What stimulated your interest in the field of IBD?
Simple: I have wanted to cure Crohn’s disease since the first day I started to take care of these patients in France 40 years ago.
How would you define the preclinical phase of Crohn’s disease, and what is known about this phase?
The preclinical phase of Crohn’s disease is what happens before the first symptoms occur and the diagnosis is made. We believe that in Crohn’s disease, as in other immune-mediated diseases, there is a silent phase during which the disease is initiating. Different phases likely happen sequentially: in people at risk for developing IBD, triggering events could lead to an altered gut microbiota, altered intestinal barrier function, and dysregulated immune responses. Then, immune system activation in the gut results in chronic inflammation and mucosal injury. Finally, these changes culminate in symptoms and a clinical diagnosis.
It is plausible that as individuals transition from one stage to another, different biomarkers can be detected in blood or stool. If this preclinical period can be diagnosed, different prediction tools could be offered to individuals at risk for developing IBD, with the goal of eventually offering prevention strategies.
What are the known risk factors for Crohn’s disease?
Thus far, factors such as inherited genetic risk loci and certain exposures have been shown to increase the risk of Crohn’s disease. Having a family member with the disease is still the strongest known risk factor for Crohn’s disease. A genetic component is well established but explains disease development only to a relatively minor extent. The early life period, from prenatal life up to 5 years of age, is critical for gut microbiome establishment and immune maturation. Exposures during this period — including infections, antibiotics, breastfeeding, and pollution — may modulate the risk of disease later in life. Later in life, factors such as urban living, smoking, and ultra-processed foods might act as triggering events in disease development.
To better understand the disease and these risk factors, we need to define: what are the events preceding the development of Crohn’s disease? What are the biomarkers? What is the timing? We see that as a continuum. Importantly, can we interfere with those events? What is the link between those biomarkers, and from that, how can we develop therapeutics?
This gets to our question: Is prevention achievable in IBD?
How might we learn from other immune-mediated diseases — for example, type 1 diabetes — to better understand the preclinical phase and prevention of Crohn’s disease?
The recent approval of the first drug for the delay of clinical type 1 diabetes (Teplizumab, TZIELD) is a fantastic encouragement for everyone working on the prevention of immune-mediated diseases. It has been shown to delay the development of clinical (stage 3) type 1 diabetes in those in stage 2, preclinical type 1 diabetes. Stage 2 is defined by the presence of multiple islet autoantibodies, which are indicative of a very high likelihood of progression to clinical disease development, with abnormal blood sugar but often without symptoms. This approval demonstrates that we can intervene in disease course and is an important step toward prevention of immune-mediated diseases. There are many things we can learn here.
First, it takes a long time — more than 30 years in that case — to develop prevention strategies. We also saw that it can only succeed through large, collaborative international efforts. There is no way one team can develop a drug by itself; we need to work together.
To select people for whom an intervention can be offered, we need a predictive tool with high accuracy. In the example of type 1 diabetes, the presence of islet cell autoantibodies is highly predictive of clinical disease development. Lastly, this research needs to be conducted in close collaboration with patients and their families so that we can understand the benefits and risks they would be willing to accept for a prediction tool and a prevention strategy.
What kind of studies are underway to better understand the preclinical stage of Crohn’s disease?
There are three ways to look at preclinical life:
The first is prospective studies where you follow asymptomatic at-risk individuals, mostly from families where already one or several members have Crohn’s disease. Some of them will develop disease, and some won’t. We collect samples when they enroll in the trial. We then look at the differences in these samples between those who go on to develop Crohn’s disease compared to those who don’t, as these may indicate additional disease-contributing or disease-associated factors.
One example of such a study is the Crohn’s and Colitis Canada Genetic, Environmental, and Microbial (GEM) Project, which is funded in part by Helmsley. This is a prospective cohort of healthy first-degree relatives who have been recruited from 2008 to 2021. Individuals who developed Crohn’s disease were matched to healthy controls. The median time to develop disease in this cohort was about 3.5 years. Some exciting results have come out of this study, such as increased intestinal permeability as a strong risk factor for developing Crohn’s disease. More recently, the GEM team reported changes in the microbiome preceding the development of Crohn’s disease and developed a microbiome risk score. They found that certain taxa of bacteria are associated with Crohn’s disease. This is the first study to show that the gut microbiome as a community may be contributing to the future risk of Crohn’s disease.
The second way to study preclinical development is through nested case-control studies, which involve the analysis of samples collected from people with Crohn’s disease before their first symptom onset. The example here is the PREDICTS (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects) study. It looks at people with Crohn’s disease within the Defense Medical Surveillance System and is linked to the Department of Defense serum repository, which can be used to study many diseases, including Crohn’s disease. Blood samples are available from the time of diagnosis and at several timepoints years before diagnosis, allowing us to look at the trajectory of blood biomarkers over time. This amazing resource has been leveraged using a “multi-omic” approach, studying biomarkers including microbial, proteome, metabolome, glycome, and more recently, the exposome, in order to define the different pathways leading to the development of Crohn’s disease.
In one study from this cohort, in recruits who develop Crohn’s disease, ASCA — antibodies against the yeast S. Cerevisiae — are already elevated in the blood up to six years before diagnosis. In another example, GM-CSF autoantibodies (antibodies against a human cytokine) are elevated in the blood of people with Crohn’s disease up to 10 years before diagnosis.
The third, more indirect, method is to study birth cohorts to understand early life factors that may lead to gut microbiome perturbations, immune changes, and preclinical intestinal inflammation.
Examples of this study design include the MECONIUM (Exploring Mechanisms of Disease Transmission in Utero Through the Microbiome), MELODY (Modulating Early Life Microbiome through Dietary Intervention in Pregnancy), and PLANET (Exploring the Role of Plastics and Toxins in Intestinal Inflammation) studies. These cohorts enroll pregnant women with and without Crohn’s disease and their children. They look at a variety of biomarkers to identify multi-omic signatures and environmental factors that may be associated with intestinal inflammation, and they also explore the role of an early-life dietary intervention. The MECONIUM study, for example, found that the microbiome diversity and calprotectin of babies born to mothers with IBD are already different at birth and during the first year of life. It’s unknown if these children will develop Crohn’s disease because they are still very young, but this shows that even at birth, there are differences.
You might say, “OK, you have all these biomarkers. So what?” Now, we need to link the biomarkers. We need computational analysis. We need to integrate the data. Are there pathways leading to the development of Crohn’s disease? Is there something linking all these biomarkers? Take the data to find the pathways that lead to disease.
Thanks to support from Helmsley, the goal is now to combine data from multiple cohorts and create a large collaborative consortium on prediction and prevention of Crohn’s disease. The aim will be to first assess the predictive performance of the individual biomarkers within each cohort. Then we will integrate multiple parameters that predict CD within each cohort. These integrated risk models defined in each cohort will be compared and validated across the cohorts. Lastly, diverse omics datasets will be integrated in a network analysis aimed at identifying key early drivers and pathways important in the development of Crohn’s disease. Given the different timing of our measurements before diagnosis in each cohort, we will be able to create a timeline of the likely sequence of events before diagnosis.
You’re learning so much about what’s happening before Crohn’s disease. How might that information benefit people who have Crohn’s disease or are at risk of Crohn’s disease?
The ultimate goal of our studies is to build a predictive tool that can be applied to people at risk of Crohn’s disease, such as first-degree relatives of patients with Crohn’s disease, and then to start the first prevention trial. When we are looking at all these preclinical biomarkers, this is teaching us something about the cause of Crohn’s disease. Meanwhile, because the disease is a continuum, we also believe prevention drugs for those at risk may also be beneficial later on, at diagnosis or beyond. So, what we are learning in the preclinical phase may be very useful for new therapeutics in later phases as well.
Despite great progress in the treatment of Crohn’s disease, we are plateauing primarily because our current drugs target the mucosal immune system. Data from GEM and PREDICTS are bringing strong support to developing novel approaches such as enhancers of intestinal barrier function, new formulations of GM-CSF, or glycan-based therapies.
What has been the most rewarding part of your four decades of work in the field of IBD?
This is a very easy question for me. It’s all about changing the lives of patients and people. Most of the papers that I have published will be buried in history. The only thing that matters is the lives that you have changed. The most rewarding achievement in our lives as doctors is when you see your patients going back to their normal lives. Second, the lives of your trainees. I have mentored people from all over the world, and I hope changed their lives for the better. They have the same passion about the disease, and this is the only thing that will matter.
Finally, I am not sure that I will see the success of the first prevention trials, but at least I would have participated in their origin!
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