Fraunhofer Cluster of Excellence Immune-Mediated Diseases
Fraunhofer Cluster of Excellence Immune-Mediated Diseases

Development of new therapeutic strategies for the treatment of chronic inflammatory bowel diseases

Development of a novel therapeutic concept for chronic inflammatory bowel disease (IBD) via non-toxic ligands of the aryl hydrocarbon receptor

The collective term “chronic inflammatory bowel disease” (CIBD) is used to describe a number of illnesses that are characterized by intermittent or continuous inflammatory changes in the bowel. The most important chronic inflammatory bowel diseases are Crohn's disease and ulcerative colitis. Around 300,000 people in Germany currently suffer from these two diseases, which are associated with years of abdominal pain and diarrhea, but also with severe fatigue. After a long period of illness, numerous extraintestinal manifestations (e.g. arthritis) may occur. In most cases, the diseases occur between the ages of 20 and 30, but young children and adolescents are also affected. The exact cause of these diseases is still unknown. It is assumed that there is a genetic predisposition that leads to the onset of the disease as a result of environmental influences.

© Fraunhofer CIMD

Both diseases usually require long-term therapy

In both diseases, symptoms can be alleviated and complications can be avoided, at least in part, with medication and surgery. Crohn's disease is incurable to date; ulcerative colitis could be cured by surgical removal of the entire colon, including the rectum. Surgical measures are often associated with complications and a reduced quality of life.

 

The aim of therapy for both diseases is to reduce the inflammation with anti-inflammatory drugs. Since these are chronic diseases, drug therapy is usually permanent. In addition, these are system-related therapies. There is still no therapeutic approach that sustainably improves the dysregulation of the intestinal immune system.

 

The aryl hydrocarbon receptor represents a promising target in chronic inflammatory diseases

The intestinal flora (microbiome), which is significantly influenced by diet but also by the use of antibiotics, plays an important role in the development of inflammatory bowel disease. Therefore, diet and alternatives to antibiotic therapy are playing an increasingly important role in the treatment of these diseases.

Recent studies have shown that the aryl hydrocarbon receptor (AhR) is a novel and promising therapeutic target for chronic inflammatory diseases. Numerous studies have now shown that the AhR plays an important role in the innate and adaptive immune system in maintaining immune homeostasis and in the regulation of inflammatory responses.

The project aims to identify suitable AhR ligands

The AhR is of central importance for the communication between immune cells and intestinal epithelial cells. AhR ligands from food or the intestinal flora activate the AhR, thereby promoting the survival and proliferation of immune cells and thus contributing significantly to immune cell homeostasis.

The preclinical proof of therapeutic efficacy of two non-toxic AhR ligands has already been demonstrated in the mouse model of chronic sodium dextran sulfate (DSS)-induced colitis, which is the most widely accepted standard animal model for IBD. On the basis of this preclinical proof-of-concept study, the aim of this project is to identify suitable AhR ligands that have already been approved for other indications or for which initial results from clinical studies are already available (repurposing). The efficacy of identified AhR ligands will then be tested in the chronic DSS colitis model and in a bacterial-induced chronic colitis model in the mouse.

 

General approach

The identification of AhR ligands will be carried out by screening the repurposing libraries at the Fraunhofer ITMP ScreeningPort. The newly identified candidates are then tested for efficacy in vivo (in animal models) at the Fraunhofer IZI. The analysis of the disease models includes in vivo monitoring (endoscopy) as well as histology, immunophenotyping, microbiome analysis, proteome and transcriptome analysis and is carried out at the Fraunhofer IZI and IIS.

 

Aim and outlook

Chronic inflammatory bowel diseases are associated with long-term therapy, possible surgery and a significant loss of quality of life for those affected. If the therapeutic efficacy of AhR ligands for the treatment of chronic inflammatory bowel diseases can be proven in both animal and further clinical studies in humans, a novel approach to treating these diseases would be available.

AhR ligands that show both efficacy for the treatment of IBD and are safe and well tolerated in the in vivo test must then also demonstrate their efficacy and safety in humans in an initial proof-of-concept study.