New therapeutic avenues in ulcerative colitis: thinking out of the box

Torres, Joana; Danese, Silvio; Colombel, Jean Fréd́eric

doi:10.1136/gutjnl-2012-303959

Cited by 58 publications

(34 citation statements)

References 145 publications

(142 reference statements)

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“…It follows that restitution of the defective barrier is a desired therapeutic aim in patients with UC and CD. Nevertheless, very few efforts have reached the clinical stage, thus far (49). It should be noted that a major mode of action of mesalazine may be the improvement of epithelial integrity through its function as an agonist for peroxisome proliferator-activated receptor-γ (PPAR-γ) (50).…”

Section: A “Pathogenetic” Approach To Ibd Treatmentmentioning

confidence: 99%

Pathway-based approaches to the treatment of inflammatory bowel disease

Bamias

Pizarro

Cominelli

2016

Translational Research

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Crohn’s disease (CD) and ulcerative colitis (UC), collectively termed inflammatory bowel disease (IBD), are immunological disorders that represent the prototypes of chronic intestinal inflammation. Their pathogenesis involves the dysregulated interaction between the intestinal microbiota and the gut-associated mucosal immune system that takes place when genetically predisposed individuals are exposed to detrimental environmental triggers. In recent years, the therapeutic dogma in IBD has shifted away from the administration of non-specific immunosuppressives towards a pathway-based approach. In this review we will present an oulook of IBD treatment, based on this new conceptual approach. Firstly, we will provide an overview of the major aspects of IBD pathogenesis with emphasis on specific pathway-based defects. Subsequently, we will examine in detail the development of novel therapeutic approaches that can be used to target genetics, dysbiosis, the epithelial barrier, pro inflammatory cytokines, and leukocyte trafficking. Most of these strategies are still in the developmental phase, but promising approaches include: fecal microbiota transplantation as a means to correct IBD-related dysbiosis; administration of modified phosphatidylcoline (PC) to enhance the function of the intestinal mucous and tighten the defective epithelial barrier; the reduction of over-reactive pro-inflammatory pathways through the blockade of novel, non-TNF inflammatory mediators, via monoclonal antibodies against the common p40 chain of IL-12 and IL-23, JAK kinase inhibitors, or antisense oligonuclotides against inhibitors of the immunosuppressive cytokine TGF-β1; and, finally, inhibition of leukocyte trafficking to the gut via neutralization of the gut-specific integrin α4β7 integrin. Availability of such diverse treatment modalities with specific pathway-based targets will increase the therapeutic options for patients with IBD.

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Section: A “Pathogenetic” Approach To Ibd Treatmentmentioning

confidence: 99%

Pathway-based approaches to the treatment of inflammatory bowel disease

Bamias

Pizarro

Cominelli

2016

Translational Research

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“…Despite the best available therapies and recent advances, many patients stay symptomatic and present with a damaged colon with ulcerations, many requiring colectomy . Many strategies were developed for UC remission including use of monoclonal antibodies against molecules involved in leucocytes migration such as integrins, adhesion molecules, chemokines and its receptors (antiadhesion strategy); oral JAK inhibitors (Tofacitinib) and PPARγ ligands (5‐aminosalicylic acid); restoring the altered mucosal barrier function by administering phosphatidylcholine; treatment with anti‐inflammatory cytokines such as IL‐10‐secreting transgenic bacteria . However, dose‐related side effects, differential patient response and short‐term benefits question for the effective but safe therapy for chronic UC .…”

Section: Introductionmentioning

confidence: 99%

“…including use of monoclonal antibodies against molecules involved in leucocytes migration such as integrins, adhesion molecules, chemokines and its receptors (antiadhesion strategy); oral JAK inhibitors (Tofacitinib) and PPARγ ligands (5-aminosalicylic acid); restoring the altered mucosal barrier function by administering phosphatidylcholine; treatment with anti-inflammatory cytokines such as IL-10-secreting transgenic bacteria. [10][11][12] However, doserelated side effects, differential patient response and short-term benefits question for the effective but safe therapy for chronic UC. [13][14][15][16] Finding ways to control elicited intestinal, immunological and inflammatory processes might contribute to the best therapeutic options in IBD.…”

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confidence: 99%

Human filarial proteins attenuate chronic colitis in an experimental mouse model

Togre

Bhoj

Goswami

et al. 2018

Parasite Immunology

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Encouraged by our earlier results of promising therapeutic effect of filarial recombinant proteins BmALT2, BmCys and WbL2 individually in the mouse model of acute ulcerative colitis, in this study, these proteins have been explored individually and in different combinations for their therapeutic potential in dextran sulphate sodium (DSS)-induced chronic colitis mice. These mice, treated with filarial proteins, showed reduced disease parameters including body weight loss, disease activity index, macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Among various treatment schemes, rBmALT2 + rBmCys which showed most pronounced therapeutic implication was found to downregulate the mRNA expressions of IFN-γ and TNF-α and upregulate IL-10 and TGF-β expression in the splenocytes. Also, increase in level of IgG1 and IgG2a isotypes in the sera of rBmALT2 + rBmCys-treated colitis mice was noted. Activated NF-κB level was found to be reduced in the colon of treated colitis mice compared to untreated one. In conclusion, filarial proteins in combination have been shown to improve the clinicopathologic status of chronic colitis through suppression of pro-inflammatory immune response most possibly in NF-κB-dependent manner. We propose this therapeutic strategy to be tested further to be considered as an effective option in chronic colitis.

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“…Two recent reviews describe many more complementary and alternative therapies in IBD [45,46]. Even though, as in the example of the T. suis ova, promising approaches may fail in the end, some may survive and help us in clinical practice [47]. …”

Section: Natural Productsmentioning

confidence: 99%

Trichuris suis Ova, Lecithin and Other Fancy Molecules

Schölmerich

2014

Dig Dis

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During the last 20 years, treatment paradigms as well as drugs used for IBD have changed significantly. However, there are still many unmet needs and a significant number of patients needing better therapy. It is obvious from this situation that many attempts have been made to implement new drugs and treatment algorithms including biologicals, new formulations of old drugs and ‘fancy molecules or approaches'. For about 10 years, the application of Trichuris suis ova has been promoted and used in quite a number of patients. Two early studies suggested positive effects in ulcerative colitis as well as in Crohn's disease. These studies were based on experimental data in animal models as well as in vitro experiments. However, two large randomized controlled trials were not able to provide significant clinical effects in active Crohn's disease as compared to placebo, although a biological reaction (eosinophilia) was found. Another approach is the use of locally released phosphatidylcholine in ulcerative colitis. This approach is based on decreased phosphatidylcholine concentrations in the colonic mucus in patients, and showed positive effects in a number of monocentric trials in steroid-refractory and chronic active ulcerative colitis. A dose-finding study gave a positive signal in the highest-dose group and this approach is being tested further in controlled trials. Many other ‘fancy molecules' including cannabis, vitamin D, thalidomide, hyaluronic acid, lidocaine, clonidine, chondroitin sulfate, naltrexone and melatonin have been tested in patients with claims of success. For most of those, however, controlled data in appropriate studies are lacking. Many more substances have been used in animal models and are probably applied in individual patients. Results of preliminary studies on some of the molecules mentioned are presented.

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New therapeutic avenues in ulcerative colitis: thinking out of the box

Cited by 58 publications

References 145 publications

Pathway-based approaches to the treatment of inflammatory bowel disease

Pathway-based approaches to the treatment of inflammatory bowel disease

Human filarial proteins attenuate chronic colitis in an experimental mouse model

Trichuris suis Ova, Lecithin and Other Fancy Molecules

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