Understanding the Biology and Genetics of IBD

Dr. Jean-Frederic Colombel is director of The Leona M. and Harry B. Helmsley Charitable Trust Inflammatory Bowel Disease Center at Mount Sinai Hospital where he oversees research aimed at advancing the understanding of IBD and developing effective treatments for the estimated 1.4 million people in the U.S. suffering from IBD.

Inflammatory bowel disease, IBD, refers to a group of medical conditions that cause chronic inflammation in the intestines and colon, most notably Crohn’s disease and ulcerative colitis. Symptoms can be debilitating and include persistent diarrhea, internal bleeding, chronic inflammation and severe pain. Scientists have made significant strides in understanding IBD in the last decade. Recently, Dr. Colombel shared with us his review of these discoveries and promising approaches to IBD treatment. An expanded version of his thoughts appears in the November issue of Nature Reviews: Gastroenterology & Hepatology

Jean-Frederic Colombel

HCT: Our understanding of IBD is constantly evolving. How have treatment options and research approaches changed in recent years?

Dr. Colombel: The IBD treatment paradigm has fundamentally shifted in the last 10 years. There are several major drivers for this new knowledge, one being the recognition that IBD is not an intermittent but rather a progressive disease that leads to bowel damage and disability in the long term. We also now have disease-modifying drugs available that are able to halt disease progression.

In addition, there is evidence that therapeutic decisions should be based on objective markers such as endoscopy or biomarkers and that combination therapy using an anti-tumor necrosis factor (TNF) and an immunosuppressor is the most effective therapeutic strategy. Anti-TNFs and immunosuppressants provide most patients with relief and are useful in effective long-term treatment options as they reduce inflammation. Finally, we know that treatment early in the disease course is associated with improved efficacy of drugs and better outcomes, such as reduced risk for surgery.

HCT: How have genetic discoveries helped us understand Crohn’s and colitis in the past decade?

Dr. Colombel: Treating IBD, particularly Crohn’s disease, is complex. Promising research on genetic markers suggests that a better understanding of our common genetic code is within reach. In the last 10 years, we have witnessed landmark genetics discoveries. Genetic studies have led to the identification of 163 loci that contribute to IBD, many of which are also implicated in other immune-mediated disorders, such as ankylosing spondylitis and psoriasis.

It is worth mentioning that the loci discovered to date represent approximately 20 percent of the potential inherited risk of developing IBD. This ‘missing heritability’ component has led to the conclusion that some forms of IBD – especially the familial forms – could be due to the profound effect of rare variants whose causes are yet to be discovered.

HCT: What other aspects of IBD do we know now that we didn’t know 10 years ago?

Dr. Colombel: Another contribution from the field of genetics is the discovery of the prominent Crohn’s disease risk gene ATG16L1, which introduced the idea of defective autophagy as a fundamental disease mechanism, something that hadn’t been considered before. Autophagy describes how cells replace themselves and their components over time; in scientific language, it is the process whereby cytoplasmic components are isolated from the rest of the cell within autophagosomes, which are then fused with lysosomes and degraded. It also plays an important role in the destruction of intracellular pathogens.

The role of the gut microbiome has also proven to be critical in the development of IBD. Researchers have found that patients with IBD have fewer anti-inflammatory intestinal bacteria and/or more inflammatory bacteria than healthy individuals.

HCT: What do you believe are the greatest causes for optimism around IBD research and treatment?

Dr. Colombel: Our hope is that there will be more clinical applications translating basic science insights from bench to bedside. For instance, we need to be able to predict disease outcomes in IBD. One example would be a biomarker-based method for predicting severity of Crohn’s disease and ulcerative colitis so that by measuring components in the blood or stool we will know who is at risk for complications or flares. This method could potentially predict the need to increase or decrease therapeutic intervention. From a therapeutic standpoint, using biomarkers would help doctors provide targeted care to patients who most closely fit the recommended treatment profile.

Finally, although most current treatments in IBD work by dampening the immune system, which has unavoidable adverse effects, there is great hope that balancing the gut microbiota through diet or medications will be beneficial for many patients. As researchers and doctors continue to investigate these promising approaches, we want to be able to improve the patient experience and more consistently reach more desirable health outcomes.