High FODMAP diet causes barrier loss via lipopolysaccharide-mediated mast cell activation.
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ABSTRACT:
SUBMITTER: Singh P
PROVIDER: S-EPMC8663790 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community leads to intestinal pathology. We fed rats an HFM and showed that HFM increases rat fecal Gram-negative bacteria, elevates lipopolysaccharides (LPS), and induces intestinal pathology, as indicated by inflammation, barrier dysfunction, and visceral hypersensitivity (VH). These manifestations were prevented by antibiotics and reversed by low-FODMAP (LFM) diet. Additionally, intracolonic administration of LPS or fecal supernatant (FS) from HFM-fed rats caused intestinal barrier dysfunction and VH, which were blocked by the LPS antagonist LPS-RS or by TLR4 knockdown. Fecal LPS was higher in IBS patients than in healthy subjects (HS), and IBS patients on a 4-week LFM diet had improved IBS symptoms and reduced fecal LPS levels. Intracolonic administration of FS from IBS patients, but not FS from HS or LFM-treated IBS patients, induced VH in rats, which was ameliorated by LPS-RS. Our findings indicate that HFM-associated gut dysbiosis and elevated fecal LPS levels induce intestinal pathology, thereby modulating visceral nociception and IBS symptomatology, and might provide an explanation for the success of LFM diet in IBS patients.
| S-EPMC5749529 | biostudies-literature
Project description:BackgroundClinical and experimental analyses have identified a central role for IgE/FcεRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis.ObjectiveWe examined the effect of LPS exposure on the induction of IgE-mast cell (MC) mediated reactions in mice.MethodsC57BL/6 WT, tlr4-/- and IL10-/- mice were exposed to LPS, and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE, and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+ -mobilization and the expression of FcεRI on peritoneal MCs were quantitated.ResultsWe show that LPS exposure of C57BL/6 WT mice constraints IgE-MC-mediated reactions. LPS-induced suppression of IgE-MC-mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcεRI on MCs and loss of sensitivity to IgE activation. Notably, LPS-induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcεRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcεRI surface expression.Conclusions & clinical relevanceCollectively, these studies suggest that LPS-induced IL-10 promotes the down-regulation of MC surface FcεRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10 pathway may be used as a therapeutic approach to prevent adverse IgE-mediated reactions.
| S-EPMC5865592 | biostudies-literature
Project description:During inflammation, the disruption of the endothelial barrier leads to increased microvascular permeability. Whether tension along cell junctions contributes to histamine-induced endothelial barrier disruption remains unknown. Rapid Ca2+ influx induced by both histamine and thrombin was accompanied by endothelial barrier breakdown revealed as drop of transendothelial electric resistance in primary human microvascular endothelial cells. Interestingly, GLISA measurements revealed activation of RhoA but not inactivation of Rac1 at the time-point of barrier breakdown. FRET measurements showed activation of RhoA at intercellular junctions after both thrombin and histamine exposure. Breakdown coincided with increased stress fiber formation but not with translocation of vinculin, which was located along junctions in the resting state similar to postcapillary venules ex vivo. Moreover, increased tension at AJs was indicated by immunostaining with a conformation-sensitive antibody targeting the ?18-subunit of ?-catenin. Ca2+ chelation by BAPTA-AM and ROCK1 inhibition by Y27632 abolished both increase of tension along AJs as well as barrier dysfunction. Moreover, BAPTA-AM decreased RhoA activation following histamine stimulation, indicating a key role of Ca2+ signaling in barrier breakdown. Taken together, in response to histamine, Ca2+ via RhoA/ROCK activation along endothelial adherens junctions (AJs) appears to be critical for barrier disruption and presumably correlated with enhanced tension. However, vinculin appears not to be critical in this process.
| S-EPMC6125323 | biostudies-literature
Project description:Previous studies by our group as well as others have shown that acute adenosine exposure enhances lung vascular endothelial barrier integrity and protects against increased permeability lung edema. In contrast, there is growing evidence that sustained adenosine exposure has detrimental effects on the lungs, including lung edema. It is well established that adenosine modulates lung inflammation. However, little is known concerning the effect of sustained adenosine exposure on lung endothelial cells (ECs), which are critical to the maintenance of the alveolar-capillary barrier. We show that exogenous adenosine plus adenosine deaminase inhibitor caused sustained elevation of adenosine in lung ECs. This sustained adenosine exposure decreased EC barrier function, elevated cellular reactive oxygen species levels, and activated p38, JNK, and RhoA. Inhibition of equilibrative nucleoside transporters (ENTs) prevented sustained adenosine-induced p38 and JNK activation and EC barrier dysfunction. Inhibition of p38, JNK, or RhoA also partially attenuated sustained adenosine-induced EC barrier dysfunction. These data indicate that sustained adenosine exposure causes lung EC barrier dysfunction via ENT-dependent intracellular adenosine uptake and subsequent activation of p38, JNK, and RhoA. The antioxidant N-acetylcysteine and the NADPH inhibitor partially blunted sustained adenosine-induced JNK activation but were ineffective in attenuation of p38 activation or barrier dysfunction. p38 was activated exclusively in mitochondria, whereas JNK was activated in mitochondria and cytoplasm by sustained adenosine exposure. Our data further suggest that sustained adenosine exposure may cause mitochondrial oxidative stress, leading to activation of p38, JNK, and RhoA in mitochondria and resulting in EC barrier dysfunction.
| S-EPMC3547102 | biostudies-literature
Project description:BackgroundShort-chain fatty acids (SCFAs) are fermented dietary components that regulate immune responses, promote colonic health, and suppress mast cell-mediated diseases. However, the effects of SCFAs on human mast cell function, including the underlying mechanisms, remain unclear. Here, we investigated the effects of the SCFAs (acetate, propionate, and butyrate) on mast cell-mediated pathology and human mast cell activation, including the molecular mechanisms involved.MethodPrecision-cut lung slices (PCLS) of allergen-exposed guinea pigs were used to assess the effects of butyrate on allergic airway contraction. Human and mouse mast cells were co-cultured with SCFAs and assessed for degranulation after IgE- or non-IgE-mediated stimulation. The underlying mechanisms involved were investigated using knockout mice, small molecule inhibitors/agonists, and genomics assays.ResultsButyrate treatment inhibited allergen-induced histamine release and airway contraction in guinea pig PCLS. Propionate and butyrate, but not acetate, inhibited IgE- and non-IgE-mediated human or mouse mast cell degranulation in a concentration-dependent manner. Notably, these effects were independent of the stimulation of SCFA receptors GPR41, GPR43, or PPAR, but instead were associated with inhibition of histone deacetylases. Transcriptome analyses revealed butyrate-induced downregulation of the tyrosine kinases BTK, SYK, and LAT, critical transducers of FcεRI-mediated signals that are essential for mast cell activation. Epigenome analyses indicated that butyrate redistributed global histone acetylation in human mast cells, including significantly decreased acetylation at the BTK, SYK, and LAT promoter regions.ConclusionKnown health benefits of SCFAs in allergic disease can, at least in part, be explained by epigenetic suppression of human mast cell activation.
| S-EPMC7703657 | biostudies-literature
Project description:Intestinal barrier dysfunction is an important clinical problem in various acute and chronic pathological conditions. Ferulic acid (FA) can attenuate the intestinal epithelial barrier dysfunction, however, the underlying mechanism remains unclear. The present study aimed to uncover the protective effect of FA on intestinal epithelial barrier dysfunction in a Caco-2 cell model of lipopolysaccharide (LPS) stimulation and the underlying mechanism. Caco-2 cells were pretreated with FA and then exposed to LPS stimulation. The barrier function of Caco-2 cells was evaluated by measuring trans-epithelial resistance (TER) and 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4) flux, and analyzing the tight junction protein expression and structure. The results showed that decreased TER and increased FITC-FD4 flux were observed in Caco-2 cells stimulated with LPS, but these effects were attenuated by FA pretreatment. FA pretreatment inhibited LPS-induced decrease in occludin and ZO-1 mRNA and protein expression. LPS stimulation decreased miR-200c-3p expression, whereas this decrease was inhibited by FA pretreatment. Furthermore, overexpression of miR-200c-3p strengthened the protective effects of FA on LPS-induced Caco-2 cell barrier dysfunction by decreasing epithelial permeability, increasing occludin and ZO-1 protein expression, and maintaining of ZO-1 protein distribution, while suppression of miR-200c-3p reversed the protective effects of FA. LPS treatment increased the expression of PTEN protein and decreased expression of phosphorylated PI3K and AKT proteins. However, pretreatment of FA inhibited expression of PTEN protein and promoted activation of PI3K/AKT signaling pathway in the LPS-treated Caco-2 cells, and this regulatory effect of FA on the PTEN/PI3K/AKT signaling pathway was strengthened or weakened by miR-200c-3p overexpression or suppression, respectively. Our findings suggested that in Caco-2 cells, FA promotes activation of PI3K/AKT pathway by miR-200c-3p-mediated suppression of the negative mediator PTEN, which, in turn, maintains TJ function and thus ameliorates LPS-induced intestinal epithelial barrier dysfunction.
| S-EPMC7145943 | biostudies-literature
Project description:Food is often considered to be a precipitating factor of irritable bowel syndrome (IBS) symptoms. In recent years, there has been a growing interest in FODMAPs (Fermentable Oligo-, Di-, Mono-saccharides, And Polyols), which can be found in many common foods. A low FODMAP diet (LFD) is increasingly suggested for IBS treatment. However, long-term, large, randomized controlled studies are still lacking, and certainties and doubts regarding LFDs have grown, often in a disorderly and confused manner. Some potential LFD limitations and concerns have been raised, including nutritional adequacy, cost, and difficulty in teaching the diet and maintaining it. Most of these limitations can be solved with the involvement of a skilled nutritionist, who can clearly explain the different phases of the LFD and ensure nutritional adequacy and compliance. Further studies should focus on new methods of teaching and learning the LFD and on predictors of response. Moreover, particular interest should be focused on the possible use of LFD in gastrointestinal diseases other than functional disorders and, possibly, also in non-gastrointestinal diseases. The aim of the present review was to clarify the effective and appropriate indications and limitations of an LFD and to discuss its possible future uses.
| S-EPMC7019579 | biostudies-literature
Project description:Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×104 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×104 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×104 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×104 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findings provide a potentially new therapeutic approach to COPD and severe asthma.
| S-EPMC5613638 | biostudies-literature
Project description:Altered intestinal microbial composition promotes intestinal barrier dysfunction and triggers the initiation and recurrence of inflammatory bowel disease (IBD). Current treatments for IBD are focused on control of inflammation rather than on maintaining intestinal epithelial barrier function. Here, we show that the internalization of Gram-negative bacterial outer membrane vesicles (OMVs) in human intestinal epithelial cells promotes recruitment of caspase-5 and PIKfyve to early endosomal membranes via sorting nexin 10 (SNX10), resulting in LPS release from OMVs into the cytosol. Caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, which in turn promotes nuclear translocalization of Snail/Slug, downregulation of E-cadherin expression, and intestinal barrier dysfunction. SNX10 deletion or treatment with DC-SX029, a novel SNX10 inhibitor, rescues OMV-induced intestinal barrier dysfunction and ameliorates colitis in mice by blocking cytosolic LPS release, caspase-5 activation, and downstream signaling. Our results show that targeting SNX10 may be a new therapeutic approach for restoring intestinal epithelial barrier function and promising strategy for IBD treatment.
| S-SCDT-EMBOJ-2021-108080 | biostudies-other
Project description:Crohn's disease (CD) is a chronic, progressive, and destructive granulomatous inflammatory bowel disorder that can involve any part of the gastrointestinal tract. It has been presumed that different types of diet might improve gastrointestinal symptoms in CD patients. The aim of this review was to clarify the efficiency and indications of a low-"fermentable oligo-, di-, mono-saccharides and polyols" (FODMAP) diet (LFD) in CD and to further analyze the available data on other types of diets. PubMed, Cochrane Library, EMBASE and WILEY databases were screened for relevant publications regarding the effect of FODMAP diets on CD. Our search identified 12 articles analyzing the effect of an LFD in CD, 5 articles analyzing the effect of a Mediterranean diet (MD), 2 articles analyzing the effect of a vegetarian diet (VD), and 2 articles analyzing the effect of a low-lactose diet (LLD). The majority of the studies included in this review show the significant efficiency of the LFD in CD patients. We found significant evidence demonstrating that the LFD has a favorable impact on gastrointestinal symptoms in CD patients. Notwithstanding the evidence, it remains to be established if an LFD is more efficient than other types of diets in the short term and especially in the long term.
| S-EPMC7762196 | biostudies-literature