Mouse Model Of Experimental Colitis Research Articles

A high cholesterol diet aggravates experimental colitis through SREBP2-modulated endocytosis and degradation of occludin and Zo-1 proteins.

Disrupted cholesterol homeostasis plays a critical role in the development of multiple diseases, such as cardiovascular disease and cancer. However, the role of cholesterol in inflammatory bowel disease (IBD) remains unclear. In the present study, we investigated whether and how high levels of cholesterol in the diet affect experimental colitis in mice. A normal diet supplemented with 1.25% cholesterol (high cholesterol diet) caused more severe colitis and aggravated the disruption of intestinal tight junction structure, accompanied by higher colonic tissue total cholesterol (TC) levels in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Cholesterol aggravated DSS-induced intestinal epithelial barrier impairment and nuclear sterol regulatory element-binding protein 2 (nSREBP2) inhibition both in vivo and in vitro. In addition, nSREBP2 overexpression ameliorated cholesterol-induced intestinal epithelial barrier disruption in Caco2 cells. Interestingly, inhibition of SREBP2 disrupted intestinal epithelial barrier in the absence of cholesterol. Furthermore, SREBP2 regulated the protein expression of tight junction proteins (occludin/Zo-1) via modulating caveolin-1-mediated endocytosis and lysosomal degradation. Analysis of UK Biobank data indicated that, in fully adjusted models, higher serum TC concentrations were an independent protective factor for IBD incidence. The sterol regulatory element-binding factor 2 (SREBF2) gene rs2228313 (G/C) genetic variant was associated with the incidence of IBD and the CC genotype of SREBF2 rs2228313 was associated with higher serum TC levels and decreased the risk of IBD. In summary, a high cholesterol diet aggravates DSS-induced colitis in mice by down-regulating nSREBP2 expression, thereby promoting the endocytic degradation of tight junction proteins. In humans, SREBF2 gene single nucleotide polymorphism rs2228313 and serum TC levels are associated with IBD incidence.

Umbelliprenin attenuates comorbid behavioral disorders in acetic acid-induced colitis in mice: mechanistic insights into hippocampal oxidative stress and neuroinflammation.

Inflammatory bowel disease (IBD) is often accompanied by psychiatric disorders. Emerging evidence suggests that neuroinflammation and oxidative stress contribute to the psychiatric symptoms associated with IBD. Umbelliprenin (UMB) possesses several pharmacological properties, including anti-inflammatory and antioxidant effects. This study aimed to investigate the protective effects of UMB on comorbid behavioral disorders in a mouse model of experimental colitis, focusing on its potential anti-neuroinflammatory and antioxidant activities. After inducing colitis with acetic acid, male NMRI mice were treated for 7 consecutive days with UMB, saline, or dexamethasone. Behavioral assessments included the forced swimming test (FST), splash test, open field test (OFT), and elevated plus maze (EPM). Histopathological changes in the colon were evaluated, and total antioxidant capacity (TAC), malondialdehyde (MDA) levels, and the expression of inflammatory genes (TNFα, IL1β, and TLR4) were measured in the hippocampus. Colitis was associated with increased immobility time in the FST, reduced entries and time spent in the open arms of the EPM, decreased grooming behavior in the splash test, and reduced time spent in the central zone of the OFT. Colitis also resulted in a reduction in TAC and an increase in MDA levels and inflammatory gene expression in the hippocampus. UMB treatment mitigated the behavioral disorders associated with colitis, reduced neuroinflammation and oxidative stress in the hippocampus, and alleviated histopathological alterations in the colon. In conclusion, UMB may reduce behavioral disorders induced by colitis by decreasing oxidative stress and neuroinflammation in the hippocampus.

Establishment and Evaluation of a Mouse Model of Experimental Ulcerative Colitis Induced by the Gavage Administration of Dextran Sulfate Sodium.

Given the critical role of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse models in the appraisal of associated therapeutic drugs, the optimization of the administration method and dosages is of paramount importance. Therefore, UC was induced in mice through the gavage administration of a DSS solution instead of free drinking water. The effects of varying daily dosages (2, 4, 6, and 8 g/kg) and frequencies (once or twice) of administration on the body weight and survival rate of the model mice were evaluated. Concurrently, the inflammatory indicators and tissue sections of the model mice were thoroughly evaluated. The results revealed that when the daily dosage reached 8 g/kg, the dosage exhibited a high level of toxicity, resulting in a high mortality rate among the mice. The DSS administration of 6 g/kg*2 not only elicited conspicuous symptoms, significant weight loss, substantial shortening of the colon, and significant changes in various inflammatory indicators, such as myeloperoxidase (MPO), nitric oxide (NO), reactive oxygen species (ROS), and glutathione (GSH), but it also maintained a high survival rate in the UC mice. The findings from this experiment lay a solid experimental foundation for future research on drugs intended for the treatment of UC.

Non-canonical NF-κB signaling limits the tolerogenic β-catenin-Raldh2 axis in gut dendritic cells to exacerbate intestinal pathologies

Dendritic cell (DC) dysfunction is known to exacerbate intestinal pathologies, but the mechanisms compromising DC-mediated immune regulation in this context remain unclear. Here, we show that intestinal dendritic cells from a mouse model of experimental colitis exhibit significant levels of noncanonical NF-κB signaling, which activates the RelB:p52 heterodimer. Genetic inactivation of this pathway in DCs alleviates intestinal pathologies in mice suffering from colitis. Deficiency of RelB:p52 diminishes transcription of Axin1, a critical component of the β-catenin destruction complex, reinforcing β-catenin-dependent expression of Raldh2, which imparts tolerogenic DC attributes by promoting retinoic acid synthesis. DC-specific impairment of noncanonical NF-κB signaling leads to increased colonic numbers of Tregs and IgA+ B cells, which promote luminal IgA production and foster eubiosis. Experimentally introduced β-catenin haploinsufficiency in DCs with deficient noncanonical NF-κB signaling moderates Raldh2 activity, reinstating colitogenic sensitivity in mice. Finally, inflammatory bowel-disease patients also display a deleterious noncanonical NF-κB signaling signature in intestinal DCs. In sum, we establish how noncanonical NF-κB signaling in dendritic cells can subvert retinoic acid synthesis to fuel intestinal inflammation.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Inhibition of HMGB1 improves experimental mice colitis by mediating NETs and macrophage polarization

ObjectiveInflammatory bowel disease (IBD) is listed by the World Health Organization as one of the modern intractable diseases. High mobility histone box 1 (HMGB1), originally described as a non-histone nucleoprotein involved in transcriptional regulation, was later identified as a pro-inflammatory cytokine that may contribute to the pathogenesis of inflammatory diseases such as IBD. Neutrophil extracellular traps (NETs) play an important role in the pathophysiology of IBD The aim of this study was to investigate the role of HMGB1 in experimental colitis mice and its potential mechanisms of action. MethodsWe first constructed the experimental colitis mouse model. Intervention of mice by rhHMGB1 supplementation or HMGB1 inhibition. The pathological morphology of the colon was observed using HE staining. Apoptosis of colonic tissue intestinal epithelial cells was evaluated using Tunel assay. The expression of HMGB1, ZO-1 and occludin in colon tissue was detected by immunohistochemistry, ELISA and western-blot. We also assessed the effects of HMGB1 on colonic injury, NETs content, macrophage polarization and inflammatory cells in mice. The regulatory effect of HMGB1 inhibition on NETs was assessed by combining DNase I. ResultsInhibition of HMGB1 significantly reduced the inflammatory model in experimental colitis mice, as evidenced by reduced body weight, increased colonic length, reduced DAI scores and apoptosis, reduced inflammatory response, and improved colonic histopathological morphology and intestinal mucosal barrier function. Meanwhile, inhibition of HMGB1 was able to reduce the expression of CD86, citH3 and MPO and increase the expression of CD206 in the colonic tissue of mice. In addition, DNase I intervention was also able to improve colonic inflammation in mice. And the best effect was observed when DNase I and inhibition of HMGB1 were intervened together. ConclusionInhibition of HMGB1 ameliorates IBD by mediating NETs and macrophage polarization.

The effect of peptidyl arginine deiminase 4 (PAD4) inhibition on neutrophil extracellular traps (NETs) formation in DSS-induced mouse model of experimental colitis

The effect of peptidyl arginine deiminase 4 (PAD4) inhibition on neutrophil extracellular traps (NETs) formation in DSS-induced mouse model of experimental colitis

Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis

The link between the gut and the brain in Parkinson’s disease (PD) pathogenesis is currently a subject of intense research. Indeed, gastrointestinal dysfunction is known as an early symptom in PD and inflammatory bowel disease (IBD) has recently been recognised as a risk factor for PD. The leucine-rich repeat kinase 2 (LRRK2) is a PD- and IBD-related protein with highest expression in immune cells. In this study, we provide evidence for a central role of LRRK2 in gut inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimental colitis based on chronic dextran sulphate sodium (DSS) administration. Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental colitis model. Furthermore, partial pharmacological inhibition of LRRK2 kinase activity also reduced the colitis phenotype and inflammation. Moreover, chronic experimental colitis also induced neuroinflammation and infiltration of peripheral immune cells into the brain of G2019S knock-in mice. Finally, combination of experimental colitis with overexpression of α-synuclein in the substantia nigra aggravated motor deficits and dopaminergic neurodegeneration in G2019S knock-in mice. Taken together, our results link LRRK2 with the immune response in colitis and provide evidence that gut inflammation can impact brain homeostasis and contribute to neurodegeneration in PD.

HIF-1α-Overexpressing Mesenchymal Stem Cells Attenuate Colitis by Regulating M1-like Macrophages Polarization toward M2-like Macrophages

A modified mesenchymal stem cell (MSC) transplantation is a highly effective and precise treatment for inflammatory bowel disease (IBD), with a significant curative effect. Thus, we aim to examine the efficacy of hypoxia-inducible factor (HIF)-1α-overexpressing MSC (HIF-MSC) transplantation in experimental colitis and investigate the immunity regulation mechanisms of HIF-MSC through macrophages. A chronic experimental colitis mouse model was established using 2,4,6-trinitrobenzene sulfonic acid. HIF-MSC transplantation significantly attenuated colitis in weight loss rate, disease activity index (DAI), colon length, and pathology score and effectively rebuilt the local and systemic immune balance. Macrophage depletion significantly impaired the benefits of HIF-MSCs on mice with colitis. Immunofluorescence analysis revealed that HIF-MSCs significantly decreased the number of M1-like macrophages and increased the number of M2-like macrophages in colon tissues. In vitro, co-culturing with HIF-MSCs significantly decreased the expression of pro-inflammatory factors, C-C chemokine receptor 7 (CCR-7), and inducible nitric oxide synthase (INOS) and increased the expression of anti-inflammatory factors and arginase I (Arg-1) in induced M1-like macrophages. Flow cytometry revealed that co-culturing with HIF-MSCs led to a decrease in the proportions of M1-like macrophages and an increase in that of M2-like macrophages. HIF-MSCs treatment notably upregulated the expression of downstream molecular targets of phosphatidylinositol 3-kinase-γ (PI3K-γ), including HIF-1α and p-AKT/AKT in the colon tissue. A selected PI3K-γ inhibitor, IPI549, attenuated these effects, as well as the effect on M2-like macrophage polarization and inflammatory cytokines in colitis mice. In vitro, HIF-MSCs notably upregulated the expression of C/EBPβ and AKT1/AKT2, and PI3K-γ inhibition blocked this effect. Modified MSCs stably overexpressed HIF-1α, which effectively regulated macrophage polarization through PI3K-γ. HIF-MSC transplantation may be a potentially effective precision therapy for IBD.

Anthocyanin extract from black rice attenuates chronic inflammation in DSS-induced colitis mouse model by modulating the gut microbiota

AbstractThere is substantial evidence for the probiotic activity of anthocyanins, but the relationship between anthocyanins involved in the regulation of microbiota and intestinal inflammation has not been fully elucidated. The aim of this study was to investigate the regulatory effects of black rice anthocyanin extract (BRAE) on intestinal microbiota imbalance in mice with dextran sulfate sodium (DSS)-induced chronic colitis. DSS was added into drinking water to induce a mouse model of chronic experimental colitis, and BRAE was given by gavage (200 mg/kg/day) for 4 weeks. Body weight, fecal viscosity, and hematochezia were monitored during administration. After mice were sacrificed, the serum concentrations of TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay, and the composition of intestinal flora was analyzed by 16S rDNA sequencing. The results showed that BRAE significantly suppressed DSS-induced colonic inflammatory phenotypes and maintained colon length in mice. In addition, BRAE reduced intestinal permeability and improved intestinal barrier dysfunction in mice with colitis. Gut microbiota analysis showed that BRAE significantly improved the imbalance of intestinal microecological diversity caused by DSS, inhibited the increase in the relative abundance of inflammatory bacteria, and promoted the abundance of anti-inflammatory probiotics includingAkkermansiaspp.

Aloe-derived nanovesicles attenuate inflammation and enhance tight junction proteins for acute colitis treatment.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the digestive tract that causes pain and weight loss and also increases the risk of colon cancer. Inspired by the benefits of plant-derived nanovesicles and aloe, we herein report aloe-derived nanovesicles, including aloe vera-derived nanovesicles (VNVs), aloe arborescens-derived nanovesicles (ANVs), and aloe saponaria-derived nanovesicles (SNVs) and evaluate their therapeutic potential and molecular mechanisms in a dextran sulfate sodium (DSS)-induced acute experimental colitis mouse model. Aloe-derived nanovesicles not only facilitate markedly reduced DSS-induced acute colonic inflammation, but also enable the restoration of tight junction (TJ) and adherent junction (AJ) proteins to prevent gut permeability in DSS-induced acute colonic injury. These therapeutic effects are ascribed to the anti-inflammatory and anti-oxidant effects of aloe-derived nanovesicles. Therefore, aloe-derived nanovesicles are a safe treatment option for IBD.

Stronger gut microbiome modulatory effects by postbiotics than probiotics in a mouse colitis model

Probiotics are increasingly used as adjunctive therapy to manage gastrointestinal diseases, such as ulcerative colitis. However, probiotic use has posed some safety concerns. Thus, postbiotics are proposed as alternatives to probiotics in clinical applications. However, no study has directly compared the clinical benefits of probiotics and postbiotics. This study compared the beneficial effect of postbiotics and probiotics derived from the strain, Bifidobacterium adolescentis B8589, in a dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Four groups of mice (n = 7 per group) were included in this work: Control (received water plus saline), DSS (received DSS without postbiotic/probiotic), Postbiotic (received DSS plus postbiotic), and Probiotic (received DSS plus probiotic). Our results showed that intragastric administration of both probiotic and postbiotic ameliorated colitis, reflected by decreased histology scores in Postbiotic and Probiotic groups compared with DSS group (P < 0.05). The fecal microbiota alpha diversity was not significantly affected by DSS-, postbiotic, or probiotic treatment. However, the postbiotic treatment showed stronger effects on modulating the fecal microbiota beta diversity, composition, and metagenomic potential than the probiotic treatment. Overall, our findings suggested that probiotics and postbiotics had similar ability to improve disease phenotype but had distinct ability to regulate the gut microbiota and metabolic pathways in the context of ulcerative colitis. In view of the smaller safety concern of postbiotics compared with probiotics and its stronger modulatory effect on the host gut microbiota, we propose that postbiotics are to be considered for use as next-generation biotherapeutics in managing ulcerative colitis or even other diseases.

Expression of the methylcytosine dioxygenase ten-eleven translocation-2 and connexin 43 in inflammatory bowel disease and colorectal cancer.

Inflammatory bowel disease (IBD) constitutes a substantial risk factor for colorectal cancer. Connexin 43 (Cx43) is a protein that forms gap junction (GJ) complexes involved in intercellular communication, and its expression is altered under pathological conditions, such as IBD and cancer. Recent studies have implicated epigenetic processes modulating DNA methylation in the pathogenesis of diverse inflammatory and malignant diseases. The ten-eleven translocation-2 (TET-2) enzyme catalyzes the demethylation, hence, regulating the activity of various cancer-promoting and tumor-suppressor genes. To investigate Cx43 and TET-2 expression levels and presence of 5-hydroxymethylcytosine (5-hmC) marks under inflammatory conditions both in vitro and in vivo. TET-2 expression was evaluated in parental HT-29 cells and in HT-29 cells expressing low or high levels of Cx43, a putative tumor-suppressor gene whose expression varies in IBD and colorectal cancer, and which has been implicated in the inflammatory process and in tumor onset. The dextran sulfate sodium-induced colitis model was reproduced in BALB/c mice to evaluate the expression of TET-2 and Cx43 under inflammatory conditions in vivo. In addition, archived colon tissue sections from normal, IBD (ulcerative colitis), and sporadic colon adenocarcinoma patients were obtained and evaluated for the expression of TET-2 and Cx43. Expression levels were reported at the transcriptional level by quantitative real-time polymerase chain reaction, and at the translational level by Western blotting and immunofluorescence. Under inflammatory conditions, Cx43 and TET-2 expression levels increased compared to non-inflammatory conditions. TET-2 upregulation was more pronounced in Cx43-deficient cells. Moreover, colon tissue sections from normal, ulcerative colitis, and sporadic colon adenocarcinoma patients corroborated that Cx43 expression increased in IBD and decreased in adenocarcinoma, compared to tissues from non-IBD subjects. However, TET-2 expression and 5-hmC mark levels decreased in samples from patients with ulcerative colitis or cancer. Cx43 and TET-2 expression levels were also investigated in an experimental colitis mouse model. Interestingly, mice exposed to carbenoxolone (CBX), a GJ inhibitor, had upregulated TET-2 levels. Collectively, these results show that TET-2 levels and activity increased under inflammatory conditions, in cells downregulating gap junctional protein Cx43, and in colon tissues from mice exposed to CBX. These results suggest that TET-2 expression levels, as well as Cx43 expression levels, are modulated in models of intestinal inflammation. We hypothesize that TET-2 may demethylate genes involved in inflammation and tumorigenesis, such as Cx43, potentially contributing to intestinal inflammation and associated carcinogenesis.

Highly Sensitive, Flow Cytometry-Based Measurement of Intestinal Permeability in Models of Experimental Colitis

Increased intestinal permeability is seen in a variety of inflammatory conditions such as enteric infections and inflammatory bowel disease. Because barrier function can provide a key biomarker of disease severity, it often is assayed in animal models. A common methodology involves gavaging mice with fluorescein isothiocyanate-conjugated dextran (FITC-D), followed by cardiac puncture to assay plasma fluorescence on a spectrophotometer. Although the FITC-D method is relatively simple, its sensitivity is limited and enables only a single measurement because the test requires killing the subject. Herein, we describe a novel flow cytometry-based method of intestinal permeability measurement based on detection of orally gavaged ovalbumin (OVA) that leaks out of the gut. Our approach uses minute blood volumes collected from the tail vein, permitting repeated testing of the same subject at multiple time points. By comparing this assay against the gold standard FITC-D method, we show the expanded utility of our OVA assay in measuring intestinal permeability. We directly compared our OVA assay against the FITC-D assay by co-administering both probes orally to the same animals and subsequently using their respective methodologies to measure intestinal permeability by detecting probe levels in the plasma. Permeability was assessed in mice genetically deficient in intestinal mucus production or glycosylation. In addition, wild-type mice undergoing dextran sodium sulfate-induced colitis or infected by the enteric bacterial pathogen Citrobacter rodentium also were tested. The OVA assay showed very high efficacy in all animal models of intestinal barrier dysfunction tested. Besides identifying intestinal barrier dysfunction in mice with impaired mucin glycosylation, the assay also allowed for repeated tracking of intestinal permeability within the same animal over time, providing data that cannot be easily acquired with other currently applied methods. The OVA assay is a highly sensitive and effective method of measuring intestinal permeability in mouse models of barrier dysfunction and experimental colitis.

Gut-Brain Axis: Insights from Hippocampal Neurogenesis and Brain Tumor Development in a Mouse Model of Experimental Colitis Induced by Dextran Sodium Sulfate.

Chronic inflammatory bowel disorders (IBD) are idiopathic diseases associated with altered intestinal permeability, which in turn causes an exaggerated immune response to enteric antigens in a genetically susceptible host. A rise in psych cognitive disorders, such as anxiety and depression, has been observed in IBD patients. We here report investigations on a model of chemically induced experimental colitis by oral administration of sodium dextran sulfate (DSS) in C57BL/6 mice. We investigate, in vivo, the crosstalk between the intestine and the brain, evaluating the consequences of intestinal inflammation on neuroinflammation and hippocampal adult neurogenesis. By using different DSS administration strategies, we are able to induce acute or chronic colitis, simulating clinical characteristics observed in IBD patients. Body weight loss, colon shortening, alterations of the intestinal mucosa and fecal metabolic changes in amino acids-, lipid- and thiamine-related pathways are observed in colitis. The activation of inflammatory processes in the colon is confirmed by macrophage infiltration and increased expression of the proinflammatory cytokine and oxidative stress marker (Il-6 and iNOS). Interestingly, in the hippocampus of acutely DSS-treated mice, we report the upregulation of inflammatory-related genes (Il-6, Il-1β, S-100, Tgf-β and Smad-3), together with microgliosis. Chronic DSS treatment also resulted in neuroinflammation in the hippocampus, indicated by astrocyte activation. Evaluation of stage-specific neurogenesis markers reveals deficits in the dentate gyrus after acute and chronic DSS treatments, indicative of defective adult hippocampal neurogenesis. Finally, based on a possible causal relationship between gut-related inflammation and brain cancer, we investigate the impact of DSS-induced colitis on oncogenesis, using the Ptch1+/−/C57BL/6 mice, a well-established medulloblastoma (MB) mouse model, finding no differences in MB development between untreated and DSS-treated mice. In conclusion, in our experimental model, the intestinal inflammation associated with acute and chronic colitis markedly influences brain homeostasis, impairing hippocampal neurogenesis but not MB oncogenesis.

Pseudoamaolides A-O, anti-inflammatory triterpene spiroketal lactones from seeds of Pseudolarix amabilis

Fifteen new triterpenoids (1–15), along with twenty known ones (16–35), were isolated from Pseudolarix amabilis. The triterpenoid structures include multiple skeleton types, such as 2,3-seco-cycloartane, 3,4-seco-cycloartane, 3,4:9,10-diseco-cycloartane, and 3,4:8,9:9,10-triseco-cycloartane, as elucidated by extensive spectroscopy (1D NMR, 2D NMR, HRESIMS, and IR) and single-crystal X-ray diffraction. The anti-inflammatory activities of compounds 1–35 were evaluated. Compounds 3, 11, 16, 24, 25, and 26 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-Luc cells with IC50 values of 0.12, 0.10, 0.30, 0.09, 0.49, and 0.35 μM, respectively. In addition, compound 16 showed anti-inflammatory activity against xylene-induced ear swelling in vivo with an inhibition rate of 44.7 % (30 mg/kg). Compound 16 significantly improved the disease activity index (DAI) of ulcerative colitis at a dose of 400 mg/kg in a dextran sodium sulfate (DSS)-induced mouse model of experimental ulcerative colitis (P < 0.01).

Visualization of Inflammation in Experimental Colitis by Magnetic Resonance Imaging Using Very Small Superparamagnetic Iron Oxide Particles.

Inflammatory bowel diseases (IBD) comprise mainly ulcerative colitis (UC) and Crohn´s disease (CD). Both forms present with a chronic inflammation of the (gastro) intestinal tract, which induces excessive changes in the composition of the associated extracellular matrix (ECM). In UC, the inflammation is limited to the colon, whereas it can occur throughout the entire gastrointestinal tract in CD. Tools for early diagnosis of IBD are still very limited and highly invasive and measures for standardized evaluation of structural changes are scarce. To investigate an efficient non-invasive way of diagnosing intestinal inflammation and early changes of the ECM, very small superparamagnetic iron oxide nanoparticles (VSOPs) in magnetic resonance imaging (MRI) were applied in two mouse models of experimental colitis: the dextran sulfate sodium (DSS)-induced colitis and the transfer model of colitis. For further validation of ECM changes and inflammation, tissue sections were analyzed by immunohistochemistry. For in depth ex-vivo investigation of VSOPs localization within the tissue, Europium-doped VSOPs served to visualize the contrast agent by imaging mass cytometry (IMC). VSOPs accumulation in the inflamed colon wall of DSS-induced colitis mice was visualized in T2* weighted MRI scans. Components of the ECM, especially the hyaluronic acid content, were found to influence VSOPs binding. Using IMC, co-localization of VSOPs with macrophages and endothelial cells in colon tissue was shown. In contrast to the DSS model, colonic inflammation could not be visualized with VSOP-enhanced MRI in transfer colitis. VSOPs present a potential contrast agent for contrast-enhanced MRI to detect intestinal inflammation in mice at an early stage and in a less invasive manner depending on hyaluronic acid content.

Ophiopogonin D Inhibiting Epithelial NF-κB Signaling Pathway Protects Against Experimental Colitis in Mice.

The sustained activation of the nuclear factor κB (NF-κB) signaling pathway has been observed in human inflammatory bowel disease (IBD). Ophiopogonin D (OP-D) is a small molecular compound isolated from Ophiopogon japonicus, a widely used herbal remedy. In this study, dextran sodium sulfate was used to make a mouse model of experimental colitis and verify the effect of OP-D on the mouse model of experimental colitis. Small molecule-protein molecular docking approaches were also used to discover the mechanisms underlying the OP-D-induced regulation of colitis. In colitis, the OP-D can inhibit the apoptosis of intestinal mucosa cells, restore the intestinal barrier, and alleviate inflammation. The molecular docking simulations showed that OP-D had a high affinity with the REL-homology domain of NF-κB-p65 that affected its translocation to the nucleus. In a cell study, the effects of OP-D on inflammation and barrier dysfunction were significantly decreased by a small interfering RNA targeting NF-κB-p65. Further, the LPS-induced increase in NF-κB-p65 in the nucleus was also significantly inhibited by OP-D. OP-D alleviated experimental colitis by inhibiting NF-κB. New insights into the pathogenesis and treatment options of colitis are provided through this study.

Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists

ObjectiveDysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological...

Oyster (Crassostrea gigas) Extract Attenuates Dextran Sulfate Sodium-Induced Acute Experimental Colitis by Improving Gut Microbiota and Short-Chain Fatty Acids Compositions in Mice

Drugs for inflammatory bowel diseases can be associated with serious side effects, and the development of alternative candidate resources derived from natural products has attracted considerable attention. Oyster extract (OE) derived from Crassostrea gigas contains glycogen, taurine, and amino acids, and has been assigned diverse health-promoting properties. This study investigated the anti-colitis effect of OE intake on fecal microbiota and its metabolites of acute experimental colitis mouse model induced by dextran sulfate sodium (DSS). C57BL/6J mice (male) were divided into three groups: (1) American Institute of Nutrition (AIN) 93G diet + DSS-untreated, (2) AIN93G diet + DSS-treated, and (3) 5% OE diet + DSS-treated. Mice were fed each diet for 21 days, and then administered 2.5% DSS solution to induce acute colitis for 7 days. In DSS-induced colitis mice, OE decreased body weight loss and increased disease activity index during the DSS-induced period. In addition, OE tended to decrease the colon length shortening and the relative spleen weight and alleviated colonic tissue damage. Moreover, OE improved fecal short-chain fatty acids compositions and altered the structure of fecal microbiota. These results provide insight into the health-promoting property of OE in alleviating DSS-induced acute colitis, providing a basis for the development and use of functional foods.