Dietary Polydextrose Prevents Inflammatory Bowel Disease in Trinitrobenzenesulfonic Acid Model of Rat Colitis

Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder that involves interactions among the immune system, genetic susceptibility, and environmental factors, especially the bacterial flora. Polydextrose, a polysaccharide constituted by 90% nondigestible and nonabsorbable soluble fibers, has several physiological effects consistent with those of dietary fibers, including proliferation of colon microflora. Because sulfasalazine presents serious side effects through long-term use at high doses, the aim of the present study was to evaluate the preventative effect of polydextrose on trinitrobenzenesulfonic acid-induced intestinal inflammation and its effects on the intestinal anti-inflammatory activity of sulfasalazine. Results indicated that polydextrose and its association with sulfasalazine present an anti-inflammatory effect that reduces myeloperoxidase activity, counteracts glutathione content, and promotes reductions in lesion extension and colonic weight/length ratio.

Effects of Rhizophora mangle on Experimental Colitis Induced by TNBS in Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Intestinal antiinflammatory activity of a lyophilized infusion of Turnera ulmifolia in TNBS rat colitis

Turnera ulmifolia is a plant popularly known in Brazil and South America as chanana. Some species of Turnera are widely used in folk medicine for different types of inflammatory diseases. In this study, the preventive intestinal antiinflammatory activity of a lyophilized infusion obtained from the aerial parts of T. ulmifolia was tested in the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. The results obtained revealed that pretreatment to colitic rats with the extract, at 250 and 500 mg/kg, significantly attenuated the colonic damage induced by TNBS. This beneficial effect was associated with an improvement in the colonic oxidative status, since the infusion prevented the glutathione depletion that occurred as a consequence of the colonic inflammation. on the other hand, this antioxidant activity was confirmed in in vitro studies. In conclusion, the preventive effect exerted by the lyophilized infusion of T. ulmifolia in the TNBS model of rat colitis is probably related to its antioxidant properties, due to its flavonoids content. (c) 2006 Elsevier B.V. All rights reserved.

Decreased Total Antioxidant Capacity in Plasma, but Not Tissue, in Experimental Colitis

The aim of the present work was to compare colonic mucosa and plasmatic oxidative stress measured concomitantly and with different degrees of injury in rats with colitis induced by trinitrobenzene sulfonic acid. Three groups were studied: control group, colitis group, and colitis exacerbated by diclofenac. Enzymatic markers of colon injury showed enhanced activity in both groups with colitis. The colitis group treated with diclofenac presented higher colonic damage score than the other groups. In both groups with colitis, higher values of tert butyl hydroperoxide-initiated-chemiluminescence and thiobarbituric acid-reactive substances in tissue and decreased total radical-trapping antioxidant potential (TRAP) levels in plasma were found. In conclusion, independently of the degree of colonic mucosa injury and inflammation, oxidative stress in tissue occurs as a consequence of pro-oxidants increase, and is not explained by a reduction of antioxidant defenses. In both conditions, TRAP determination decreases in plasma, but not in tissue.

Bone healing around titanium implants in two rat colitis models

Objective: Crohn's disease is a chronic inflammatory process that has recently been associated with a higher risk of early implant failure. Herein we provide information on the impact of colitis on peri-implant bone formation using preclinical models of chemically induced colitis. Methods: Colitis was induced by intrarectal instillation of 2,4,6-trinitro-benzene-sulfonic-acid (TNBS). Colitis was also induced by feeding rats dextran-sodium-sulfate (DSS) in drinking water. One week after disease induction, titanium miniscrews were inserted into the tibia. Four weeks after implantation, peri-implant bone volume per tissue volume (BV/TV) and bone-to-implant contacts (BIC) were determined by histomorphometric analysis. Results: Cortical histomorphometric parameters were similar in the control (n = 10), DSS (n = 10) and TNBS (n = 8) groups. Cortical BV/TV was 92.2 ± 3.7%, 92.0 ± 3.0% and 92.6 ± 2.7%. Cortical BIC was 81.3 ± 8.8%, 83.2 ± 8.4% and 84.0 ± 7.0%, respectively. No significant differences were observed when comparing the medullary BV/TV and BIC (19.5 ± 6.4%, 16.2 ± 5.6% and 15.4 ± 9.0%) and (48.8 ± 12.9%, 49.2 ± 6.2 and 41.9 ± 11.7%), respectively. Successful induction of colitis was confirmed by loss of body weight and colon morphology. Conclusions: The results suggest bone regeneration around implants is not impaired in chemically induced colitis models. Considering that Crohn's disease can affect any part of the gastrointestinal tract including the mouth, our model only partially reflects the clinical situation. © 2012 John Wiley & Sons A/S.

Anti-inflammatory intestinal activity of Arctium lappa L. (Asteraceae) in TNBS colitis model

Ethnopharmacological relevance: In Brazilian traditional medicine, Arctium lappa (Asteraceae), has been reported to relieve gastrointestinal symptoms. Aim of the study: In the present study, we investigated the effects of the lactone sesquiterpene onopordopicrin enriched fraction (ONP fraction) from Arctium lappa in an experimental colitis model induced by 2,4,6 trinitrobenzene sulfonic acid and performed experiments to elucidate the underlying action mechanisms involved in that effect. Materials and methods: ONP fraction (25 and 50 mg/kg/day) was orally administered 48, 24 and 1 h prior to the induction of colitis and 24 h after. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumor necrosis factor alpha (TNF-α) levels and a histological study of the lesions. We determined cyclooxygenase (COX)-1 and -2 protein expressions by western blotting and immunohistochemistry assays. Results: TNBS group was characterized by increased colonic wall thickness, edema, diffuse inflammatory cell infiltration, increased MPO activity and TNF-α levels. On the contrary, ONP fraction (25 and 50 mg/kg) treatment significantly reduced the macroscopic inflammation scores (p<0.05 and p<0.01, respectively) and morphological alterations associated with an increase in the mucus secretion. Similarly, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Moreover, COX-2 expression was up regulated in TNBS-treated rats. In contrast, ONP fraction (50 mg/kg) administration reduced COX-2 overexpression. Conclusions: We have shown that the ONP fraction obtained from Arctium lappa exert marked protective effects in acute experimental colitis, confirming and justifying, at least in part, the popular use of this plant to treat gastrointestinal diseases. © 2013 Elsevier B.V. All rights reserved.

Influência do estado nutricional e da composição corporal na evolução clínica dos pacientes com doença inflamatória intestinal

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Comparison of selective and non selective cyclo-oxygenase 2 inhibitors in experimental colitis exacerbation: role of leukotriene B4 and superoxide dismutase

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients

Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000 and 2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. Cytomegalovirus (CMV) immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), inflammatory bowel disease (IBD)-like colitis (25%), normal/near normal (18.8%), graft-versus-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18.75%). No graft loss occurred. Four patients died during the study period. Late-onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

Oral treatment with Hev b 13 ameliorates experimental colitis in mice

Hev b 13 is an allergenic esterase obtained from the rubber tree Hevea brasiliensis, which has been shown recently to induce human mononuclear cells to release interleukin (IL)-10 in vitro. This immunoregulatory cytokine appears to play an important role in preventing inflammation and mucosal damage in animal models of colitis and in Crohn's disease patients. The aim of this study was to evaluate the therapeutic effect of Hev b 13 in mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Two hours following colonic instillation of the haptenizing agent, and daily thereafter for 5 days, Hev b 13 was administered by oral gavage. In mice treated with daily doses of either 0.5 mg/kg or 5.0 mg/kg of Hev b 13, the clinical signs of diarrhoea, rectal prolapse and body weight loss and also histological damage of the distal colon, were reduced significantly, in comparison with water-treated diseased mice. These findings suggest a potent anti-inflammatory activity of Hev b 13; this activity is speculated to be related to its interaction with cells from the immune system.

Development of new therapeutic approaches in the treatments of Inflammatory Bowel Diseases: functional food and nutraceuticals vs synthetic peptides based vaccines

Inflammatory Bowel Diseases (IBD) are intestinal chronic relapsing diseases which ethiopathogenesis remains uncertain. Several group have attempted to study the role of factors involved such as genetic susceptibility, environmental factors such as smoke, diet, sex, immunological factors as well as the microbioma. None of the treatments available satisfy several criteria at the same time such as safety, long-term remission, histopatological healing, and specificity. We used two different approaches for the development of new therapeutic treatment for Inflammatory Bowel Disease. The first is focused on the understanding of the potential role of functional food and nutraceuticals nutrients in the treatment of IBD. To do so, we investigated the role of Curcuma longa in the treatment of chemical induced colitis in mice model. Since Curcma Longa has been investigated for its antinflammatory role related to the TNFα pathway as well investigators have reported few cases of patients with ulcerative colites treated with this herbs, we harbored the hypothesis of a role of Curcuma Longa in the treatment f IBD as well as we decided to assess its role in intestinal motility. The second part is based on an immunological approach to develop new drugs to induce suppression in Crohn’s disease or to induce mucosa immunity such as in colonrectal tumor. The main idea behind this approach is that we could manipulate relevant cell-cell interactions using synthetic peptides. We demonstrated the role of the unique interaction between molecules expressed on intestinal epithelial cells such as CD1d and CEACAM5 and on CD8+ T cells. In normal condition this interaction has a role for the expansion of the suppressor CD8+ T cells. Here, we characterized this interaction, we defined which are the epitope involved in the binding and we attempted to develop synthetic peptides from the N domain of CEACAM5 in order to manipulate it.

Chemopreventive effects of eicosapentaenoic acid free fatty acid in a murine model of colitis-associated colorectal cancer

Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyps formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA-FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control, resulted in the enrichment of Lactobacillus species in the gut microbiota and led to tumor suppressor miR34-a induction. In conclusion, our data suggest that EPA-FFA is an effective chemopreventive agent in CAC.

Mannan-binding lectin deficiency results in unusual antibody production and excessive experimental colitis in response to mannose-expressing mild gut pathogens

In Crohn's disease (CD) the deficiency of mannan-binding lectin (MBL) is associated with an increased prevalence of anti-Saccharomyces cerevisiae antibodies (ASCA) and with complicated phenotypes of the disease. However, the role of MBL in intestinal inflammation is currently unclear. A study was undertaken to analyse local MBL expression in human intestine and the consequences of MBL deficiency in experimental colitis and yeast infection.