Decrease In Disease Activity Index Research Articles

Gadolinium chloride improves the course of TNBS and DSS-induced colitis through protecting against colonic mucosal inflammation.

Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFα, IL-1β and IL-6 secretions. Also, Western blotting analysis indicated that NF-κB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS-stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-κB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD.

Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.

Supplementation of the diet with Salecan attenuates the symptoms of colitis induced by dextran sulphate sodium in mice

As a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, Salecan has an excellent toxicological profile and exerts multiple physiological effects. The aims of the present study were to investigate the protective effects of a Salecan diet in the well-defined dextran sulphate sodium (DSS) model of experimental murine colitis and to elucidate the mechanism involved in its effects with special attention being paid to its effect on the production of TNF-α, a primary mediator involved in the inflammatory response. Male C57BL/6J mice were fed a diet supplemented with either 4 or 8% Salecan for 26d and DSS was administered to induce acute colitis during the last 5d of the experimental period. Several clinical and inflammatory parameters as well as mRNA expression of TNF-α and Dectin-1 were evaluated. The results indicated that the dietary incorporation of Salecan attenuated the severity of DSS colitis as evidenced by the decreased disease activity index, reduced severity of anaemia, attenuated changes in colon architecture and reduced colonic myeloperoxidase activity. This protection was associated with the down-regulation of TNF-α mRNA levels, which might derive from its ability to increase Dectin-1 mRNA levels. In conclusion, the present study suggests that Salecan contributes to the reduction of colonic damage and inflammation in mice with DSS-induced colitis and holds promise as a new, effective nutritional supplement in the management of inflammatory bowel disease.

Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial

BackgroundSerum infliximab trough levels correlate with efficacy; dose escalation is often beneficial in patients with Crohn's disease who stop responding to infliximab treatment.ObjectiveTo carry out a post hoc analysis of...

Clinical and Structural Effects of Traditional Chinese Medicine and the Herbal Preparation, Iberogast, in a Rat Model of Ulcerative Colitis

Plant-sourced formulations such as Iberogast and the traditional Chinese medicine formulation, Cmed, purportedly possess anti-inflammatory and radical scavenging properties. We investigated Iberogast and Cmed, independently, for their potential to decrease the severity of the large bowel inflammatory disorder, ulcerative colitis. Sprague Dawley rats (n = 8/group) received daily 1 mL gavages (days 0-13) of water, Iberogast (100 μL/200 μL), or Cmed (10 mg/20 mg). Rats ingested 2% dextran sulfate sodium or water ad libitum for 7 days commencing on day 5. Dextran sulfate sodium administration increased disease activity index scores from days 6 to 12, compared with water controls (P < .05). On day 10, 200 μL Iberogast decreased disease activity index scores in colitic rats compared with colitic controls (P < .05). Neither Iberogast nor Cmed achieved statistical significance for daily metabolic parameters or colonic crypt depth. The therapeutic effects of Iberogast and Cmed were minimal in the colitis setting. Further studies of plant extracts are required investigating greater concentrations and alternative delivery systems.

Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer

The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca(2+)-induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and IL-17A. High-performance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.

Effect of the leaves of Psidium guajava Linn. on experimentally induced colitis in animal models

The aim of this study is to evaluate the effect of the ethanolic extract of the leaves of Psidium guajava (PGE) on experimentally induced colitis in animal models. Fresh tender leaves of the plant were collected, air-dried, powdered and percolated in 95% ethanol. Acute toxicity test was done according to Organization for Economic Cooperation and Development guidelines. Five groups of animals of the species Rattus norvegicus, of either sex, weighing 150–200 g, were taken for the study (n=6). Group A and Group B consisted of normal and experimental control animals (3% gum acacia, 10 ml/kg body weight), respectively. Group C and Group D were test groups (PGE 250 mg/kg body weight and PGE 500 mg/kg body weight, respectively) and Group E was administered standard [5-amino salicylic acid (5-ASA) 100 mg/kg body weight]. All animals were pretreated with the respective drugs for 5 days. Colitis was induced next morning in Groups B, C, D and E by administration of 1 ml of 4% acetic acid transrectally. All the animals were sacrificed 48 hours after colitis induction and distal 10 cm of the colon was resected. Colon was weighed for Disease Activity Index (DAI), and scored macroscopically and microscopically. Biochemical assessment included myeloperoxidase (MPO), tissue catalase (CAT), glutathione (GSH) and superoxide dismutase (SOD) estimation. Statistical analysis was done by one way analysis of variance, followed by multiple comparison tests. Groups C, D, and E showed a significant (P<0.05) decrease in DAI, and macroscopic and microscopic lesion score, as well as a significant improvement (P<0.05) in MPO, CAT, GSH and SOD levels as compared to Group B. The ethanolic extract of P. guajava leaves showed significant amelioration of experimentally induced colitis, which may be attributed to its anti-inflammatory and anti-oxidant property. Key words: Acetic acid, antioxidant, colitis, Psidium guajava

Nafamostat mesilate attenuates colonic inflammation and mast cell infiltration in the experimental colitis

Serine proteases are important in the pathogenesis of intestinal inflammation. Recent studies have shown that nafamostat mesilate (NM) can inhibit the colonic mucosal inflammation induced by TNBS in rats. The aim of this study was to investigate the anti-inflammatory effects of NM on a DSS-induced colitis. Colitis was induced in female BALB/c mice by 5% dextran sulfate sodium (DSS) for 6 days. NM (2 or 20 mg/kg body weight) was orally administered once a day for 6 days during treatment of the mice with DSS. The inflammatory response of the colon was assessed 1 week after DSS treatment. NM at a high dose, but not at a low dose significantly decreased disease activity index (DAI) and myeloperoxidase (MPO) induced by DSS. Furthermore, NM (20 mg/kg) inhibited the production of tumor necrosis factor (TNF)-α, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the colonic tissues treated with DSS. The increase in chymase activity by DSS treatment was also attenuated by the administration of NM (20 mg/kg). NM (20 mg/kg) significantly decreased the colonic mucosal injury and the infiltrated mast cell number induced by DSS. These results indicate that NM might inhibit the colonic inflammation through inhibition of both chymase activity and mast cell infiltration in colon tissues of DSS-induced colitis.

B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial

IntroductionAn over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.MethodsNine patients with SSc with mean age 40.9 ± 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.ResultsAfter 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.ConclusionsAnti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.Trial registrationISRCTN77554566.

Therapeutic potency of IL2–caspase 3 targeted treatment in a murine experimental model of inflammatory bowel disease

Background:Inflammatory bowel disease (IBD) comprises primarily the two disorders – ulcerative colitis and Crohn’s disease – that involve deregulated T cell responses. The ever-increasing incidence rate of Crohn’s disease and...

A novel mTOR inhibitor is efficacious in a murine model of colitis

Ulcerative colitis is an autoimmune-inflammatory disease characterized by increased proliferation of colonic epithelial cells, dysregulation of signal transduction pathways, elevated mucosal T cell activation, increased production of proinflammatory cytokines, and enhanced leukocyte infiltration into colonic interstitium. Several compounds that possess antiproliferative properties and/or inhibit cytokine production exhibit a therapeutic effect in murine models of colitis. Mammalian target of rapamycin (mTOR), a protein kinase regulating cell proliferation, is implicated in colon carcinogenesis. In this study, we report that a novel haloacyl aminopyridine-based molecule (P2281) is a mTOR inhibitor and is efficacious in a murine model of human colitis. In vitro studies using Western blot analysis and cell-based ELISA assays showed that P2281 inhibits mTOR activity in colon cancer cells. In vitro and in vivo assays of proinflammatory cytokine production revealed that P2281 diminishes induced IFN-gamma production but not TNF-alpha production, indicating preferential inhibitory effects of P2281 on T cell function. In the dextran sulfate sodium (DSS) model of colitis, 1) macroscopic colon observations demonstrated that P2281 significantly inhibited DSS-induced weight loss, improved rectal bleeding index, decreased disease activity index, and reversed DSS-induced shortening of the colon; 2) histological analyses of colonic tissues revealed that P2281 distinctly attenuated DSS-induced edema, prominently diminished the leukocyte infiltration in the colonic mucosa, and resulted in protection against DSS-induced crypt damage; and 3) Western blot analysis showed that P2281 blocks DSS-induced activation of mTOR. Collectively, these results provide direct evidence that P2281, a novel mTOR inhibitor, suppresses DSS-induced colitis by inhibiting T cell function and is a potential therapeutic for colitis. Given that compounds with anticancer activity show promising anti-inflammatory efficacy, our findings reinforce the cross-therapeutic functionality of potential drugs.

Cyclophosphamide pulse therapy followed by azathioprine or methotrexate induces long‐term remission in patients with steroid‐refractory Crohn's disease

In patients with steroid-refractory Crohn's disease, the therapeutic goal is to achieve both rapid remission and maintenance of clinical response. To evaluate the long-term benefit in patients treated with cyclophosphamide pulse therapy and azathioprine or methotrexate, a combination shown to be effective in a recent pilot study. Sixteen patients with acute steroid-refractory Crohn's disease participated in a prospective open-labelled uncontrolled pilot study between December 1998 and June 2003. All had a median number of 4 monthly pulses of intravenous cyclophosphamide (750 mg) and were followed until relapse of the disease. Thirteen of 16 patients (81%) achieved remission within 8 weeks after two pulses of cyclophosphamide in combination with azathioprine or methotrexate, with a Crohn's Disease Activity Index decrease from 294 to 111 (median). Remission sustained for 19 months (median, range: 1-45). Moreover, eight patients with pyoderma gangrenosum and erythema nodosum who responded to cyclophosphamide have maintained their remission for up to 30 months. In steroid refractory patients with Crohn's disease, cyclophosphamide is highly effective to induce remission. This uncontrolled study indicates that cyclophosphamide-induced remission is long-lasting under standard immunosuppressive therapy.

This Month in Gastroenterology

This Month in Gastroenterology

A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for Treatment of Crohn’s Disease

To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.

Topical Treatment of Distal Active Ulcerative Colitis With Beclomethasone Dipropionate or Mesalamine

Therapy for active ulcerative colitis (UC) usually involves rectal formulations of corticosteroids (CS), which are characterized by the risk of systemic steroid-related adverse effects. To compare the efficacy and safety of the topically acting CS beclomethasone dipropionate (BDP) versus mesalamine (5-ASA) in the treatment of active UC. Patients with mild to moderate distal active UC were randomized to a 6-week treatment with BDP 3 mg enema o.d. or 5-ASA 1 g enema daily in a single-blind, multicenter, parallel-group, controlled study. The primary efficacy variable was the decrease in Disease Activity Index (DAI) score. Safety variables were adrenal function, monitoring of adverse events, vital signs, and laboratory parameters. A total of 217 patients were enrolled and treated with BDP (n = 111) or 5-ASA (n = 106). A significant decrease in the DAI score (P < 0.05) was observed in both treatment groups, with a clinical remission rate of 36.7% in the BDP group and of 29.2% in the 5-ASA group. Both treatments were well tolerated. No changes from baseline in morning cortisol levels were observed in the BDP group. BDP administered as a rectal enema over a 6-week treatment period was efficacious and safe in patients with active UC, without interference with pituitary adrenal axis.

Maintenance infliximab infusions forever?

The authors undertook a randomized controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease defined as having a Crohn's Disease Activity Index 220. Initially, 573 patients were given a single dose of infliximab. The 335 patients (58%) who responded (Crohn's Disease Activity Index decrease of >70 points) to this treatment at 2 wk were then randomized to receive repeat infusions of placebo at wk 2 and 6 and then every 8 wk thereafter until wk 46 (group I), repeat infusions of 5 mg/kg of infliximab (group II), or 5 mg/kg of infliximab at wk 2 and 6 followed by 10 mg/kg (group III). The prespecified coprimary endpoints were the proportion of patients who responded at wk 2 and were in remission (Crohn's Disease Activity Index <150) at wk 30 and the time to loss of response up to wk 54 in patients who responded.

Maintenance infliximab infusions forever?

The authors undertook a randomized controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn’s disease defined as having a Crohn’s Disease Activity Index ≥220. Initially, 573 patients were given a single dose of infliximab. The 335 patients (58%) who responded (Crohn’s Disease Activity Index decrease of >70 points) to this treatment at 2 wk were then randomized to receive repeat infusions of placebo at wk 2 and 6 and then every 8 wk thereafter until wk 46 (group I), repeat infusions of 5 mg/kg of infliximab (group II), or 5 mg/kg of infliximab at wk 2 and 6 followed by 10 mg/kg (group III). The prespecified coprimary endpoints were the proportion of patients who responded at wk 2 and were in remission (Crohn’s Disease Activity Index <150) at wk 30 and the time to loss of response up to wk 54 in patients who responded. The authors found that at wk 30, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (OR = 2.7, 95% CI = 1.6–4.6). At 30 wk, the remission rates for each group were: 23 of 110 (21%) in group I patients, 44 of 113 (39%) in group II ( p = 0.003), and 50 of 112 (45%) in group III ( p = 0.0002). The median time to loss of response was 38 and >54 wk for groups II and III, compared with 19 wk for group I ( p = 0.002 and p = 0.0002, respectively). At wk 54, patients in group II and III were significantly more likely to have discontinued steroids and remained in remission (OR = 4.2, 95% CI = 1.5–11.5), compared with those patients in group I. For patients in whom antibodies to infliximab could be measured, they were found in 28%, 9%, and 6% in groups I, II and III, respectively. There was a trend toward a lower incidence of antibodies in patients on concurrent corticosteroids and immunosuppressive therapy. Infusion reactions occurred in 61 of 993 (6%) infusions in group II and in 45 of 1033 (4%) of infusion in group III. Infusion reactions occurred in 42 of 254 (16%) of infusions in subjects with antibodies to infliximab, compared with 55 of 656 (8%) in those without antibodies. There tended to be fewer infusion reactions in those patients receiving both corticosteroids and immunosuppressants. The incidence of serious infections was similar across all treatment groups. There was no significant difference in the incidence of serious adverse events requiring discontinuation of infusion between those receiving a single infusion and those receiving multiple infusions. The authors concluded that patients with Crohn’s disease who respond to an initial dose of infliximab are more likely: 1) to be in remission at wk 30 and 54; 2) to discontinue corticosteroids; and 3) to maintain their response for a longer period of time, when infliximab treatment is maintained every 8 wk.

Plasmapheresis Modulates TH1/TH2 Imbalance in Patients with Systemic Lupus Erythematosus According to Measurement of Intracytoplasmic Cytokines

To examine the possible effect of plasmapheresis on the ratio of Th1/Th2 type cytokine-secreting cells we recruited eight patients with active systemic lupus erythematosus into the present study. They all failed to respond to conventional therapy. A sensitive multiparametric flow cytometric analysis was used for the detection of intracellular IL-4, IL-10 and IFN n . Stimulated peripheral blood cells were analysed by this procedure. Plasmapheresis was performed every second day for three occasions, using a continuous flow type blood cell separator, and a total of 100 u ml/body weight kg plasma was removed. Patients received 1 u mg/kg/day methylprednisolone during this period. As a result of the procedure, the rate of IFN n positive Th cells increased, while the rate of IL-4 and IL-10 expressing CD4 positive cells decreased. Together with these observations the concentration of anti-ds-DNA antibodies decreased after plasmapheresis. A decrease in disease activity index (SLE-DAI) indicated the clinical effectiveness of the therapy.

Butyrate Inhibits NF-κB Activation in Lamina Propria Macrophages of Patients with Ulcerative Colitis

Background: In ulcerative colitis (UC) the activation (i.e. nuclear translocation) of nuclear factor kappa B (NF- s B) is an important step in the regulation of cytokines secreted by lamina propria macrophages. Clinical trials suggest anti-inflammatory effects of locally administered butyrate in UC. The potential effects of butyrate on NF- s B activation in lamina propria macrophages of UC patients were investigated. Methods: Eleven patients with distal UC were treated for up to 8 weeks with butyrate at 100 mM ( n = 6) or placebo ( n = 5) enemas. At entry and after 4 and 8 weeks, clinical status was noted and intestinal inflammation was graded endoscopically and histologically. Double-staining with antibodies against NF s B (p65) and CD68 was employed to detect NF- s B and macrophages, respectively. Results: In untreated patients, nuclear translocation of NF- s B was detectable in virtually all macrophages. Butyrate treatment for 4 and 8 weeks resulted in a significant reduction in the number of macrophages being positive for nuclear translocated NF- s B. In addition, butyrate significantly reduced both the number of neutrophils in crypt and surface epithelia and of the lamina propria lymphocytes/plasma cells. These findings correlated with a significant decrease in the Disease Activity Index (DAI). Conclusions: The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF- s B translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF- s B activation in these macrophages.

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<h3>Abstract</h3> Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by multi-factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that Celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and the mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR preforms the protective effect. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation approaches. CSR administration significantly ameliorated DSS-induced colitis, as evidenced by the recovery of body weight and colon length, decreased disease activity index (DAI) score, as well as decreased intestinal permeability. CSR down-regulated the secretion of proinflammatory cytokines, upregulated the anti-inflammatory mediators, and improved the balances of Treg/Th1 and Treg/Th17 to maintain colonic immune homeostasis. However, the protective effects of CSR disappeared when the antibiotic cocktail was applied to deplete the gut microbiota, and the gut microbiota-mediated effect was confirmed by FMT. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and raised the metabolic productions of pyruvate and adenosine, which probably involve in gut microbiota mediated protective effect. In conclusion, CSR ameliorates colonic inflammation in a gut microbiota-dependent manner. The underlying protective mechanism is associated with the rectified Treg/Th1 and Treg/Th17 balance, and increased pyruvate and adenosine production. The study provided the solid evidence that CSR might be a promising therapeutic drug for UC.