. 0.78 ± 0.06 μg/ml, p = 0.012), increased the ileal expression of claudin-1(1.07 ± 0.08 vs. 0.83 ± 0.07 relative densitometry, p = 0.001) and reduced intestinal IL-6 and IL-1β to levels comparable to those in WT mice. The pancreatic level of IL-6 in ob/ob mice treated with leptin was also significantly decreased relative to that of untreated ob/ob mice (4.45 ± 1.71 ng/mg vs. 8.34 ± 3.21 ng/mg, p = 0.010). Obesity may aggravate intestinal inflammation and increase intestinal permeability under the condition of acute pancreatitis. Exogenous leptin supplementation was in favour of anti-inflammation and improvement of intestinal mucosal barrier.

High-Glucose or -Fructose Diet Cause Changes of the Gut Microbiota and Metabolic Disorders in Mice without Body Weight Change.

High fat diet-induced changes in gut microbiota have been linked to intestinal permeability and metabolic endotoxemia, which is related to metabolic disorders. However, the influence of a high-glucose (HGD) or high-fructose (HFrD) diet on gut microbiota is largely unknown. We performed changes of gut microbiota in HGD- or HFrD-fed C57BL/6J mice by 16S rRNA analysis. Gut microbiota-derived endotoxin-induced metabolic disorders were evaluated by glucose and insulin tolerance test, gut permeability, Western blot and histological analysis. We found that the HGD and HFrD groups had comparatively higher blood glucose and endotoxin levels, fat mass, dyslipidemia, and glucose intolerance without changes in bodyweight. The HGD- and HFrD-fed mice lost gut microbial diversity, characterized by a lower proportion of Bacteroidetes and a markedly increased proportion of Proteobacteria. Moreover, the HGD and HFrD groups had increased gut permeability due to alterations to the tight junction proteins caused by gut inflammation. Hepatic inflammation and lipid accumulation were also markedly increased in the HGD and HFrD groups. High levels of glucose or fructose in the diet regulate the gut microbiota and increase intestinal permeability, which precedes the development of metabolic endotoxemia, inflammation, and lipid accumulation, ultimately leading to hepatic steatosis and normal-weight obesity.

Probiotics in IBD: Combining in vitro and in vivo models for selecting strains with both anti-inflammatory potential as well as a capacity to restore the gut epithelial barrier

Alteration of the gut microbiota together with an increase in intestinal permeability and persistent inflammatory responses are thought to be critical factors in the pathogenesis of inflammatory bowel disease (IBD). Taking benefit of these knowledges, a proper strategy to address the selection of efficient probiotics is needed more than ever. The present study investigated a collection of 11 strains of lactobacilli and bifidobacteria by combining in vitro approaches to select strains with anti-inflammatory activity and capacity to enhance intestinal barrier function. We identified five strains, with different characteristics that entail a high potential for the management of IBD, notably two strains that were highly protective in two different models of colitis. Notably, our results support the hypothesis that the capacity of the strains to alleviate inflammation is in part mediated by the improvement of the intestinal barrier and the restoration of tight junction proteins.

Sa1171 - The Stable Glp-2 Analog Teduglutide Acutely Reduces Lipidinduced Lps Transport Into the Portal Vein and Inhibits Intestinal Permeability Increase after Systemic Inflammation

Sa1171 - The Stable Glp-2 Analog Teduglutide Acutely Reduces Lipidinduced Lps Transport Into the Portal Vein and Inhibits Intestinal Permeability Increase after Systemic Inflammation

Inducible intestinal epithelial cell‐specific NHE3 knockout causes diarrhea and more alkaline luminal content

The Na+/H+ exchanger isoform 3 (NHE3) has an important role in intestinal and renal Na+ uptake, acid‐base regulation, and composition of the gut microbiota. Reduced intestinal NHE3 activity and/or expression were found in congenital Na+ diarrhea and inflammatory bowel disease. Previously, no viable intestinal epithelial cell‐specific NHE3 knockout model has been generated; whole body NHE3 knockout mice show 70% mortality and non‐inducible intestinal epithelial cell‐specific NHE3 knockout mice show 100% postnatal mortality. Therefore, we generated a tamoxifen‐inducible intestinal epithelial‐specific NHE3 knockout mouse (NHE3IEC‐Ko; see abstract #1519). Two weeks after tamoxifen administration, NHE3IEC‐Ko mice show ~2‐fold increase in intestinal permeability, 4 hours after oral gavage of FITC‐Dextran, compared to control mice (P&lt;0.05). The small intestine, cecum, and colon were markedly dilated in NHE3IEC‐Ko versus control mice, which was associated with a more than 2‐fold increase in total intestinal wet weight (4.9±0.5 vs 2.2±0.1 g, P&lt;0.05, n=4 and 8, respectively) and ~1.5‐fold increase in fecal water content (55±2 vs 81±4 %, P&lt;0.05). Small intestinal and colonic flush pH were 0.5 pH and 0.8 pH units more alkaline, respectively, in NHE3IEC‐Ko compared to control mice (both P&lt;0.05). Small intestinal length was not different between genotypes (36±3 vs 39±1 cm, NS), but colon length was increased in NHE3IEC‐Ko compared to control mice (8.8±0.3 vs 7.1±0.2 cm, P&lt;0.05). Although there was not an increase in intestinal length, the proximal small intestine of NHE3IEC‐Ko mice had longer villi (493±4 vs 392±19 μm, P&lt;0.05) but similar crypt depths compared to control mice (89±4 vs 79±3 μm, NS). No differences in villus length (159±11 vs 139±7 μm, NS) or crypt depth (58±2 vs 58±2 μm, NS) were observed in the distal small intestine between genotypes. In conclusion, this novel intestinal epithelial cell‐specific NHE3 knockout model is a useful tool for studying inflammatory bowel disease, and the role of intestinal pH on the microbiome as well as intestinal proliferation and apoptosis.Support or Funding InformationNIH 1R01DK110621, APS STRIDE Undergraduate Summer Research Fellowship 1R25HL115473‐01.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Oxidized Soybean Oils on Oxidative Status and Intestinal Barrier Function in Broiler Chickens

ABSTRACT The objective of this study was to evaluate the effect of oxidized soybean oils on the growth performance, metabolic oxidative status and intestinal barrier function of broiler chickens. A total of 240 one-day-old female broiler chickens were assigned to four dietary treatments with six replicates (cages) of 10 birds each. The dietary treatments comprised of a basal diet supplemented with 4% of: non-oxidized (fresh) soybean oil (control treatment, SNX); lowly-oxidized soybean oil (SLX) (oil heated for 10h at 200°C); moderately-oxidized soybean oil (SMX) (oil heated for 18h at 200°C); or highly-oxidized soybean oil (SHX) (oil heated for 30h at 200°C). Diets and water were offered ad libitum. The experiment was lasted 21d.The growth performance of broilers, determined from 1 to 14 d and from 1 to 21 d of age, was not affected by the dietary treatments (p>0.05). Broilers fed oxidized soybean oils presented higher corticosterone serum levels compared with those fed non-oxidized oil (p 0.05) by the dietary oxidized oil treatments. It was concluded that oxidized oils may cause oxidative stress by reducing intestinal and liver antioxidant capacity; increase intestinal permeability by reducing mRNA expression levels of tight-junction proteins claudin-1 and occludin; and cause inflammation by increasing mRNA expression level of the inflammation-related factor IL-22.