Effects In Experimental Colitis Research Articles

Effectiveness of Propolis on Experimental Colitis Model In Rats

Aim: This study investigated the therapeutic potential of propolis in an experimental colitis model induced by acetic acid in female Wistar albino rats. Materials and Methods: Thirty rats were divided into five groups: a control group and four experimental groups. Colitis was induced in the second, third, and fifth groups by rectal administration of 1 ml of 4% acetic acid. The third group received rectal propolis solution (50 mg/ml), while the fourth group was given only rectal propolis solution. The fifth group received 1 ml of olive oil rectally after the onset of colitis. Stool consistency and weight loss were monitored, and colon tissue samples were collected for microscopic and macroscopic evaluation. The levels of MDA, MPO, and caspase-3 in tissue, as well as TNF-α and IL-10 levels in blood samples, were examined. Results: The group administered propolis showed a significant decrease in microscopic and macroscopic scores compared to the other experimental groups. The levels of MDA, MPO, and caspase-3 in the tissue, as well as TNF-α and IL-10 levels in blood samples, were significantly decreased in the propolis group compared to the other experimental groups. Weight loss and stool consistency also showed improvement in the propolis group compared to the other experimental groups. Discussion: Propolis may have therapeutic effects in experimental colitis induced by acetic acid. The decrease in oxidative damage and inflammation seen in the propolis group indicates that it may be a useful therapeutic agent for colitis treatment.

Intestinal and hepatic benefits of BBR-EVO on DSS-induced experimental colitis in mice.

Ulcerative colitis (UC), characterized by disrupted intestinal barrier integrity and chronic inflammation, was modeled in mice via dextran sulfate sodium (DSS) induction. This study explored the therapeutic potential of berberine-evodiamine (BBR-EVO), bioactive components of the traditional Chinese medicine Yulian decoction, in DSS colitis. BBR-EVO intervention ameliorated weight loss, diarrhea, colonic shortening, and histopathological damage in colitic mice. The substance increased antioxidant activity while reducing high levels of pro-inflammatory cytokines in the colon, including as TNF-α, IL-1β, and IL-6. BBR-EVO inhibited the DSS-induced decrease in the tight junction proteins ZO-1 and occludin, according to immunohistochemistry. 16S rRNA sequencing demonstrated BBR-EVO partially attenuated DSS-elicited intestinal dysbiosis, reducing opportunistic pathogens and restoring diminished beneficial taxa. Critically, BBR-EVO alleviated secondary hepatic injury in colitic mice, mitigating immune cell infiltration, oxidative stress, cytokine production, and ultrastructural damage, likely by beneficially modulating gut-liver crosstalk. This study reveals BBR-EVO, derived from a traditional Chinese medicine, confers multi-target protective effects in experimental colitis and associated hepatic pathology, warranting further evaluation as a potential therapy for inflammatory bowel diseases like UC. The mechanisms may involve simultaneous augmentation of intestinal barrier integrity, inhibition of inflammation, microbiota regulation, and gut-liver axis optimization.

Melatonin pretreatment improves endometrial regenerative cell-mediated therapeutic effects in experimental colitis

BackgroundEndometrial regenerative cells (ERCs) have been proven to be an effective strategy for attenuating experimental colitis, but the complex in vivo microenvironment such as oxidative stress may largely limit and weaken ERC efficacy. Melatonin (MT) works as an anti-oxidative agent in a variety of preclinical diseases, and has been identified to promote mesenchymal stem cell-mediated therapeutic effects in different diseases. However, the ability of MT to enhance ERC-mediated effects in colitis is currently poorly understood. MethodsMenstrual blood was collected from healthy female volunteers to obtain ERCs and identified. In vitro, H2O2-induced oxidative stress was introduced to test if MT could prevent ERCs from damage through detection of intracellular reactive oxidative species (ROS) and apoptosis assay. In vivo, dextran sodium sulfate (DSS)-induced acute colitis was treated by ERCs and MT-primed ERCs, therapeutic effects were assayed by the disease activity index (DAI), histological features, and macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were also measured. ResultsIn vitro, ERCs that underwent MT-precondition were found to possess more anti-oxidative potency in comparison to naïve ERCs, which were characterized by decreased apoptosis rate and intracellular ROS under H2O2 stimulation. In vivo, MT pretreatment can significantly enhance the therapeutic effects of ERCs in the attenuation of experimental colitis, including decreased DAI index and damage score. In addition, MT pretreatment was found to promote ERC-mediated inhibition of Th1, Th17, and M1 macrophage and pro-inflammatory cytokines, increase of Treg, and immunomodulation of cytokines in the spleen and colon. ConclusionsMT pretreatment facilitates the promotion of cell viability under oxidative stress in vitro, while also enhancing ERC-mediated therapeutic effects in experimental colitis.

High-fat diet induces anti-inflammatory effect in experimental colitis

High-fat diet induces anti-inflammatory effect in experimental colitis

Protective Effects of Oxyberberine in 5-Fluorouracil-Induced Intestinal Mucositis in the Mice Model.

Berberine (BBR), a major active constituent of Rhizoma coptidis, was reported to exert beneficial effects on intestinal mucositis (IM) induced by 5-fluorouracil (5-FU). However, the bioavailability of BBR is extremely low, and its metabolites were perceived to contribute to its prominent pharmacological activities. Oxyberberine (OBB) is a gut metabolite of BBR, which has been reported to have a superior anti-inflammatory effect in experimental colitis. However, its anti-inflammatory effects against 5-FU-induced IM mice have not yet been investigated. Hence, the purpose of this study was to reveal the protective effects of OBB on IM induced by 5-FU and investigate its potential underlying mechanism. The IM mice model was induced by receiving 5-FU (60 mg/kg, i.p.) for five days. Meanwhile, BBR (50 mg/kg) and OBB (12.5, 25, and 50 mg/kg) were given prior to 30 min intraperitoneal injection of 5-FU for seven days. Results indicated that OBB ameliorated body weight loss, anorexia, diarrhea, and histopathological damage in 5-FU-induced IM mice. After OBB administration, the amounts of MDA, SOD, and GSH altered by IM were remarkably restored. OBB was also observed to dramatically decrease the levels of TNF-α, IL-8, IL-6, COX-2, and iNOS and promote the release of IL-10. Besides, OBB distinctly upregulated the mRNA expressions of PCNA, ZO-1, occludin, and mucin-1, which could improve intestinal homeostasis in IM mice. OBB also blocked the activation of the upstream TLR4/MyD88 signaling pathway, and then it inhibited the phosphorylation of the NF-κB and MAPK pathways. Importantly, compared with BBR, OBB displayed a superior therapeutic effect to BBR in alleviating 5-FU-induced IM mice. These results indicated that OBB has considerable potential to become a novel candidate drug against IM.

Gelidium spinosum red algae ameliorates oxidative /nitrosative stress and inflammation in DSS -induced ulcerative colitis in mice

Ulcerative colitis is characterized by oxidative / nitrosative stress and leukocyte infiltration which are shown to be important factors in the etiopathogenesis of colitis.The aim of this study was to evaluate the protective mechanism of the polysaccharide (PLS) fraction extracted from the seaweed Gelidium spinosum (PEGS) in Dextran Sulfate sodium; DSS-induced ulcerative colitis in male Swiss albino mice.The in vivo study was carried out with mice (pretreated with PEGS/mesalazine orally at 60 mg/75 Kg; 7 days; then 2.5 % (DSS); 7 days). Clinical symptoms (disease activity index; DAI), oxidative, nitrosative stress and inflammatory parameters were evaluated.The results revealed that PEGS lowered the symptoms of ulcerative colitis induced by DSS by reducing malondialdehyde, nitrosative and pro-inflammatory biomarkers (NO, S-nitrosothiol, peroxynitrite, TNF-α and IL-6). These significant protective effects of PEGS were associated with a remarkable decrease of the level of myeloperoxidase in a significant way.PEGS effectively increased the superoxide dismutase and catalase activities, and restored the glutathione metabolizing enzyme (glutathione peroxidase, glutathione S-transferase) in the colon tissue. In conclusion, these findings suggest that PEGS exerts beneficial effects in experimental colitis, and therefore we propose that it could be a potential drug in treating ulcerative colitis.

Effects of experimental colitis in rats on incretin levels, inflammatory markers, and enteric neuronal function.

IntroductionThe aim of the study was to assess the effects of chronic inflammation on incretin levels, inflammatory markers, and enteric neuronal function measured in isolated preparations of smooth muscle of rat.Material and methodsWe induced experimental colitis using 2,4-dinitrobenzenesulfonic acid (DNBS) in 17 Albino male Sprague-Dawley rats, while 16 rats were used as a control. They were housed in temperature-controlled rooms in a 12-h light/dark cycle at 22–24°C and 50 to 60% humidity. We evaluated in both inflamed and healthy rats: fasting plasma glucose concentration, fasting plasma insulin, myeloperoxidase, active glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and GLP-2 levels, adiponectin, and C-reactive protein (CRP). We also evaluated colonic longitudinal smooth muscle contractile activity.ResultsIntrarectal administration of DNBS reduced body weight gain in inflamed rats. We recorded higher levels of fasting plasma glucose, and insulin in inflamed rats. We observed higher levels of myeloperoxidase and CRP, and lower levels of ADN in inflamed rats. We recorded higher levels of GIP, GLP-1, and GLP-2 in inflamed rats compared to the healthy ones. Regarding functional response of colon intestinal smooth muscle after electrical stimulation, we recorded a lower functional response of colon intestinal smooth muscle after electrical stimulation in inflamed rats.ConclusionsWe can conclude that chronic inflammation leads to an increase of incretin levels and to a decrease of functional response of colon intestinal smooth muscle after electrical stimulation.

Hyaluronic Acid Increases Anti-Inflammatory Efficacy of Rectal 5-Amino Salicylic Acid Administration in a Murine Colitis Model.

5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.

Epithelial deletion of the glucocorticoid receptor (Nr3c1) protects the mouse intestine against experimental inflammation.

Glucocorticoids are the first line treatment for the flare-ups of inflammatory bowel disease, but they have significant limitations. The objective of this study is to investigate whether glucocorticoid epithelial actions contribute to such limitations. Intestinal epithelium glucocorticoid receptor knockout mice (Nr3c1ΔIEC ) received dextran sulfate sodium (DSS) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods, and corticoid production was measured in colonic explants. Some mice were administered budesonide. After 7 days of DSS Nr3c1ΔIEC , mice exhibited 23.1% lower disease activity index (DAI) and 37% lower diarrheal score than WT mice, with decreased weight loss in days 5-7 of colitis, attenuated tissue damage, reduced colonic expression of S100A9 and STAT3 phosphorylation, and a better overall state. Ki67 immunoreactivity was increased at the crypt base, indicating enhanced epithelial proliferation. Mice administered budesonide (6 μg·day-1 PO) showed modest antiinflammatory effects but increased weight loss, which was prevented in knockout mice. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely, knockout mice presented a worse status compared to the control group at 1 day post DSS. In a separate experiment, colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by DSS, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.

Ameliorative Effect of Probiotic Strains, Lactobacillus Acidophilus and Lactobacillus Bulgaricus against Acetic Acid-Induced Inflammation in the Mouse Colon

Probiotic bacteria with anti-inflammatory properties have the potential to be of therapeutic benefit in inflammatory bowel diseases. The present study was designed to evaluate the effect of feeding low-fat probiotic yogurt containing <i>L. acidophilus</i> and <i>L. bulgaricus</i> on acetic acid-induced inflammation in mouse colon. Inflammatory model that mimics various features of IBDs was induced by a single application of 100µl of 4.5% acetic acid in Swiss Albino mice. Mice were pretreated orally by 200µl yogurt containing both <i>L. acidophilus</i> and <i>L. bulgaricus</i> for 3 days before induction of inflammation and 200µl yogurt was given orally for a period of 7 days after acetic-acid induction. The body weight, food and water intakes, serum biomarkers, macroscopic and histopathological studies of colon tissues were performed to evaluate the anti-inflammatory effect. Combined administration of both strains prevented the damages of villous and crypts in colon epithelial cells and thus provides unique mucosal protective effects in experimental colitis. In conclusion, feeding low-fat probiotic yogurt containing <i>L. acidophilus</i> and <i>L. bulgaricus</i> prevented or ameliorated the inflammatory conditions that can be beneficial to prevent or lower risks of IBDs and its complications.

Protective role of berberine on ulcerative colitis through modulating enteric glial cells–intestinal epithelial cells–immune cells interactions

Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease. The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract. Berberine, an isoquinoline alkaloid, is known as its anti-inflammatory and therapeutic effects in experimental colitis. However, little research focused on its regulatory function on ENS. Therefore, we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro–immune interactions. Functional defects of enteric glial cells (EGCs), with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression, were observed in DSS-induced murine UC. Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC, closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation. In vitro, berberine showed direct protective effects on monoculture of EGCs, bone marrow-derived dendritic cells (BMDCs), T cells, and intestinal epithelial cells (IECs) in the simulated inflammatory conditions. Furthermore, berberine could modulate gut EGCs–IECs–immune cell interactions in the co-culture systems. In summary, our study indicated the EGCs–IECs–immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.

Effect of acute Atorvastatin treatment in an experimental model of colitis

Acute atorvastatin treatment in an experimental model of colitis was studied using the acetic acid induction modality for colitis in rats. This study was aimed to evaluate possible therapeutic effects of atorvastatin against acetic acid-induced colitis in a rat model and to find out the correlation between severity index with oxidative stress parameters and inflammatory markers. Experimental colitis was induced in rats by rectal administration of 4% acetic acid (vol/vol). Rats with colitis were received either atorvastatin 10mg/kg or sulfasalazine 100mg/kg orally for 7 days. Macroscopical and microscopical assessment and the measurement of the colonic cytokines (IL-6 and TNF-α), oxidative stress markers; myeloperoxidase (MPO) and malondialdehyde (MDA), and adhesion molecules (E-Selectin and ICAM-1). Both the macroscopical lesion area and histological colonic injury induced by acetic acid were reduced significantly by both atorvastatin and sulfasalazine. These were associated by attenuation of the increased colonic MPO activity, MDA and proinflammatory cytokines. In addition, there is the downregulation of the adhesion molecules. In the present study, Atorvastatin had shown therapeutic effects in experimental colitis. The anti-inflammatory actions involve antioxidant effect related to phenolic moiety along with inhibition of adhesion molecule synthesis in the colonic tissues.

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis

Current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated response in the gut, but no treatment is fully effective for many refractory patients. Mesenchymal stromal cells (MSC) are multi-potent cells with regulatory immunosuppressive activity that may control inflammatory diseases. In this study, we investigated the short- and especially the long-term protective effects of MSC on experimental colitis. We show that MSC elicited protection to acute intestinal inflammation with gain of weight, improvement in the clinical disease score and expressive reduction in the mortality rate of treated mice. MSC changed the population of neutrophils, eosinophils and augmented the frequency of CD4 T lymphocytes in the gut-draining lymph nodes, together with reduced accumulation of these cells in the colon intraepithelial compartment. Interestingly, there were increased levels of programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor family-related receptor (GITR) in the spleen regulatory T cells of mice that received MSC treatment, which also presented a reversal in the pattern of immune response in the gut, with diminished inflammatory, T helper type 1 (Th1) and Th17 profile, in contrast to augmented Th2 responses. Most strikingly, this balanced response elicited by a single administration of MSC during the acute colitis persisted long-term, with restored goblet cells, eosinophils and maintenance of elevated gut interleukin (IL)-4, besides increased CD4+ CD25+ PD-1+ cells in the spleen and reduced Th17 response in mesenteric lymph nodes (MLN) of treated mice on day 60. Taken together, our findings provided a significant contribution to translational immunology by pointing human adipose tissue-derived MSC as a novel therapeutic approach with long-term beneficial regulatory effects in experimental colitis.

Calcium Pyruvate Exerts Beneficial Effects in an Experimental Model of Irritable Bowel Disease Induced by DCA in Rats.

Pyruvate is a normal constituent of the body that participates in carbohydrate metabolism and functions as a scavenger of free radicals. Calcium pyruvate monohydrate (CPM) is a more stable derivative that has proved its anti-inflammatory effect in experimental colitis, among other disorders, and that could also be considered a source of calcium. Thus, it would be useful for the treatment of diseases with an inflammatory component and a high prevalence of osteoporosis like the irritable bowel syndrome (IBS). The aim of the present study is to evaluate the effects of CPM in a rat model of chronic post-inflammatory visceral pain induced by deoxycholic acid (DCA) that resembles IBS. Rats were administered DCA for three days intracolonically and then treated daily with CPM (40 and 100 mg/kg) or gabapentin (70 mg/kg) (positive control) by oral gavage for 17 days. The treatments reduced the visceral hypersensitivity measured by response to colorectal distension and referred pain. DCA induced changes in the colonic immune response characterized by increased expression of the cytokine Il-1β and the inducible enzyme Cox-2, which was reduced by the treatments. DCA also decreased the gut expression of the mucins Muc-2 and Muc-3, which was normalized by CPM, whereas gabapentin only increased significantly Muc-3. Moreover, DCA increased the expression of Tlr3, which was decreased to basal levels by all the treatments. However, the serotonin receptor Htr-4, which was also elevated, was not affected by any of the treatments, indicating no effect through this signalling pathway. In conclusion, CPM ameliorated the visceral hypersensitivity and the referred pain caused by DCA, being as effective as the control drug. Furthermore, it improved the immune status of the animals, which could contribute to the visceral analgesia and the regeneration of the intestinal epithelial barrier integrity.

The Immunomodulatory Properties of Propyl-Propane Thiosulfonate Contribute to its Intestinal Anti-Inflammatory Effect in Experimental Colitis.

Propyl-propane thiosulfonate (PTSO) is a component isolated from garlic (Allium sativum) with antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial properties. In consequence, PTSO can be a potential candidate for the treatment of inflammatory bowel diseases. The anti-inflammatory effects of PTSO are studied in two mice models of colitis: 2,4-dinitrobenzene sulfonic acid (DNBS) (PTSO doses: 0.01-10mgkg-1 ) and dextran sodium sulfate (DSS) (PTSO doses: 0.01-0.1mgkg-1 ). The immunomodulatory effects of PTSO (0.1-25µm) are also shown in vitro in Caco-2 and THP-1 cells, reducing the production of pro-inflammatory mediators and downregulating mitogen-activated protein kinases (MAPKs) signaling pathways. This compound displays beneficial effects in both models of mouse colitis by reducing the expression of different pro-inflammatory mediators and improving the intestinal epithelial barrier integrity. Moreover, PTSO ameliorates the altered gut microbiota composition observed in DSS colitic mice. PTSO exerts intestinal anti-inflammatory activity in experimental colitis in mice. This anti-inflammatory activity can be associated with the immunomodulatory properties of PTSO through the regulation of the activity of cells involved in the inflammatory response. Furthermore, PTSO is able to restore the intestinal epithelial barrier function and to ameliorate the intestinal microbiota homeostasis, thus supporting its future development in human IBD.

A partial agonist for retinoid X receptor mitigates experimental colitis.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis.

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution.

Immunomodulatory tetracyclines are well-characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation. A comparative pharmacological study was initially used to elucidate the most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline and tigecycline; other antibiotic or immunomodulatory drugs were assessed in bone marrow-derived macrophages and in dextran sodium sulfate (DSS)-induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. The sequential immune events that mediate the intestinal anti-inflammatory effect of minocycline in DSS-colitis were then characterized. Novel immunomodulatory activity of tetracyclines was identifed; they potentiated the innate immune response and enhanced resolution of inflammation. This is also the first report describing the intestinal anti-inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release in vitro, and while improving mucosal recovery in colitic mice, they up-regulated Ccl2, miR-142, miR-375 and Tlr4. In particular, minocycline initially enhanced IL-1β, IL-6, IL-22, GM-CSF and IL-4 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C- MHCII+ macrophages, Tregs and type 2 intestinal immune responses. Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.

Calprotectin protects against experimental colonic inflammation in mice.

Calprotectin is a heterodimer composed of two myeloid-related proteins, S100A8 and S100A9, that is abundant in neutrophils and monocytes/macrophages. Faecal levels of calprotectin are used routinely to monitor inflammatory bowel disease activity. We aimed to assess the role of calprotectin in intestinal inflammation, using the dextran sulfate sodium model of colitis in mice. Calprotectin was administered (50 or 100μg·day-1 ) by the intrarectal or by i.p. injection (50μg·day-1 only). The condition of the mice was characterized by morphological and biochemical methods. Intrarectal calprotectin protected significantly against colitis, as shown by lower levels of macroscopic and microscopic damage, colonic myeloperoxidase activity and decreased expression of TNFα and toll-like receptor 4. IL-17 production by spleen and mesenteric lymph node cells was reduced. Calprotectin had no effect on body weight loss or colonic thickening. There were no effects of calprotectin after i.p. injection. Calprotectin had virtually no effects in control, non-colitic mice. Calprotectin had almost no effect on the colonic microbiota but enhanced barrier function. Treatment of rat IEC18 intestinal epithelial cells in vitro with calprotectin induced output of the chemokines CXL1 and CCL2, involving the receptor for advanced glycation end products- and NFκB. Calprotectin exerted protective effects in experimental colitis when given by the intrarectal route, by actions that appear to involve effects on the epithelium.

Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection.

Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen Helicobacter pylori. In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized Smox-deficient mice to examine the role of SMOX in two murine colitis models, Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced epithelial injury. In C. rodentium-infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in Smox−/− mice. In contrast, with DSS, Smox−/− mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In C. rodentium-infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in Smox−/− mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in Smox−/− mice. In both models, putrescine and spermidine were increased in WT mice; in Smox−/− mice, the main effect was decreased spermidine and spermidine/spermine ratio. With C. rodentium, polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis via polyamine flux. Thus, SMOX contributes to the immunopathogenesis of C. rodentium infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.

Phytochemical analysis by HPLC-PDA/ESI-MS of Globularia alypum aqueous extract and mechanism of its protective effect on experimental colitis induced by acetic acid in rat

Globularia alypum L. (GA) is a mediterranean plant of the Globulariaceae family. GA aqueous extract (GAAE) is widely used to treat various ailments, including constipation, peptic ulcer, diabetes, insomnia, hernia and intestinal pain. In this study we analyzed the chemical composition of GAAE by HPLC-PDA/ESI-MS and we examined its protective effect on acetic acid (AA)-induced ulcerative colitis in rats. We firstly showed that the HPLC-PDA/ESI-MS analysis indicated high concentrations of secondary metabolites in GAAE, especially iridoids. We have also shown that rectal administration of AA provoked a severe colon mucosal injury and macroscopic edematous colon inflammation with alteration of colonic oxidative balance. However GAAE pretreatment protected significantly and dose dependently against all colonic morphological, histological and biochemical alterations induced by AA. This study suggests that GAAE possess active compounds, which exert marked protective effects in experimental colitis, possibly by regulating the colonic epithelium inflammatory mediators, oxidative balance and calcium homeostasis.