The overall goal of the CSIBD is to promote and facilitate research that will yield insight into the causes and pathogenesis of IBD and lead to improved therapeutic approaches.
The Center for the Study of Inflammatory Bowel Disease (CSIBD) is a multidisciplinary program whose goal is to define fundamental mechanisms underlying Crohn’s disease and ulcerative colitis. Our center is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. The center encompasses 111 investigators at Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Broad Institute, Harvard Medical School, Massachusetts Institute of Technology, Tufts University, the University of Massachusetts Medical School and the Harvard School of Public Health, all pursuing research in a broad spectrum of basic science relevant to inflammatory bowel disease (IBD). Since its establishment in 1991, the CSIBD has advanced our understanding of IBD through the study of relevant basic biological processes and the directed study of the diseases themselves.
Inflammatory Bowel Disease
IBD is a general term that refers a family of diseases, the major forms of which are ulcerative colitis and Crohn’s disease. More than a million individuals in the United States have a form of IBD. These diseases have no known cause, but significant progress is underway in understanding the underlying mechanisms of these disorders. Our current model of IBD is based on a combination of increased genetic risk and an immune system that overreacts to environmental and microbial stresses. We believe that IBD affects people who have inherited genetic risk factor(s) that makes them predisposed to get the disease. When a person with this predisposition is exposed to some environmental factor, the disease is triggered.
Our investigations into the IBD disease process are occurring at many levels and take many experimental approaches, from molecular biology and biochemistry to computational analysis. To help illustrate how the CSIBD research base is working to fulfill the Center’s mission, we include a brief description of the central components of IBD disease mechanisms.
Figure 1: Investigative areas targeted by the CSIBD to advance the understanding of mechanisms leading to IBD
One of the greatest challenges in the study of IBD is understanding how particular genetic risk factors contribute to the initiation of disease. More than 100 genes and genetic loci have been linked to IBD, but we are only beginning to understand the biological significance of these loci and how these genes contribute to disease susceptibility. Each of these genes has the potential to yield insight into disease mechanisms. Understanding the significance of these risk factors may also help us to develop individualized drug treatments.
IBD is among the few complex diseases for which genome-wide association studies (GWAS) have been clearly successful. These studies have identified many non-overlapping genetic risk loci, including some that are shared between Crohn’s disease and ulcerative colitis (see Khor et al., Nature 2011). Importantly, many of these genomic regions and specific genes have been confirmed in replication studies. However, the relationship between genetic factors and disease is not entirely straightforward. For example, if one twin has ulcerative colitis, the probability that the identical twin will also suffer from ulcerative colitis is only 10-15%. In the case of Crohn’s disease, the probability goes up to 30-35%. From these statistics, it is clear that risk alleles often require other genetic or environmental factors in order to cause disease. In one of the many susceptibility alleles for Crohn’s disease (ATG16L1), researchers have discovered that the mutated gene requires interaction with a viral cue to manifest disease. This model may apply to other risk alleles, in which an environmental (microbial) cue, in combination with additional environmental factors and commensal bacteria, may determine how disease is manifested in individuals carrying common risk alleles.
Although GWAS studies have identified many genes and genetic loci, it remains unknown how these genetic variations contribute to the onset or progression of IBD. In most cases, the functions of the genes have not been discovered. Characterizing these genetic variants involves (1) identifying the normal function of the affected gene, (2) determining how IBD-associated genetic variations affect the normal function of the gene, and (3) discovering how this altered function contributes to the dysregulation of intestinal homeostasis. CSIBD labs are working to achieve this understanding through many different research perspectives, including novel genomic, genetic, and chemical biology approaches.
|Figure 2: A model for IBD pathways based on genome-wide association studies.|
Healthy individuals maintain a variety of bacteria in their digestive systems. Many of these bacteria are harmless, and some are actually necessary for processing of nutrients such as certain vitamins. Evidence suggests that the interaction between these bacteria and the host digestive system may be altered in IBD. This evidence includes the therapeutic benefits of antibiotic treatment in some subsets of IBD patients and recent findings suggesting that so-called “healthy bacteria” or probiotic combinations can ameliorate IBD.
Harmless (or helpful) bacteria are normally tolerated by the immune system; that is, they do not prompt the immune system to respond to their presence. However, this tolerance may break down in IBD. Experiments suggest that individuals with IBD generate an inappropriate immune response against these normally harmless bacteria. It is also likely that patients with IBD have a different composition of bacteria in their digestive systems compared to healthy individuals. Some particular strains of bacteria have been found in IBD patients that cause a severe response by the immune system.
Researchers in CSIBD laboratories face particular challenges in investigating host-microbe interactions in IBD. Very little is known about the diversity and complexity of the bacteria that live in the digestive system, and few tools exist to answer these questions. The CSIBD is developing metagenomic and computational approaches to begin to understand how the digestive system interacts with these bacteria and how these interactions are altered in IBD.
|Figure 3: The interplay of the microbiome with physiology and pathogenesis.|
The intestinal epithelial barrier
One of the most basic defense mechanisms of the digestive lining is the physical restriction provided by intestinal epithelial cells. The main function of the epithelial barrier is to keep large molecules and bacteria from penetrating the stomach lining. Intestinal epithelial cells provide the critical components for a functional intestinal barrier. Specialized intestinal epithelial cells provide the mucus layer, trefoil factors and antimicrobial peptides to protect intestinal function. The physical barrier preventing luminal components from entering the body is regulated by the formation of tight junctions between intestinal epithelial cells. Intestinal epithelial cells are also able to directly modulate the immune responses in the intestine. This complex barrier system may break down in IBD. Some patients with Crohn’s disease show abnormal permeability of this barrier, and samples from patients show that the immune system may be decreasing the integrity of this barrier. Some of the genetic risk factors for IBD are also associated with epithelial barrier function.
When alterations occur in the epithelial mucosal barrier, the epithelium can be directly stimulated or penetrated by luminal microbiota (or their products), which can lead to disruption of the normally tolerant state of the intestinal immune system. Researchers in CSIBD laboratories are investigating the details of how this barrier normally functions, with special interest in how these normal functions go awry in IBD. Specifically, researchers are focused on how the barrier is structurally organized and how the integrity of this barrier is regulated by the immune system.
|Figure 4: The intestinal epithelial barrier.|
The immune system
IBD is driven by the immune system. Under normal conditions, the immune system monitors the digestive system for foreign objects that may cause disease, such as viruses and some bacteria. When the immune system encounters these potential threats, it mounts immune responses to destroy these molecules. The immune system also comes in contact with other objects that are considered harmless, including molecules in food, the bacteria that are normal residents of the digestive system, and the body’s own cells. The immune system learns not to respond to these molecules, establishing immunological tolerance. In IBD, this normal tolerance appears to break down. When IBD is triggered, the immune system may mistakenly recognize a harmless object as a threat and mount an attack. When the immune system attacks the digestive system, the lining of the digestive tract becomes inflamed, which causes bleeding and ulcers.
The immune system maintains a precarious balance, since it must distinguish between bacteria that are harmless/helpful and bacteria that may cause disease. Recently, researchers have found that mutations in some immune monitors – specifically, cellular receptors that recognize and respond to bacteria – are genetic risk factors associated with IBD. When these receptors signal inappropriately, a cascade of events is initiated that results in inflammation. The immune system is enormously complex and has many pathways to translate signals (such as bacteria) into responses (such as inflammation). CSIBD researchers are investigating these pathways as targets for therapeutic intervention.
Inflammation is normally a protective event to remove a threat that may cause infection. However, inflammation is also the process that causes tissue damage in IBD. Some of the major players in inflammation are molecules called cytokines. Cytokines help to amplify immune responses and are known to contribute to the development of IBD. Researchers in CSIBD laboratories are working to identify the particular cytokines that are responsible for the inflammation that occurs in IBD. They are also investigating the sequence of events that occurs between cytokine activation and inflammation, hoping to identify areas for intervention.
|Figure 5: Pathways in the immune system relevant to IBD.|