How to improve therapies for inflammatory bowel disease
About three million people in the United States suffer from inflammatory bowel disease (IBD), and while patients have more treatment options now than they did 10 years ago, IBD drugs don’t work for more than half of them. One reason could be that IBD, which includes ulcerative colitis and Crohn’s disease, results from a complex interaction between a patient’s genetics, immune system, diet, environmental exposures, and microorganisms in the gut, or the microbiome — and researchers are only now beginning to tease out the interactions that really drive the disease.
Ramnik Xavier, a core institute member and co-director of the Infectious Disease and Microbiome Program at the Broad Institute of MIT and Harvard, co-director of the Center for Microbiome Informatics and Therapeutics at MIT and a gastroenterologist who sees IBD patients at Massachusetts General Hospital (MGH), and Daniel Graham, a senior group leader at Broad and a member of the Center for the Study of Inflammatory Bowel Disease at MGH, answer our questions about how the IBD field should move forward and what the future of IBD treatment looks like.
They and others co-authored a recent review paper in Cell, where they discussed the challenges in IBD research and opportunities for better therapies.
Q: Why is IBD so challenging to understand?
Graham: One of the major challenges in understanding the disease is the fact that it’s so different between individuals. Each patient may experience disease in a different way and then progress in a different trajectory. That’s probably a reflection of many genetic risk factors interacting with many different environmental factors to produce different outcomes. The fact that we don’t fully understand all of those genetic and environmental risk factors has been a limitation for developing new treatments.
Xavier: IBD was initially defined as Crohn’s disease and ulcerative colitis, based on a constellation of symptoms and the distribution of disease in the gut. What’s become clear is that defining this as two disease types is rather simplified. It’s more likely that there are probably a dozen variations within those two diseases. Across those subtypes, there are differences in not just clinical manifestations but also in how people respond to treatments.
Q: You write in your review that existing drugs for IBD work in only about 60 percent of patients, and that 13-46 percent of patients who initially respond to medications become resistant to the drugs within a year. Why is that?
Xavier: Actually, the number of patients who respond is a significant advancement. Twenty years ago, we had a limited cabinet of drugs to treat patients with IBD. Now that’s significantly expanded. But these drugs are being made to a small set of targets, so they’re acting on only a limited number of pathways involved in the disease. That explains the lower percentage of patients who respond to drugs. For patients who lose response, there are many reasons for drug resistance. IBD is a complex ecosystem, and human genetics can provide clues to novel drug targets and pathways.
Q: What is the biggest knowledge gap that is contributing to this low treatment response rate?
Xavier: We need to define the subtypes of Crohn’s disease and ulcerative colitis, treat the disease early, and better define biomarkers that we can use to monitor drug response, define disease remission, and maintain people in remission for much longer.
Q: What area of research is most needed to improve our understanding of IBD?
Graham: In looking at IBD and how it manifests, the field is starting to view this as a gut ecosystem: a constellation of many microbes inhabiting the gut that interact with the immune system. The relationship between our immune system and our microbiome can be somewhat volatile. In IBD, the immune system overreacts to normally harmless gut microbes. This can lead to a vicious cycle of inflammation and an unbalanced microbiome ecosystem. Ongoing research will hopefully help us understand the cause-and-effect relationship between inflammation and microbiome disruption. The ultimate goal of this research is to someday figure out how to stop the vicious cycle of inflammation in the gut.
Q: What do you think the next generation of more effective IBD drugs will look like?
Xavier: Using human genetics as a starting point for drug discovery programs will become more prominent. Microbiome-based therapies are also emerging, but one needs to learn a lot more about the underlying mechanism behind the interactions between the microbiome and the gut immune system. I fully expect that, as outlined in our article, there’s a roadmap for doing that.
Graham: We are finding a lot of new therapeutic entry points from looking at the genetics of patients who experience IBD. Historically, a lot of the most commonly used and effective therapies have been anti-inflammatory medications. Emerging genetics is now telling us that there are many other biological processes that are impacted in IBD and may represent unique points of entry for new therapeutics.
We’re also finding genetic variants that are associated with protection from IBD. Genetics typically teaches us about disease, but by looking at genetic factors that are protective against disease, we can learn about health. This is a unique perspective, and untapped in terms of finding new therapeutic modalities.
Q: Would new therapies take a personalized medicine approach?
Xavier: We need new approaches to drug discovery, better ways to classify patients by disease type, and innovative clinical trials to bring new drugs to patients faster. Those drugs will have to treat a broader set of patients, but how the drugs are introduced to the patient, and the time at which they are introduced, is likely to be personalized. This will result in better quality of life and more rational use of resources.
Q: Your paper discusses different efforts to leverage the microbiome in IBD treatment. What looks promising from that end?
Graham: One way to re-establish a balanced microbiome is through dietary intervention. The field is in the very early stages of understanding how to do this in a precise, directed way. This is the direction that the field is going in and this is what we have been focusing on at the Broad.
Xavier: Our review article proposed four approaches to finding microbiome therapeutics, like using microorganisms and microbial products, as a basis for drug development. But it’s very important that those approaches are coupled with a better understanding of the activity and location of inflammation in the gut, a patient’s particular clinical history, and also some idea of what drugs that patient has responded to or failed to respond to in the past. The successes seen in microbiome therapies for a condition called C. difficile colitis are very different from what’s needed to treat inflammatory bowel disease.
Q: What is the main take-home message from your review?
Graham: The field of microbiome research is converging with host biology and immunology in a way where, through collaborations, we are gaining new insights into diseases like IBD and other immune phenomena that are impacted by the microbiome. This review was an effort to synthesize research across different fields and provide a view of where the field will go collectively in the near future.