Article by Kyla Trkulja

Graphic design by Michie (Xingyu) Wu

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal (GI) tract that affects millions of people worldwide.¹ IBD includes conditions such as Crohn’s disease and ulcerative colitis, and is one of the most prevalent GI diseases with accelerating incidence in newly industrialized countries.¹ In this condition, chronic inflammation of the GI tract causes an influx of immune cells that produce cytokines and free radicals that damage the intestinal epithelium, causing painful ulcers and symptoms such as abdominal pain, diarrhea, bloody stools, and weight loss.¹ 

The exact cause of IBD remains largely unknown, but is thought to be a complex combination of genetic susceptibility, composition of the intestinal microbiome, environmental factors, and abnormalities in the immune system.¹ The lack of a clear etiology makes this disease very difficult to treat; in fact, for decades, treatment focused only on controlling the symptoms instead of the underlying disease.² Thankfully, recent advances in the past 20 years have generated treatments aimed at helping patients achieve remission, allowing patients to achieve a better quality of life.² However, the complexity of the disease results in patients presenting clinically different from each other, known as heterogeneity; this makes it difficult to find an optimal therapy that works for all patients.²

One researcher working to help overcome this issue is Dr. Mark Silverberg, a clinician-scientist at Mount Sinai Hospital. He has been involved in many of the treatment advances made in IBD, and continues to research new treatments and ways to tailor them appropriately to patients. He was a student at the University of Toronto for many years, where he completed his medical education, gastroenterology residency, and PhD studying the genetics of IBD. Dr. Silverberg has been taking care of patients with IBD for over 20 years and has led many clinical trials and research studies to improve disease management. His research looks for causes of IBD, treatments, and ways to develop tools that allow clinicians to predict a patient’s clinical course with the disease based on their genetic and bacterial signatures. 

Dr. Silverberg was inspired to study IBD by his mentors during his training. He worked under a clinician-scientist who he said, “was probably the first person that got me excited about the area that I ended up pursuing.” During his PhD, genetics of complex diseases was just starting to become a “hot topic” as a result of the ongoing Human Genome Project, and researchers thought that finding genes for chronic diseases was going to be the key to curing them. “That was why I started in the research field and in looking for genetic variants that lead to inflammatory bowel disease,” Dr. Silverberg explained. 

However, as research unveiled that chronic diseases involve both genetic susceptibility and environmental contributions, Dr. Silverberg realized that focusing on genetics alone was not going to be the answer to the problem. “So, I started to shift into more of the environmental side. In particular, I was always interested in diet and food and its effect on disease and in particular, on the microbiome,” he described. Over the next several years, he pivoted his work to combine his knowledge of genetics with the environmental aspect of IBD, inspiring his research in biomarkers related to disease severity, clinical markers related to treatment outcomes, and the microbiome and its effect on prognosis. 

An example of this can be seen in one of his recent projects, where his team examined gene expression and microbiome profiles in patients with IBD. This knowledge was used to better understand whether the treatment target for IBD should be bowel healing, as seen during a colonoscopy, or histological healing, as seen by looking at the patient’s tissue sample under a microscope. Gene expression and microbiome patterns in IBD patients who only healed in one of these two ways were compared to that of IBD-free individuals. Their results showed patients with histological healing had gene expression and microbial patterns that were similar to healthy individuals without the disease. The project “proved from a biomarker standpoint, from a biologic standpoint… that histologic healing is a better target,” Dr. Silverberg explained. With a clearer idea of the optimal treatment goal for IBD patients, doctors will be able to better monitor and care for their patients. 

Despite the challenges of precision medicine in IBD, Dr. Silverberg still has hope that progress will be made on this front. “It’s a very heterogeneous disease… personalized medicine and precision medicine is probably going to be critical in making better progress in treatment and understanding etiology,” he said. To get there, Dr. Silverberg says, “the next few years will focus on gut bacteria and how its composition will define precision medicine. By finding relationships between the microbiome and the type of IBD a patient has, how aggressive it is, what parts of the bowel are affected, and whether they respond to different therapies, better precision medicine targets will hopefully be achieved.” 

Part of Dr. Silverberg’s success in this field has been due to his role as a clinician-scientist. He describes the role as challenging, as “you need to stay up to date and be progressive when you have clinical responsibilities, and to try to compete for grants and write papers at the same time as making sure you answer your patients’ questions and help them when they’re not doing well. So, it’s a tricky balance.” However, the challenges of the role are what allow his work to be so ground-breaking; as Dr. Silverberg describes, “a lot of our research questions and approaches all derive from clinical problems that we face. It’s the questions that we see in the office and with patients that drive our excitement to do the research to solve it.” Through his dual role and hard-working, innovative team, knowledge on underlying causes and optimal treatments for IBD will continue to advance. 

References 

1. Guan Q. A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease. J Immunol Res. 2019 Dec 1;2019:7247238. doi: 10.1155/2019/7247238. 
2. Jeong DY, Kim S, Son MJ, et al. Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review. Autoimmun Rev. 2019 May;18(5):439-454. doi: 10.1016/j.autrev.2019.03.002.