Story of discovery: discoveries moving towards understanding and personalized treatment of inflammatory bowel disease
After leaving the stomach, ingested food travels through approximately 25 feet of small and large intestines. The innermost part of the intestinal lining that comes in direct contact with food—called the intestinal epithelium—is composed of a diverse mix of cells that perform critical roles for digestion, including absorption of nutrients and secretion of substances that aid in the sensing and movement of intestinal contents. Surrounding the epithelium is a conglomeration of blood vessels, nerves, and muscle cells. Also within the intestinal lining are immune cells that act as sentinels ready to defend the body against gastrointestinal pathogens. These immune cells are overly active in people with inflammatory bowel disease (IBD), leading to painful inflammation that can devastate the intricate intestinal lining. The accompanying symptoms can be crippling. For example, diarrhea results if inflammation shuts down absorption in the intestine. In severe cases, lesions develop, accompanied by intestinal bleeding. IBD can also lead to malnutrition when nutrients from food cannot be absorbed, a condition that is especially harmful to children because it can stunt growth.
The development of effective IBD treatments has been inhibited by a lack of understanding of the causes of the underlying inflammatory process. But in recent years, researchers have discovered ways in which the bacteria and other microbes that reside in the gut—the gut microbial community or microbiome—can affect risk of IBD, and efforts such as NIDDK’s IBD Genetics Consortium are shedding new light on the genetic foundations of the disease. With its Intestinal Stem Cell Consortium and clinical research efforts, the NIDDK is already leveraging those insights to test new approaches to therapy for IBD. The story of IBD is one of increasing complexity, but also the discovery of new immunologic, genetic, and microbial links to the disease, and the potential for novel, more effective therapies.
An Early Picture of IBD: Crohn’s Disease and Ulcerative Colitis
Inflammation is normally a part of the immune system’s response to fighting infection, but in the latter half of the 19th century clinicians described cases of intestinal inflammation that did not seem to have an infectious origin. By the 1930s, it had become apparent that most of these cases could be segregated into two separate diseases: ulcerative colitis and Crohn’s disease. These two diseases would eventually be grouped under the umbrella term “IBD.”
There are fundamental differences between Crohn’s disease and ulcerative colitis. In ulcerative colitis, the inflammation encompasses only the colon (large intestine) and is generally limited to the innermost layers that make up the intestinal wall. In Crohn’s disease, which is not as common as ulcerative colitis, the inflammation may involve any part of the gastrointestinal tract (although it usually manifests in the small intestine and the beginning of the colon) and is not continuous, resulting in patchy lesions. These lesions also tend to be deeper than in ulcerative colitis, producing strictures (places where the intestines narrow) and fistulas (abnormal passageways between areas of the intestine).
Early treatments for IBD were limited to surgical removal of the affected area—a strategy that is still in practice today for people who have severe inflammation that does not respond to other therapies. For people with ulcerative colitis, this usually means removal of the entire colon. For Crohn’s disease, surgery is limited to smaller affected areas. However, removal of a lesion does not cure Crohn’s disease, and it is possible that additional lesions will appear elsewhere.
The recognition that IBD encompasses two distinct but related entities was a major step toward understanding these diseases, but researchers sought to understand the excessive inflammation underlying both forms. They would eventually discover that the intestinal inflammation results from multiple interplaying factors, including the immune system, genetics, and the environment.
Suppressing the Immune Response
The knowledge that inflammation was the driving force behind the symptoms of IBD led naturally to the first useful, non-surgical therapeutic approach: reducing inflammation. Since the 1950s, for example, clinicians have prescribed anti-inflammatory drugs such as corticosteroids, which are fast-acting and powerful enough to suppress flareups (the sudden worsening of symptoms) but cannot be used as a long-term treatment because of potentially serious side-effects. Aminosalicylates, such as mesalamine-based drugs, are another class of anti-inflammatory medications. While they are generally well-tolerated, they may not be effective for people with severe IBD symptoms, so their use is generally limited to people with mild to moderate cases.
Other medications reduce the inflammatory response by hampering the immune processes that drive it. These therapies, called immunomodulators, have been used to treat people with IBD since the 1960s. Although they can be an effective treatment for those who do not respond to (or cannot tolerate) corticosteroids or aminosalicylates, immunomodulator-based treatments are not without risks. They could produce potentially severe side-effects, including an increased risk of infections because the drugs reduce the activity of the body’s immune system.
Despite the long history of using immunomodulators to treat IBD, the risk-benefit profile of one such medication has only recently been thoroughly ascertained: methotrexate, an inexpensive yet potentially toxic immunomodulator that is prescribed for adult Crohn’s disease patients in whom established therapies have failed. The NIDDK funded the Methotrexate Response in Treatment of Ulcerative Colitis (MERIT-UC) study to determine its risk-benefit profile in the more common form of IBD. Recent results from this study showed that methotrexate did not improve ulcerative colitis symptoms compared to a placebo, suggesting that this drug, which could lead to chronic liver disease and liver fibrosis, is not beneficial for colitis patients.
Other means of modulating the inflammatory response in IBD have been suggested by advances in basic research on the immune system. For example, immunologists have identified several key molecular signals that trigger inflammation. Among these are molecules called cytokines, which are secreted by immune cells and play important roles in driving the inflammation in the gut. The pro-inflammatory cytokines found to be involved in IBD include tumor necrosis factor alpha (TNFα) and interleukin-12/interleukin-23 (IL-12/IL-23), which play major roles in other inflammatory diseases such as arthritis and psoriasis. Researchers found that blocking the activity of these cytokines can suppress inflammation in the gut. There are numerous drugs that have been developed to target TNFα and IL-12/IL-23, or the cellular signals that are elicited by these cytokines. Other drugs have been developed to block molecules, called integrins, that immune cells use to stick to the walls of blood vessels as they move out of the blood and into the tissue where they contribute to inflammation. Not every person with IBD responds to these anti-cytokine and anti-integrin treatments, however, and these drugs too can cause serious side-effects, including a heightened risk of infections. Also, most of these drugs are proteins and would be digested and broken down before they reach the site of inflammation if taken orally. Therefore, they must be administered through regular injections.
Digging Through the Genetics of IBD
By the end of the 20th century, with evidence mounting that IBD varies significantly from person to person, it was apparent that developing safer, more effective therapies would likely depend on determining the factors that contribute to the inflammation in ulcerative colitis and Crohn’s disease. IBD tends to run in families, so scientists strongly suspected that genetic factors were important. Identifying the genes involved in the disease could reveal new targets for therapy. A better understanding of IBD genetics might also enable clinicians to screen for people at risk for IBD—and early detection might make it possible to prevent the inflammation before it starts and becomes difficult to restrain. Genetic studies might even lead to personalized therapy by predicting which individuals would respond best to different types of IBD treatment.
Therefore, through grants to researchers at academic medical research institutions across the United States, NIDDK established the IBD Genetics Consortium (IBDGC) in 2002 to identify genes that are involved in IBD susceptibility. In collaboration with the International IBD Genetics Consortium, of which it is a member, the IBDGC has enrolled thousands of IBD patients and identified about 200 regions of the human genome that are associated with risk of IBD. This work has yielded important new insights into the complex and individual nature of the disease. In one IBDGC study, for example, researchers analyzed data from over 29,000 men and women with IBD and found that, in Crohn’s disease, inflammation in the ileum of the small intestine (near the junction with the colon) has distinct genetic causes from forms of Crohn’s in which inflammation occurs in the colon. In other words, there are actually at least three distinct types of IBD—ulcerative colitis and two forms of Crohn’s disease—which could help guide targeted treatments in the future. Other advances from the IBDGC have identified genetic variants that affect the microbiome (the diverse community of bacteria and viruses living in the gut), the immune system, or the integrity of the intestinal epithelium—all of which play important roles in IBD. Despite these advances, many of the specific genes involved in IBD, along with their respective genetic variants that contribute to IBD susceptibility, have yet to be precisely identified. A goal of the current phase of the IBDGC, which was renewed in 2017, is not only to continue identifying regions of the genome associated with genetic risk for IBD, but also to identify the specific genes and genetic variants within these regions that influence IBD susceptibility. Consortium members are also exploring the role of epigenetics—how genes are turned on and off independently of their DNA sequences—and how genetic factors influence the development of IBD by investigating the functions of candidate genes.
Exploring the genetics of IBD has provided insight into its origins, along with an abundance of possible molecular targets for screening or therapy. It also has cemented the understanding of IBD as a disease that could vary greatly from person to person, depending on genetic backgrounds, highlighting the need for more personalized approaches to treatment and prevention.
The Role of the Microbiome
IBD was rarely diagnosed before the 20th century, and today it is more common in industrialized regions of the world. Although this may stem in part from greater awareness of the disease, it also suggests that while genetics are an important contributor to IBD susceptibility, environmental factors—including the microbiome or factors that affect the microbiome—also likely play a role. Scientists thinking along these lines considered the possibility that an abnormal immune reaction to components of the microbiome might provide the long-sought explanation for the inflammation that leads to IBD. In fact, numerous studies have shown correlations between IBD and changes in either the microbiome or in how the body reacts to it.
Early support for this idea came from a study in a rat model that found a link between the composition of gut microbes and colitis. Scientists also showed that feeding a diet high in saturated fats from milk to mice with a genetic susceptibility to intestinal inflammation altered their intestinal microbial communities, the composition of their bile acids, induced changes in their immune function, and increased intestinal inflammation. More recently, a study in children and teens showed that different treatments for Crohn’s disease, such as immunosuppressive medication or a defined formula diet, have varying effects on the gut microbiome—a finding with implications for approaches to monitoring treatment response and for potentially developing microbiome-targeted therapies.
Important insights are also coming from the NIH’s Human Microbiome Project (HMP), which was launched in 2007 to characterize the community of microbes present in humans. As part of the HMP, the NIDDK co-funded and managed a study designed to understand how the gut microbiome is altered in IBD. This study integrated many different types of measurements of gut microbes as they change within IBD patients, including both children and adults, over time. The researchers found that the microbiomes of people with IBD were more volatile and fluctuated to a greater extent than those of healthy people, providing still more evidence that changes in the microbiome are closely linked to the disease.
Future research will seek to elucidate the specific ways in which components of the microbiome may promote IBD—or protect from the disease. Microbiome analyses in individuals with IBD may one day even help personalize treatment of their disease.
The Future of IBD Therapy: Personalized Medicine
Armed with what they’ve learned about the many factors affecting susceptibility to IBD, researchers are now seeking to develop personalized therapeutic approaches that consider the complex interactions among the immune system, genetics, and the environment driving development of the disease in any given individual.
It is now becoming possible to correlate specific genetic variants and other clinical test results with disease severity and responsiveness to therapies. For example, the NIDDK-sponsored Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) study has been evaluating whether a combination of clinical, genetic, and immunologic tests can be used to predict response to standard medical therapy for children newly diagnosed with ulcerative colitis. Recent results from the PROTECT study found that higher amounts of an immunologic biomarker called pANCA in the blood correlates with disease severity, suggesting that this biomarker, which also may be associated with resistance to standardized therapy, could potentially be used as a diagnostic tool to help plan individualized treatments for children with the disease.
Another personalized approach that holds promise is the manipulation of the microbiome to maintain it in a healthy state. This could be accomplished by restoring a health-promoting profile of bacteria in the gut of a person with IBD using tailored probiotics to reintroduce underabundant bacterial species, or by fecal microbiota transplant whereby the gut bacteria from a healthy donor would be introduced into a person with IBD.
An additional therapeutic approach would be to use cellular models of the gut to develop new personalized treatments in the laboratory and to possibly replace the damaged tissue in a person with IBD. Toward this goal, members of the NIDDK-supported Intestinal Stem Cell Consortium (ISCC) are developing methods to generate small conglomerations of cells that look and behave like a miniature portion of a human intestine. The ISCC has demonstrated that these “mini-intestines” can be generated using adult cells as starting material, suggesting that a patient’s own cells could be used to screen for drugs that would be effective for that individual’s disease. Personalized mini-intestines could also be potentially invaluable research models to study the genetic roots of IBD and how the intestine heals itself when injured. Additionally, mini-intestines may one day be implanted to repair or replace areas of the gut that have been damaged by inflammation, and because they could be derived from a patient’s own cells, they would less likely be rejected by the immune system. ISCC scientists have already used these mini-intestines to generate a functional enteric nervous system—the mesh-like arrangement of nerves that governs the function of the gastrointestinal tract—demonstrating their potential as models for bona fide intestines. They also generated mini-intestines that resemble different parts of the intestine, such as the ileum (the lower end of the small intestine) and duodenum (the section of the small intestine closest to the stomach). This is important from a replacement therapy standpoint because distinct regions of the intestine have different functional roles in digestion. Although research into regenerative medicine-based approaches is still in its early stages, these advances hint that the coming years may eventually see intestinal stem cell-based therapies for IBD.
IBD is indeed a complicated disease with many players. But for every cytokine, gene, or bacterial species linked to IBD, a new path opens for the development of a method to detect, prevent, or treat the disease. With more research into how combinations of factors drive the disease, and how they vary from person to person, we come closer to a future of far better health outcomes for people with IBD.