Published on 09.05.2022
In ulcerative colitis, the chronic inflammation affects exclusively the colon. In contrast, in Crohn's disease, all parts of the digestive tract, from the mouth to the anus, can be affected, with a greater frequency of lesions in the distal part of the small intestine and the colon. IBD usually results from a complex interaction between environmental and genetic factors. Some rare forms may be monogenic diseases, linked to mutations in a single gene. They are characterized by their severity and their very early onset.
IBD, serious pathologies due to environmental and genetic factors
Inflammatory bowel diseases cause symptoms that can greatly alter the quality of life of patients: severe fatigue, frequent and severe diarrhea, abdominal pain, loss of appetite, weight loss, fever, and even joint, eye or skin inflammation. They have a considerable impact on the daily, social and school life of children.
Nadine Cerf-Bensussan's intestinal immunity research team seeks to elucidate the molecular mechanisms that alter the intestinal barrier and cause pathological intestinal inflammation.
"The numerous studies underway indicate that IBD is the consequence of pathological interactions between the microbiota and the immune system in genetically predisposed individuals," she explains. In these individuals, the immune system overreacts to microbes in the gut lumen, leading to inflammation and destruction of the gut barrier.
A very large number of genetic variants conferring susceptibility to IBD have been identified. Nevertheless, in the vast majority of patients, their individual or collective contribution to the onset of these diseases is minor.
The environment and diet play an important role, especially in influencing the composition of the microbiota. Thus, "the balance between the microbiota and its host has been progressively disturbed by environmental and lifestyle changes over the last 40 to 50 years. In industrialized countries and particularly under the influence of a diet rich in sugar and fat, the microbiota has lost its diversity. The proportion of bacteria with naturally anti-inflammatory effects has been reduced in favor of bacteria capable of excessively stimulating the immune system. The physiological inflammation that develops in the intestine in response to colonization by the microbiota gradually shifts to pathological inflammation. This, in turn, favors the selection of more aggressive bacteria, creating a vicious circle that can ultimately trigger and maintain IBD."
Identify and understand monogenic forms
Some rare but very severe cases of chronic inflammatory bowel diseases may be the consequence of the alteration of a single gene that is essential for the proper functioning of the intestinal immune barrier or for its regulation. These monogenic diseases most often begin in the first months or years of life.
"While IBD is generally an adult disease, we have observed that more and more children are developing these diseases very early in life. We wondered about the importance of genetic factors in the appearance of these very early forms," explains Nadine Cerf-Bensussan.
Over the past six years, the team has studied approximately 500 children who develop diarrhea and intestinal inflammation before the age of 6 years and identified 30% of single-gene diseases.
"These generally present in two ways. In the first case, the lesions are located in the upper part of the intestine, simulating celiac disease. These high forms are very often associated with strong autoimmunity and severe allergic diseases. Causal mutations are frequently identified. In the second case, the disease affects the lower intestine causing colitis and in some cases severe perianal lesions. A single gene disease is somewhat less common and is mostly detected when there are perianal lesions. Nevertheless, it is advisable to look for a monogenic disease in very early onset forms, whatever their presentation, because the identification of a mutated gene allows to optimize the management".
In addition to making a contribution to diagnosis, the team's work is helping to identify the genes that are essential for the construction of the epithelial barrier and its protection by the immune system. The team has thus identified several new monogenic intestinal diseases.
Beyond diagnosis, the objective is to improve the treatment of IBD.
In monogenic forms, the identification of the mutated gene is a key step in the management of the disease as it allows the optimization of the therapeutic strategy. When the mutated gene exclusively affects the immune component of the intestinal barrier, many solutions exist today. In the most severe forms, the immune system can be replaced with a bone marrow transplant. In other forms, a growing number of treatments allow to target the altered signaling pathway. In case of monogenic disease affecting the epithelial component of the epithelium, therapeutic solutions remain unsatisfactory and our team has chosen to invest in the development of new innovative approaches.
In common forms of IBD, optimizing treatment remains very difficult and, despite a growing number of therapeutic tools, many patients are or become refractory to the chosen treatment. Indeed, the mechanisms causing inflammation vary from one patient to another and "it is therefore now key to be able to identify the mechanism to be targeted first in order to optimize the treatment of each of them".
To help with this stratification of common forms of IBD, "we have set ourselves the goal of establishing an atlas of functional signatures characteristic of each monogenic disease. Ultimately, we hope that it will provide a baseline for analyzing the functional signatures of patients with common forms of IBD and guide the choice of treatment."
A necessary complementarity between researchers, physicians and patients
"France is at the forefront of research on inflammatory bowel diseases thanks to the concerted work of its expert teams, its dedicated reference centers, and thanks to patient associations, which are very involved in the financing of research projects and in supporting patients," says Nadine Cerf-Bensussan.
Institut Imagine is an example of this work and of this complementary care. The Institute's research laboratory works closely with the Reference Center for Rare Digestive Diseases (MARDI) at Hôpital Necker-Enfants malades (AP-HP), coordinated by Prof. Frank Ruemmele, and in particular with the patient association AFA-Association François Aupetit, whose deputy director is Anne Buisson. The three of them will give a lecture on the subject of IBD on the occasion of the International Rare Diseases Day on February 28, 2021.