P070 Efficacy of a novel non-covalent oral small molecule Nrf2 activator in a rat model of Inflammatory Bowel Disease

Abstract Background Inflammatory Bowel Disease (IBD) is characterised by chronic inflammation and increased oxidative stress in the intestinal mucosa of patients. NF-E2-related factor 2 (Nrf2) plays a key role in the antioxidant response by regulating the transcription of antioxidant genes as well as reducing expression of inflammatory mediators. A role for the Nrf2 pathway in IBD has been demonstrated in rodent models previously but these studies have predominantly used compounds such as Dimethyl Fumarate that are covalent Nrf2 activators that have the potential for significant off-target activities. C4X Discovery has identified C4X_6746, a novel potent and selective non-covalent Nrf2 activator, that disrupts the interaction between Nrf2 and its repressor Keap1 and is being investigated as an oral treatment for inflammatory disorders. Methods Male Han Wistar rats were given 3% Dextran Sodium Sulphate (DSS) in drinking water for 8 days in order to induce colitis and were dosed once daily by oral gavage with vehicle, C4X_6746 (0.3, 3 or 30 mg/kg) or Cyclosporine A (CsA, 20 mg/kg). The Disease Activity Index (DAI) was assessed daily based on stool consistency, faecal blood and body weight. On study termination, the colon weight and length were measured, and additional endpoints assessed (colon macroscopic score, histology, colon markers of inflammation and antioxidant response). Results C4X_6746 caused a dose-dependent decrease in the DAI with 30 mg/kg showing similar efficacy to the reference comparator CsA. C4X_6746 (3 and 30 mg/kg) resulted in a statistically significant reduction in the colon weight:length ratio and the macroscopic score. The compound also reduced the DSS-induced histological changes including inflammatory cell infiltrate, epithelial damage and mucosal architecture changes. Analysis of the colon tissue showed that C4X_6746 reduced inflammation (MPO activity) and upregulated the antioxidant response (SOD activity, ratio of reduced:oxidised glutathione). Efficacy of C4X_6746 in the model correlated with the dose-dependent induction of NQO1 mRNA in the colon and blood as a biomarker for Nrf2 pathway activation. Conclusion The efficacy of C4X_6746 in the rat DSS model supports development of non-covalent oral Nrf2 activators to significantly reduce oxidative tissue damage and chronic inflammation in IBD.

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GUT-DIRECTED SELF-HYPNOSIS FOR INFLAMMATORY BOWEL DISEASE PROTOCOL: COMPLIMENTARY PSYCHOTHERAPY FOR REMISSION AUGMENTATION, IBS-LIKE SYMPTOMS, AND SURGERY RECOVERY

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.126 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S53-S53

Author(s):

Joshua Paulton ◽

Amanjot Gill ◽

Joelle Prevost

Keyword(s):

Inflammatory Bowel Disease ◽

Stress Response ◽

Mechanism Of Action ◽

Bowel Disease ◽

Relaxation Techniques ◽

Markers Of Inflammation ◽

Post Surgery ◽

Patient Goals ◽

History Of ◽

Inflammatory Bowel

Abstract Background Gut-directed hypnosis (GDH) is a complimentary therapy for Inflammatory Bowel Disease (IBD), that can be learnt by patients to practice self-hypnosis. GDH in IBD has augmented remission and improved inflammation. GDH has a history of successful use for Irritable Bowel Syndrome (IBS). In IBD it may also improve IBS-like symptoms in remission and recovery from surgery. GDH is suitable for youth and adult IBD patients. In hypnosis, a relaxed state is inducted then suggestions to subconscious mind processes are made. In IBD, the mechanism of action of GDH is unknown but may influence the disease stress response. Aims Aims are the development of a GDH self-hypnosis protocol for IBD, with appropriate target symptoms. Patients first learn to practice with a clinician, then as complimentary psychotherapy for remission augmentation, IBS-like symptoms, and surgery recovery. Methods GDH is practiced first with a clinician, and then by patients as self-hypnosis (table 1). Patients receive psycho-education on GDH for IBD. Next, appropriate treatment goals are made, based on target symptoms. Relaxation techniques induce patient to a deeply relaxed state. Therapeutic suggestions specific to patient goals are given: verbal suggestions, visualizations, and post-hypnotic suggestions. Suggestions can focus on having a healthy digestive system, inflammation and symptoms reduction, and achievement and sustainment of remission. Patients emerge from hypnosis, are debriefed, and encouraged to practice ongoing self-hypnosis. Results In IBD, GDH self-hypnosis can be learnt from clinicians and practiced by patients as a complimentary therapy. Patients’ achievement and sustainment of remission, with clinical markers of inflammation can be monitored. Patients can monitor subjective improvement of IBS-like symptoms and post surgery, recovery progress can be monitored. Conclusions GDH has a history of use for IBS. In IBD, it has been shown to modulate remission, and may improve IBS-like symptoms, and in surgery recovery. The mechanism of action of GDH in IBD may influence the disease stress response. Clinicians trained in GDH are limited currently. Patients may learn GDH self- hypnosis to as a complimentary psychotherapy.

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Abdominal aortic calcification as a marker of chronic inflammation-mediated atherosclerosis in patients with inflammatory bowel disease

Atherosclerosis ◽

10.1016/j.atherosclerosis.2021.06.251 ◽

2021 ◽

Vol 331 ◽

pp. e86

Author(s):

A. Mantaka ◽

N. Galanakis ◽

D. Tsetis ◽

I. Koutroubakis

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Aortic Calcification ◽

Abdominal Aortic Calcification ◽

Abdominal Aortic ◽

Inflammatory Bowel

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(Poly)phenols in Inflammatory Bowel Disease and Irritable Bowel Syndrome: A Review

Molecules ◽

10.3390/molecules26071843 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1843

Author(s):

Marilyn Hagan ◽

Bu' Hussain Hayee ◽

Ana Rodriguez-Mateos

Keyword(s):

Inflammatory Bowel Disease ◽

Irritable Bowel Syndrome ◽

Bowel Disease ◽

Evidence Base ◽

Therapeutic Benefit ◽

Markers Of Inflammation ◽

Related Quality ◽

Health Related ◽

Inflammatory Bowel ◽

Irritable Bowel

(Poly)phenols (PPs) may have a therapeutic benefit in gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). The aim of this review is to summarise the evidence-base in this regard. Observational evidence does not give a clear indication that PP intake has a preventative role for IBD or IBS, while interventional studies suggest these compounds may confer symptomatic and health-related quality of life improvements in known patients. There are inconsistent results for effects on markers of inflammation, but there are promising reports of endoscopic improvement. Work on the effects of PPs on intestinal permeability and oxidative stress is limited and therefore conclusions cannot be formed. Future work on the use of PPs in IBD and IBS will strengthen the understanding of clinical and mechanistic effects.

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Thrombotic Complications in Inflammatory Bowel Disease

Russian Journal of Gastroenterology Hepatology Coloproctology ◽

10.22416/1382-4376-2019-29-2-23-26 ◽

2019 ◽

Vol 29 (2) ◽

pp. 23-26

Author(s):

A. V. Borota ◽

A. A. Borota ◽

E. V. Onishchenko

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Intestinal Wall ◽

Coagulation Cascade ◽

Coagulation System ◽

Primary Disease ◽

Prevention And Treatment ◽

Thrombotic Complications ◽

Inflammatory Bowel

The risk of thrombotic complications is known to be 3 times higher in patients with inflammatory bowel disease (IBD) than in healthy individuals, with the relative risk being 15 times higher during the periods of relapses. Aim. To study and generalize literature data available on the prevention and treatment of IBD thrombotic complications.Key findings. In the сonditions under study, the presence of chronic inflammation and increased bleeding of the intestinal wall is shown to activate the coagulation system, impair the fibrinolysis system and reduce the activity of natural anticoagulation mechanisms. The concentration of fibrinogen — a protein of the acute inflammation phase — increases significantly. This results in an imbalance of the blood coagulation system with a tendency to hypercoagulation, which significantly increases the risk of thrombotic complications and the disseminated intravascular coagulation syndrome. In turn, the activation of the coagulation cascade may trigger the inflammatory response, which eventually leads to the formation of a vicious circle between chronic inflammation and thrombosis. The pathogenesis of thrombosis in inflammatory colon diseases is a multifactor process, which remains to be understood.Conclusion.The management of patients with IBD in combination with thromboembolic complications requires an individual multidisciplinary approach. Taking into account the pathogenetic factors, the following options are possible in the prevention and treatment of thrombotic complications in IBD: strengthening the basic therapy of the primary disease; administration of prophylactic doses of anticoagulants under dynamic continuous laboratory control in the acute period using the methods of conservative therapy of thrombotic complications (elastic compression of the lower extremities) in the period of exacerbation of the primary disease.

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Effects of dietary tryptophan supplementation in the acetic acid-induced colitis mouse model

Food & Function ◽

10.1039/c8fo01025k ◽

2018 ◽

Vol 9 (8) ◽

pp. 4143-4152 ◽

Cited By ~ 8

Author(s):

Shuai Chen ◽

Meiwei Wang ◽

Lanmei Yin ◽

Wenkai Ren ◽

Peng Bin ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Acetic Acid ◽

Gastrointestinal Tract ◽

Mouse Model ◽

Chronic Inflammation ◽

Bowel Disease ◽

Intestinal Immunity ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and is strongly associated with intestinal immunity and the microbiome.

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Inflammatory bowel disease: autoimmunity or chronic inflammation?

Trends in Inflammatory Bowel Disease Therapy 1999 ◽

10.1007/978-94-011-4002-7_5 ◽

2000 ◽

pp. 46-53

Author(s):

L. Mayer

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Inflammatory Bowel

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Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication

Digestive Diseases ◽

10.1159/000449079 ◽

2017 ◽

Vol 35 (1-2) ◽

pp. 25-31 ◽

Cited By ~ 23

Author(s):

Dominik Bettenworth ◽

Florian Rieder

Keyword(s):

Inflammatory Bowel Disease ◽

Chronic Inflammation ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Cell Types ◽

Stricture Formation ◽

Intestinal Fibrosis ◽

Conventional View ◽

Multiple Cell ◽

Inflammatory Bowel

Background: Intestinal fibrosis with stricture formation is a common feature of inflammatory bowel disease (IBD) and leads to a significantly impaired quality of life in affected patients, intestinal obstruction as well as to the need for surgical intervention. This constitutes a major treatment challenge. Key Messages: Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. Similarly to what occurs in other organs, the underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by the activation of both immune and non-immune cells. Other environmental factors as well as chronic inflammation will certainly impact the quality and quantity of intestinal fibrosis. Finally, the composition of the intestinal extracellular matrix is dramatically altered in chronic gut inflammation and actively promotes fibrosis through its mechanical properties. The conventional view that intestinal fibrosis is an inevitable and irreversible process is gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline its pathogenesis. In addition, clinical observations in patients who undergo strictureplasty have shown that stricture formation is reversible. Conclusions: Identification of the unique mechanisms of intestinal fibrogenesis should create a practical framework to target and block specific fibrogenic pathways, estimate the risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, allow the development of treatment methods customized to each patient's type and degree of intestinal fibrosis.

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